Section 5 Hypothyroidism

**129**

**Chapter 8**

**Abstract**

Hypothyroidism

increase of 10% of the dose monthly.

thyroid diseases

**1. Introduction**

be 0.2 and 5.3% [12].

ism [1–11].

*Mauricio Alvarez Andrade and Oscar Rosero Olarte*

Hypothyroidism is a condition that results from thyroid hormone deficiency that can range from an asymptomatic condition to a life-threatening disease. The prevalence of hypothyroidism varies according to the population, from up to 3 to 4% in some populations and in the case of subclinical hypothyroidism up to 5–10%. Clinical symptoms of hypothyroidism are diverse, broad, and non-specific and can be related to many systems, reflecting the systemic effects of thyroid hormones. The severity of the symptoms is usually related to the severity of the thyroid hormone deficit. The most common form of hypothyroidism, primary hypothyroidism, is diagnosed when there is elevation of TSH and decrease in the level of free T4 and Subclinical hypothyroidism is diagnosed when there is an elevation of TSH with normal levels of free T4. The most frequent cause of primary hypothyroidism in populations without iodine deficiency is Hashimoto's thyroiditis or chronic lymphocytic thyroiditis. Iodine deficiency is the main cause of hypothyroidism in populations with deficiency of iodine intake. The treatment of choice for hypothyroidism is thyroxine (T4), which has shown efficacy in multiple studies to restore the euthyroid state and improve the symptoms of hypothyroidism. In subclinical hypothyroidism, the treatment depends on the age, functionality, and comorbidities of the patients. The total replacement dose of levothyroxine in adults is approximately 1.6 mcg/kg; however in elderly patients with heart disease or coronary heart disease, the starting dose should be from 0.3 to 0.4 mcg/kg/day with progressive

**Keywords:** hypothyroidism, autoimmune, Hashimoto's disease, thyroxine,

Hypothyroidism is a common disease in many populations, and prevalence varies depending on the sex and the age of the population studied, the iodine status of the population, and the cut points used to define overt and subclinical hypothyroid-

Hypothyroidism is 10 times more prevalent in women than in men [2]. It is more prevalent in the elderly people, ranging from 2 to 5% of the population. In iodine-sufficient populations, hypothyroidism ranges from 1 to 2%, while in iodine deficient areas, the prevalence can be as high as 3–4% [2–14]. Prevalence in the USA in the Colorado trial can range from 0.3% and 3.7%, while in Europe can

The prevalence of subclinical hypothyroidism is even higher; in one of the larg-

est studies in the USA, it reaches 9% of the population [12].

### **Chapter 8** Hypothyroidism

*Mauricio Alvarez Andrade and Oscar Rosero Olarte*

### **Abstract**

Hypothyroidism is a condition that results from thyroid hormone deficiency that can range from an asymptomatic condition to a life-threatening disease. The prevalence of hypothyroidism varies according to the population, from up to 3 to 4% in some populations and in the case of subclinical hypothyroidism up to 5–10%. Clinical symptoms of hypothyroidism are diverse, broad, and non-specific and can be related to many systems, reflecting the systemic effects of thyroid hormones. The severity of the symptoms is usually related to the severity of the thyroid hormone deficit. The most common form of hypothyroidism, primary hypothyroidism, is diagnosed when there is elevation of TSH and decrease in the level of free T4 and Subclinical hypothyroidism is diagnosed when there is an elevation of TSH with normal levels of free T4. The most frequent cause of primary hypothyroidism in populations without iodine deficiency is Hashimoto's thyroiditis or chronic lymphocytic thyroiditis. Iodine deficiency is the main cause of hypothyroidism in populations with deficiency of iodine intake. The treatment of choice for hypothyroidism is thyroxine (T4), which has shown efficacy in multiple studies to restore the euthyroid state and improve the symptoms of hypothyroidism. In subclinical hypothyroidism, the treatment depends on the age, functionality, and comorbidities of the patients. The total replacement dose of levothyroxine in adults is approximately 1.6 mcg/kg; however in elderly patients with heart disease or coronary heart disease, the starting dose should be from 0.3 to 0.4 mcg/kg/day with progressive increase of 10% of the dose monthly.

**Keywords:** hypothyroidism, autoimmune, Hashimoto's disease, thyroxine, thyroid diseases

#### **1. Introduction**

Hypothyroidism is a common disease in many populations, and prevalence varies depending on the sex and the age of the population studied, the iodine status of the population, and the cut points used to define overt and subclinical hypothyroidism [1–11].

Hypothyroidism is 10 times more prevalent in women than in men [2]. It is more prevalent in the elderly people, ranging from 2 to 5% of the population. In iodine-sufficient populations, hypothyroidism ranges from 1 to 2%, while in iodine deficient areas, the prevalence can be as high as 3–4% [2–14]. Prevalence in the USA in the Colorado trial can range from 0.3% and 3.7%, while in Europe can be 0.2 and 5.3% [12].

The prevalence of subclinical hypothyroidism is even higher; in one of the largest studies in the USA, it reaches 9% of the population [12].

#### **2. Physiology**

Thyroid word comes from the Greek shield because of its shape. The weight is from 10 to 20 g. Changes of thyroid shape and volume are dependent on age and sex. In the adult population, the usual length is 40–60 mm and the diameter 13–18 mm. The volume is 10–15 ml for females and 12–18 ml for males [15, 16].

The thyroid gland is composed of functional secretory units known as follicles where thyroid hormones are synthetized and storage in the follicular cells and the lumen of the follicles where colloid is stored. The colloid contains high amounts of thyroglobulin (Tg), a 660 kDa glycoprotein, where thyroid hormones are stored [17].

Thyroid hormones are composed by an inner ring, the tyrosine molecule, and the outer ring with a phenyl ring. The active forms of thyroid hormones are thyroxine or T4, with four iodine atoms, and triiodothyronine or T3, with three iodine atoms. Under physiologic states, 90% of thyroid gland output is T4 and 10% is T3. The half-life of thyroid hormones is of few hours for T3 and 7 days for T4 [17].

The follicular cells contain a sodium iodide active symporter responsible for iodine transport against a concentration gradient to synthesize thyroid hormones; it can increase iodine concentration in the follicular cell by more than 20 times above the serum concentration. Iodine is then transported by pendrin in the apical membrane to the colloid in a passive manner [17].

Iodine must be organified to be attached to the tyrosine residues of thyroglobulin. The thyroid peroxidase (TPO) is the enzyme of the selenoprotein group, with hydrogen peroxide organifying iodine to thyroglobulin. Once in the colloid, iodine is organifid to thyroglobuline to produce, monoiodothyrosine and diiodothyrosine wich finally are coupled to produce T4 and T3, this process is catalyzed by the TPO [17].

TPO activity is regulated by iodine concentration and can be blocked by an excess of iodine concentration, which is known as the Wolff-Chaikoff effect and can lead to a temporary hypothyroidism with an escape mechanism. On the other side, an iodine-depleted thyroid gland that is exposed to iodine can increase thyroid synthesis, which is known as the Jod-Basedow effect, and lead to hyperthyroidism [17].

TPO is the enzyme related to autoimmune hypothyroidism as most of the patients have positive anti-TPO antibodies [16, 17].

#### **2.1 Regulation of thyroid hormones production**

Thyroid hormone production is regulated by the hypothalamus pituitary axis. At the hypothalamus, thyrotropin-releasing hormone (TRH) is produced. TRH stimulates the pituitary to produce thyroid-stimulating hormone (TSH) [17].

What trigger thyroid hormone synthesis and release is the stimulation of the TSH in the basolateral receptor of the follicular cell, which is a receptor of the seven transmembrane domain G protein-coupled receptors proteins. The effects of the TSH receptor in the follicular cells are derived to the increased concentration in intracellular cyclic adenosine monophosphate (cAMP) that results in increased iodine uptake and increased protein synthesis to enhance the production of thyroid hormones as well as produce a trophic effect at the thyroid gland [17].

#### **3. Definitions**

Hypothyroidism is a condition that results from thyroid hormone deficiency which can range from an asymptomatic condition to a life-threatening condition of the patient life [17–19].

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*Hypothyroidism*

hypothalamus.

**4.1 Adults**

**4.2 Myxedema**

**5. Etiology**

**5.1 Diagnosis**

**4.3 Congenital hypothyroidism**

*DOI: http://dx.doi.org/10.5772/intechopen.88859*

**4. Manifestations of hypothyroidism**

**3.1 Subclinical hypothyroidism**

Hypothyroidism can be primary due to a decrease in the production of thyroid

Subclinical hypothyroidism is a biochemical diagnosis in which there is an eleva-

Clinical symptoms of hypothyroidism are diverse, broad, and neither sensitive nor specific to make the diagnosis of hypothyroidism and can be related to many systems, reflecting the systemic effects of thyroid hormones. The severity of the symptoms is usually related to the severity of the thyroid hormone deficit.

Systemic symptoms include lethargy, cold intolerance, goiter, and weight gain. At the cardiovascular system hypothyroidism can produce bradycardia, cardiac failure, angina, and pericardial effusion. Gastrointestinal symptoms are constipation and ileus, neuromúscular manifestations include myalgia, hoarse voice, slow relaxing reflexes, depression, emotional lability, psychosis an carpal tunnel syndrome. Hematologic changes include macrocytic anemia, pernicious anemia, and iron deficiency anemia. Skin manifestations include, myxoedema, hair loss, and coarse skin. In the reproductive system menorrhagia and infertility and finally,

Myxedema coma is a severe state of hypothyroidism and an endocrine emergency. Manifestations are depressed mental state and hypothermia with a hypometabolic state with bradycardia. Decreased myocardial contractility and pericardial effusion lead to hypotension. Other features are anemia, hyponatremia, and renal dysfunction [22].

Thyroid hormones are necessary to have a normal neurodevelopment and growth. Symptoms and signs of congenital hypothyroidism are goiter, poor feeding, macroglossia, prolonged jaundice, developmental delay hypothermia, bradycardia,

The diagnosis of hypothyroidism is made biochemically. The elevation of TSH levels associated with low levels of free T4 confirms the diagnosis of primary hypothyroidism; in this case it is not necessary to measure levels of free T3 or T3 because in the state of hypothyroidism the peripheral conversion of T4 to T3 is increased so

hormones in the thyroid gland, secondary due to deficit in the production of TSH in the pituitary or tertiary due to a deficit in the production of TRH in the

tion of TSH with a normal level of free thyroid hormones in plasma.

hyperlipidaemia as the main metabolic manifestation [17–21].

edema, large fontanelles, umbilical hernia, and poor growth [23].

that T4 will be more diminished than T3 [18, 19, 24].

#### *Hypothyroidism DOI: http://dx.doi.org/10.5772/intechopen.88859*

Hypothyroidism can be primary due to a decrease in the production of thyroid hormones in the thyroid gland, secondary due to deficit in the production of TSH in the pituitary or tertiary due to a deficit in the production of TRH in the hypothalamus.

#### **3.1 Subclinical hypothyroidism**

Subclinical hypothyroidism is a biochemical diagnosis in which there is an elevation of TSH with a normal level of free thyroid hormones in plasma.

#### **4. Manifestations of hypothyroidism**

#### **4.1 Adults**

Clinical symptoms of hypothyroidism are diverse, broad, and neither sensitive nor specific to make the diagnosis of hypothyroidism and can be related to many systems, reflecting the systemic effects of thyroid hormones. The severity of the symptoms is usually related to the severity of the thyroid hormone deficit.

Systemic symptoms include lethargy, cold intolerance, goiter, and weight gain. At the cardiovascular system hypothyroidism can produce bradycardia, cardiac failure, angina, and pericardial effusion. Gastrointestinal symptoms are constipation and ileus, neuromúscular manifestations include myalgia, hoarse voice, slow relaxing reflexes, depression, emotional lability, psychosis an carpal tunnel syndrome. Hematologic changes include macrocytic anemia, pernicious anemia, and iron deficiency anemia. Skin manifestations include, myxoedema, hair loss, and coarse skin. In the reproductive system menorrhagia and infertility and finally, hyperlipidaemia as the main metabolic manifestation [17–21].

#### **4.2 Myxedema**

Myxedema coma is a severe state of hypothyroidism and an endocrine emergency. Manifestations are depressed mental state and hypothermia with a hypometabolic state with bradycardia. Decreased myocardial contractility and pericardial effusion lead to hypotension. Other features are anemia, hyponatremia, and renal dysfunction [22].

#### **4.3 Congenital hypothyroidism**

Thyroid hormones are necessary to have a normal neurodevelopment and growth. Symptoms and signs of congenital hypothyroidism are goiter, poor feeding, macroglossia, prolonged jaundice, developmental delay hypothermia, bradycardia, edema, large fontanelles, umbilical hernia, and poor growth [23].

#### **5. Etiology**

#### **5.1 Diagnosis**

The diagnosis of hypothyroidism is made biochemically. The elevation of TSH levels associated with low levels of free T4 confirms the diagnosis of primary hypothyroidism; in this case it is not necessary to measure levels of free T3 or T3 because in the state of hypothyroidism the peripheral conversion of T4 to T3 is increased so that T4 will be more diminished than T3 [18, 19, 24].

In secondary hypothyroidism, decreased T4 is found, and TSH is low or normal (not elevated), which means that the pituitary is not responding adequately to a deficit of thyroid hormones.

Subclinical hypothyroidism is diagnosed in patients with elevated TSH despite having normal levels of free T4. These patients may or may not be symptomatic [18, 19, 24].

Although the differential diagnosis in hypothyroidism involves multiple pathologies, with symptoms and signs related to hypothyroidism such as anemia and hyponatremia, among others, the differential diagnosis must also be among the various pathologies that produce hypothyroidism that will be discussed in the etiology section [25, 26].

However, it is important to take into account the sick euthyroid syndrome that refers to alterations in thyroid function tests that can be found in patients with critical illness and can vary depending on the severity and duration of the disease.

In laboratory alterations, there is a decrease in T3 and a smaller proportion of T4, due to an increase in the activity of reverse T3. Subsequently, there is a progressive decrease in TSH followed by a progressive elevation and finally normalization of all thyroid function tests once the injury is resolved [25, 26].

#### **6. Differential diagnosis**

#### **6.1 Primary hypothyroidism**

#### *6.1.1 Chronic autoimmune thyroiditis or Hashimoto's thyroiditis*

It is the most prevalent cause of hypothyroidism in iodine-sufficient countries. Chronic autoimmune thyroiditis can be goitrous or atrophic. Goitrous hypothyroidism is called Hashimoto thyroiditis [27].

More than 90% of patients have elevated anti-thyroglobulin or anti-peroxidase (microsomal antigen) or anti-sodium iodine transporter. Antibodies against thyroid gland produce chronic autoimmune thyroiditis with lymphocytic infiltration and fibrosis, leading to goiter or atrophy of the thyroid gland [27–29].

Women are five times more affected than men. After the age of 45, the rates of hypothyroidism increase [27].

Based on one of the most representative studies of the population of the USA that included 17,353 people, it found a prevalence of 4.6% of hypothyroidism, 0.3% frank hypothyroidism and 4.3% subclinical hypothyroidism [30].

The course of chronic autoimmune thyroiditis is a gradual loss of thyroid function. The spectrum ranges from subclinical hypothyroidism with positive antibodies to frank hypothyroidism, a process that affects approximately 5% patients per year.

The majority of patients present hypothyroidism for life; however it may be transient [28].

The risk factors for Hashimoto's thyroiditis are multiple; the female gender and the older age are two risk factors. There is a genetic factor associated with multiple polymorphisms in human leukocyte antigen (HLA) genes, T cell receptors, and immunomodulatory molecules. Patients with Down or Turner syndrome have a higher prevalence. Chronic autonomic thyroiditis can be part of the autoimmune type 2 polyglandular syndrome, and affected patients are more likely to develop other autoimmune diseases such as diabetes and adrenal insufficiency [27, 31, 32].

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*Hypothyroidism*

*6.1.2 Iodine deficiency*

*6.1.3 Iatrogenic disease*

*6.1.4 Drugs*

roidism [37].

**6.2 Thyroiditis**

in 5% of patients [38, 39].

category [38, 39].

roidism [40–42].

*DOI: http://dx.doi.org/10.5772/intechopen.88859*

this effect is usually transient [33, 34].

becomes a more prevalent etiology [35, 36].

*6.2.1 Subacute or granulomatous thyroiditis*

decrease in iodine uptake diffusely [38, 39].

*6.2.2 Silent thyroiditis or postpartum thyroiditis*

patients remain hypothyroid [40–42].

Iodine deficiency, defined as the daily intake of less than 100 mcg of iodine, is the most common cause of hypothyroidism worldwide and the most prevalent cause of hypothyroidism in populations with iodine deficiency. As previously described, excess iodine can produce hypothyroidism due to Wolff-Chaikoff effect; however

Post-thyroidectomy state, radioactive iodine therapy for thyroid cancer, or hyperthyroidism and neck radiation at doses greater than 25 Gy are the main causes of iatrogenic hypothyroidism, and as the use of these therapies increases, it

Thionamides, lithium, tetracyclines, thalidomide, ethionamide, and iodinecontaining drugs like amiodarone can cause hypothyroidism. Thyrosine kinase inhibitors can cause thyroiditis; sorafenib can produce hypothyroidism by increased type 3 deiodination. Immune therapy including pembrolizumab, nivolumab, ipilimumab, alemtuzumab, interleukin 2, and interferon alfa can produce hypothy-

Subacute or granulomatous thyroiditis is an acute inflammation of the thyroid gland of viral etiology that presents with hyperthyroidism, followed by hypothyroidism and subsequent recovery of thyroid function. Transient hypothyroidism usually lasts from a few weeks to a maximum of 3–6 months and may be permanent

The presentation consists of acute pain in the thyroid region that increases when swallowing or moving the head and radiates to the jaw. Symptoms may vary depending on whether the patient is in the hyperthyroid, euthyroid, or hypothyroid

The findings in thyroid gammagraphy are compatible with thyroiditis due to a

Silent thyroiditis or postpartum thyroiditis corresponds to a thyroiditis of autoimmune etiology, which occurs in the first year postpartum. It presents with hyperthyroidism in up to 30% of patients, followed by hypothyroidism in up to 50% of patients; however it can only be present as hypothyroidism or hyperthy-

It is more frequent in patients with type 1 diabetes mellitus and patients with positive anti-peroxidase antibodies. The prevalence can reach up to 17%. It has been associated with deterioration or onset of postpartum depression. Up to 30% of

#### *Hypothyroidism DOI: http://dx.doi.org/10.5772/intechopen.88859*

#### *6.1.2 Iodine deficiency*

Iodine deficiency, defined as the daily intake of less than 100 mcg of iodine, is the most common cause of hypothyroidism worldwide and the most prevalent cause of hypothyroidism in populations with iodine deficiency. As previously described, excess iodine can produce hypothyroidism due to Wolff-Chaikoff effect; however this effect is usually transient [33, 34].

#### *6.1.3 Iatrogenic disease*

Post-thyroidectomy state, radioactive iodine therapy for thyroid cancer, or hyperthyroidism and neck radiation at doses greater than 25 Gy are the main causes of iatrogenic hypothyroidism, and as the use of these therapies increases, it becomes a more prevalent etiology [35, 36].

#### *6.1.4 Drugs*

Thionamides, lithium, tetracyclines, thalidomide, ethionamide, and iodinecontaining drugs like amiodarone can cause hypothyroidism. Thyrosine kinase inhibitors can cause thyroiditis; sorafenib can produce hypothyroidism by increased type 3 deiodination. Immune therapy including pembrolizumab, nivolumab, ipilimumab, alemtuzumab, interleukin 2, and interferon alfa can produce hypothyroidism [37].

#### **6.2 Thyroiditis**

#### *6.2.1 Subacute or granulomatous thyroiditis*

Subacute or granulomatous thyroiditis is an acute inflammation of the thyroid gland of viral etiology that presents with hyperthyroidism, followed by hypothyroidism and subsequent recovery of thyroid function. Transient hypothyroidism usually lasts from a few weeks to a maximum of 3–6 months and may be permanent in 5% of patients [38, 39].

The presentation consists of acute pain in the thyroid region that increases when swallowing or moving the head and radiates to the jaw. Symptoms may vary depending on whether the patient is in the hyperthyroid, euthyroid, or hypothyroid category [38, 39].

The findings in thyroid gammagraphy are compatible with thyroiditis due to a decrease in iodine uptake diffusely [38, 39].

#### *6.2.2 Silent thyroiditis or postpartum thyroiditis*

Silent thyroiditis or postpartum thyroiditis corresponds to a thyroiditis of autoimmune etiology, which occurs in the first year postpartum. It presents with hyperthyroidism in up to 30% of patients, followed by hypothyroidism in up to 50% of patients; however it can only be present as hypothyroidism or hyperthyroidism [40–42].

It is more frequent in patients with type 1 diabetes mellitus and patients with positive anti-peroxidase antibodies. The prevalence can reach up to 17%. It has been associated with deterioration or onset of postpartum depression. Up to 30% of patients remain hypothyroid [40–42].

#### *6.2.3 Infiltrative diseases*

Riedel's thyroiditis is a fibrosclerosing thyroiditis of unknown etiology, with a probable primary anti-immune or fibrotic origin similar to retroperitoneal fibrosis, fibrosing mediastinitis, sclerosing cholangitis, and lacrimal fibrosis, among others [43, 44].

Riedel's thyroiditis is characterized by slow, non-painful growth, sensation of pressure in the neck, dysphagia, dysphonia, and hypoparathyroidism. From 30 to 60% of patients present clinical or subclinical hypothyroidism. It is one of the IgG4-related disease varieties, together with Fibrosing hashimoto thyroiditis, Igg4 related Hashimoto's disease, and Graves' disease associated with IgG4 [43–45].

Other infiltrative diseases like hemochromatosis, scleroderma, leukemia, cystinosis, *M. tuberculosis* infection, and *P. carinii* are less frequent causes of hypothyroidism.

#### **6.3 Secondary hypothyroidism**

Central hypothyroidism is a much less frequent form of hypothyroidism, with a prevalence of 1:16,000 to 1:100,000 in the general population. It can be congenital or acquired [46].

The causes of acquired central hypothyroidism are usually related to the causes of hypopituitarism like a pituitary sellar region mass, usually a pituitary adenoma, which produces secondary hypothyroidism by thyrotropic cell compression, or tertiary hypothyroidism with decreased production of TRH by the hypothalamus. Other lesions of the sellar region, such as meningiomas, cysts, abscesses, metastasis, craniopharyngiomas, and dysgerminomas, can produce central hypothyroidism [46, 47].

In addition to space-occupying injuries, radiation with doses greater than 40 Gray performed for brain, orbital, or nasal lesions can produce central hypothyroidism [46, 47].

Other less frequent causes of central hypothyroidism are hypophyseal infiltrative pathologies such as haemochromatosis, sarcoidosis or tuberculosis, cranial trauma, Sheehan syndrome, and the use of drugs as checkpoint inhibitors [46, 47].

#### **7. Treatment**

#### **7.1 Clinical hypothyroidism**

Since the nineteenth century, levothyroxine has been used for the treatment of hypothyroidism. Usually hypothyroidism requires treatment with lifelong hormone replacement with levothyroxine. In a few cases, transient hormonal substitution due to transient secondary hypothyroidism is required, for example, to subacute thyroiditis or drug-induced hypothyroidism [48–50].

The treatment of choice is thyroxine (T4), which has shown efficacy in multiple studies to restore the euthyroid state and improve the symptoms of hypothyroidism [51–54].

The goal of treatment of primary hypothyroidism is to take the patient to the normal range of TSH. However, the normal range of TSH varies depending on the age and population studied. Most people are in the range of 0.5–4.5 mU/L; however as the age of people increases, the normal range of TSH increases, leading to values of up to 7.0 mU/L in those over 90 years. In contrast, most young and healthy patients are in the range of 0.5–2.5 mU/L [50].

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*Hypothyroidism*

*DOI: http://dx.doi.org/10.5772/intechopen.88859*

For this reason, in the treatment of hypothyroidism, the dose of levothyroxine and the goal of TSH depend on the age of the patient and the comorbidities [49, 50]. Levothyroxine (T4) is a prohormone and requires deionization to T3 which is the active form of thyroid hormone. Levothyroxine is absorbed in the small intestine. The meal affects the time of maximum concentration, which in normal conditions is 2 h. The bioavailability is from 60 to 80%. The metabolism is catabolized by the thyroid deionidase enzyme that removes the iodine from carbon 5 of the outer ring to transform T4 into T3. Approximately half of T4 is deionized to rT3 (inactive form) and half to T3 (active form). Both T3 and reverse T3 are metabolized to diiodothyronine (T2) and monoiodothyronamine (T1) and T2 and T1 reverses [48]. Multiple medications interact with the function or pharmacokinetics of levothyroxine, amiodarone, androgens, calcium carbonate and citrate, carbamazepine, cholestyramine, ferrous sulfate, glucocorticoids, orlistat, phenytoin, proton pump inhibitors, salicylates, sucralfate, and tamoxifen, which are just some of the medications that alter bioavailability, metabolism, protein binding, or hormone levels [48]. The total replacement dose of levothyroxine in adults is approximately 1.6 mcg/

kg, given that the body's requirements for thyroid hormones are proportional to weight. In healthy young patients, the starting dose could be 1.6 mcg/kg/day; however in elderly patients with heart disease or coronary heart disease, the starting dose should be from 0.3 to 0.4 mcg/kg/day with a progressive increase of 10% in the dose every 4–6 weeks [50]. Levothyroxine must be taken with empty stomach

The thyroid function is monitored with TSH at 4–6 weeks after starting treatment. If the TSH goal is not achieved, the dose of levothyroxine should be adjusted by increasing or decreasing 10% of the dose ideally, especially in older adults [50]. In the case of secondary hypothyroidism, TSH levels are low or inappropriately normal for a low free T4. Therefore, the follow-up is not done with TSH levels but

In the case of subclinical hypothyroidism, the treatment also depends on the age,

For patients younger than 75 years, with TSH greater than 10 mU/L, treatment is recommended. However, in those patients with TSH between 4.5 and 10 mU/L, treatment depends on the presence of symptoms and especially the presence of goiter or anti-TPO antibodies, which predict progression to clinical hypothyroid-

In patients older than 75 years, treatment depends on the patient's frailty and should be limited to functional patients with TSH greater than 10 mU/L or patients with TSH of 6–10 mU/L in the presence of antithyroid antibodies, symptoms, and concomitant diseases in that they can be impaired by hypothyroidism such as heart failure. Fragile patients, more than 75 years old, may be advisable to be observed

Hypothyroidism is a highly prevalent chronic disease, widely studied by medi-

cal science, with a wide spectrum of severity, ranging from subclinical hypothyroidism to the hypothyroid myxedematous state. In some cases of subclinical hypothyroidism, treatment may not be necessary; however in other cases such as in myxedematous states, the treatment may be lifesaving. There are multiple trials

with free T4 levels, to achieve a normal level for the reference range.

30–60 min before the next meal, usually, breakfast.

functionality, and comorbidities of the patients [50].

**7.2 Subclinical hypothyroidism**

ism [54–56].

without treatment [50].

**8. Conclusion**

#### *Hypothyroidism DOI: http://dx.doi.org/10.5772/intechopen.88859*

For this reason, in the treatment of hypothyroidism, the dose of levothyroxine and the goal of TSH depend on the age of the patient and the comorbidities [49, 50].

Levothyroxine (T4) is a prohormone and requires deionization to T3 which is the active form of thyroid hormone. Levothyroxine is absorbed in the small intestine. The meal affects the time of maximum concentration, which in normal conditions is 2 h. The bioavailability is from 60 to 80%. The metabolism is catabolized by the thyroid deionidase enzyme that removes the iodine from carbon 5 of the outer ring to transform T4 into T3. Approximately half of T4 is deionized to rT3 (inactive form) and half to T3 (active form). Both T3 and reverse T3 are metabolized to diiodothyronine (T2) and monoiodothyronamine (T1) and T2 and T1 reverses [48].

Multiple medications interact with the function or pharmacokinetics of levothyroxine, amiodarone, androgens, calcium carbonate and citrate, carbamazepine, cholestyramine, ferrous sulfate, glucocorticoids, orlistat, phenytoin, proton pump inhibitors, salicylates, sucralfate, and tamoxifen, which are just some of the medications that alter bioavailability, metabolism, protein binding, or hormone levels [48].

The total replacement dose of levothyroxine in adults is approximately 1.6 mcg/ kg, given that the body's requirements for thyroid hormones are proportional to weight. In healthy young patients, the starting dose could be 1.6 mcg/kg/day; however in elderly patients with heart disease or coronary heart disease, the starting dose should be from 0.3 to 0.4 mcg/kg/day with a progressive increase of 10% in the dose every 4–6 weeks [50]. Levothyroxine must be taken with empty stomach 30–60 min before the next meal, usually, breakfast.

The thyroid function is monitored with TSH at 4–6 weeks after starting treatment. If the TSH goal is not achieved, the dose of levothyroxine should be adjusted by increasing or decreasing 10% of the dose ideally, especially in older adults [50].

In the case of secondary hypothyroidism, TSH levels are low or inappropriately normal for a low free T4. Therefore, the follow-up is not done with TSH levels but with free T4 levels, to achieve a normal level for the reference range.

#### **7.2 Subclinical hypothyroidism**

In the case of subclinical hypothyroidism, the treatment also depends on the age, functionality, and comorbidities of the patients [50].

For patients younger than 75 years, with TSH greater than 10 mU/L, treatment is recommended. However, in those patients with TSH between 4.5 and 10 mU/L, treatment depends on the presence of symptoms and especially the presence of goiter or anti-TPO antibodies, which predict progression to clinical hypothyroidism [54–56].

In patients older than 75 years, treatment depends on the patient's frailty and should be limited to functional patients with TSH greater than 10 mU/L or patients with TSH of 6–10 mU/L in the presence of antithyroid antibodies, symptoms, and concomitant diseases in that they can be impaired by hypothyroidism such as heart failure. Fragile patients, more than 75 years old, may be advisable to be observed without treatment [50].

#### **8. Conclusion**

Hypothyroidism is a highly prevalent chronic disease, widely studied by medical science, with a wide spectrum of severity, ranging from subclinical hypothyroidism to the hypothyroid myxedematous state. In some cases of subclinical hypothyroidism, treatment may not be necessary; however in other cases such as in myxedematous states, the treatment may be lifesaving. There are multiple trials that evaluate the treatment of hypothyroidism in different populations, and there is still controversy regarding the treatment of subclinical hypothyroidism in some populations. It is very important for the primary care physicians to have a broad knowledge of hypothyroidism since they will face hypothyroid patients in the day-to-day clinical practice.

### **Author details**

Mauricio Alvarez Andrade1 \* and Oscar Rosero Olarte2

1 Endocrinólogo, Organización Sanitas Internacional, Keralty, Bogotá, Colombia

2 Endocrinólogo, Instituto de Osteoporosis de los Llanos, Osteollanos, Regional Hospital, Villavicencio, Colombia

\*Address all correspondence to: mauricioalvarez613@gmail.com

© 2019 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, provided the original work is properly cited.

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*DOI: http://dx.doi.org/10.5772/intechopen.88859*

[1] Vanderpump MP. The epidemiology of thyroid disease. British Medical

[9] Sgarbi JA, Matsumura LK,

2010;**162**:569-577

Kasamatsu TS, Ferreira SR, Maciel RM. Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5-year follow-up: The Japanese-Brazilian thyroid study. European Journal of Endocrinology.

[10] Amouzegar A et al. Natural course of euthyroidism and clues for early diagnosis of thyroid dysfunction: Tehran Thyroid Study. Thyroid. 2017;**27**:616-625

[11] Amouzegar A et al. The prevalence, incidence and natural course of positive antithyroperoxidase antibodies in a population-based study: Tehran Thyroid Study. PLoS One. 2017;**12**:e0169283

[12] Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Archives of Internal Medicine. 2000;**160**:526-534

[13] Asvold BO, Vatten LJ, Bjoro T. Changes in the prevalence of hypothyroidism: The HUNT Study in Norway. European Journal of Endocrinology. 2013;**169**:613-620

[14] McGrogan A, Seaman HE,

Wright JW, de Vries CS. The incidence of autoimmune thyroid disease: A systematic review of the

[15] Mihai R. Physiology of the pituitary, thyroid, parathyroid and adrenal glands. Surgery (Oxford). 2014;**32**(10):504-512

literature. Clinical Endocrinology.

[16] Chaudhary V, Bano S. Thyroid ultrasound. Indian Journal of Endocrinology and Metabolism.

[17] Stathatos N. Thyroid physiology. The Medical Clinics of North America. 2012;**96**(2):165-173. DOI: 10.1016/j.

2013;**17**(2):219-227. DOI: 10.4103/2230-8210.109667

2008;**69**:687-696

[2] Bjoro T et al. Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The Health Study of Nord-Trondelag (HUNT). European Journal of Endocrinology.

[3] Konno N et al. Screening for thyroid diseases in an iodine sufficient area with sensitive thyrotrophin assays, and serum thyroid autoantibody and urinary iodide determinations. Clinical Endocrinology.

[4] Walsh JP. Managing thyroid disease in general practice. The Medical Journal

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in an older population. Internal Medicine Journal. 2010;**40**:642-649

[6] Laurberg P, Pedersen KM, Vestergaard H, Sigurdsson G. High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area versus high incidence of Graves' disease in the young in a high iodine intake area: Comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland. Journal of Internal Medicine. 1991;**229**:415-420

[7] Flynn RW, MacDonald TM, Morris AD, Jung RT, Leese GP. The thyroid epidemiology, audit, and research study: Thyroid dysfunction in the general population. The Journal of Clinical Endocrinology and Metabolism.

[8] Valdes S et al. Population-based national prevalence of thyroid dysfunction in Spain and associated factors: Diabetes study. Thyroid.

2004;**89**:3879-3884

2017;**27**:156-166

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[30] Hollowell SN, Flanders W, Hannon WH, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). The Journal of Clinical Endocrinology and Metabolism. 2002;**87**(2):489-499

[31] Tomer Y, Davies TF. Searching for the autoimmune thyroid disease susceptibility genes: From gene mapping to gene function. Endocrine Reviews. 2003;**24**(5):694-717

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[33] Andersson M, Takkouche B, Egli I, et al. Current global iodine status and progress over the last decade towards the elimination of iodine deficiency. Bulletin of the World Health Organization. 2005;**83**:518

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1984;**311**:426

1991;**34**:71

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2006;**16**:573

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Clinical presentation, treatment and outcomes. Endocrine. 2018;**60**(1):185-192

[44] Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel's thyroiditis and multifocal fibrosclerosis are part of the IgG4 related systemic disease spectrum. Arthritis Care & Research (Hoboken).

[45] Kottahachchi D, Toplissa DJ. Immunoglobulin G4-related thyroid diseases. European Thyroid Journal.

[46] Persani L. Clinical review: Central hypothyroidism: Pathogenic, diagnostic, and therapeutic challenges. The Journal of Clinical Endocrinology and Metabolism. 2012;**97**(9):3068-3078

[47] Persani L, Cangiano B, Bonomi M. The diagnosis and management of central hypothyroidism in 2018. Endocrine Connections.

[48] Colucci P, Yue CS, Ducharme M,

[49] Clarke N, Kabadi UM. Optimizing

Benvenga S. A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism.

European Endocrinology.

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evidence for the treatment of hypothyroidism with levothyroxine/ levotriiodothyronine combination therapy versus levothyroxine

2010;**62**(9):1312-1318

2016;**5**(4):231-239

2019;**8**(2):R44-R54

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[41] De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: An Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology and

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[42] Stagnaro-Green A. Approach to the patient with postpartum thyroiditis. The Journal of Clinical Endocrinology and

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Calissendorff J. Riedel's thyroiditis:

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[36] Franklyn JA, Daykin J, Drolc Z, et al. Long-term follow-up of treatment of thyrotoxicosis by three different methods. Clinical Endocrinology. 1991;**34**:71

[37] Rizzo LFL, Mana DL, Serra HA. Drug-induced hypothyroidism. Medicina (Buenos Aires). 2017;**77**(5):394-404

[38] Singer PA. Thyroiditis. Acute, subacute, and chronic. The Medical Clinics of North America. 1991;**75**(1):61-77

[39] Slatosky J, Shipton B, Wahba H. Thyroiditis: Differential diagnosis and management. American Family Physician. 2000;**61**(4):1047-1052; 1054

[40] Nicholson WK, Robinson KA, Smallridge RC, et al. Prevalence of postpartum thyroid dysfunction: A quantitative review. Thyroid. 2006;**16**:573

[41] De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: An Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism. 2012;**97**:2543

[42] Stagnaro-Green A. Approach to the patient with postpartum thyroiditis. The Journal of Clinical Endocrinology and Metabolism. 2012;**97**:334

[43] Falhammar H, Juhlin CC, Barner C, Catrina S-B, Karefylakis C, Calissendorff J. Riedel's thyroiditis:

Clinical presentation, treatment and outcomes. Endocrine. 2018;**60**(1):185-192

[44] Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel's thyroiditis and multifocal fibrosclerosis are part of the IgG4 related systemic disease spectrum. Arthritis Care & Research (Hoboken). 2010;**62**(9):1312-1318

[45] Kottahachchi D, Toplissa DJ. Immunoglobulin G4-related thyroid diseases. European Thyroid Journal. 2016;**5**(4):231-239

[46] Persani L. Clinical review: Central hypothyroidism: Pathogenic, diagnostic, and therapeutic challenges. The Journal of Clinical Endocrinology and Metabolism. 2012;**97**(9):3068-3078

[47] Persani L, Cangiano B, Bonomi M. The diagnosis and management of central hypothyroidism in 2018. Endocrine Connections. 2019;**8**(2):R44-R54

[48] Colucci P, Yue CS, Ducharme M, Benvenga S. A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism. European Endocrinology. 2013;**9**(1):40-47

[49] Clarke N, Kabadi UM. Optimizing treatment of hypothyroidism. Treatments in Endocrinology. 2004;**3**(4):217-221

[50] Calsolaro V, Niccolai F, Pasqualetti G, Tognini S, Magno S, Riccioni T, et al. Hypothyroidism in the elderly: Who should be treated and how? Journal of the Endocrine Society. 2019;**3**(1):146-158

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**141**

Section 6

Uremia and Lipid

Disorders

Section 6

## Uremia and Lipid Disorders

**143**

**Chapter 9**

**Abstract**

**1. Introduction**

Lipid Disorders in Uremia

*Valdete Topçiu-Shufta and Valdete Haxhibeqiri*

linked with their metabolic alteration associated with uremia.

**Keywords:** chronic uremia, lipoproteins, dyslipidemia, cardiovascular risk

Urea cycle is one of the most important pathways in the human body. The continuous degradation and synthesis of cellular proteins occur in all forms of life. High rates of protein degradation occur in tissue undergoing structural rearrangements. Approximately 75% of liberated amino acids are reutilized. Since the excess amino acids are not stored, those not immediately incorporated into new proteins are degraded rapidly. The excess nitrogen from amino acids forms urea. As a hydrosoluble compound, urea is excreted by the kidney. Uremia is a clinical syndrome marked by elevated concentrations of urea in the blood and is associated with many metabolic disorders such as acidosis, abnormalities in lipids, mineral and homocysteine metabolism, oxidative stress, chronic inflammation, insulin and erythropoietin resistance, vitamin D deficiency, and malnutrition. Uremia more commonly develops with chronic kidney disease (CKD), but it also may occur with acute kidney injury if loss of renal function is rapid. Nearly all body organs and systems are affected by the toxicity of uremic compounds retained in the course of renal dysfunction. According to the European Uremic Toxin Work Group, uremic toxins are defined as accumulated solutes, normally excreted by the kidneys, that interact negatively with biological functions [1]. This has shown the need for the search for new uremic compounds, combining them into panels of substances involved in the pathophysiological processes. As example we can mention uridine adenosine, a strong vasoconstrictor, which is considered as a new uremic toxin. It has been demonstrated that uremic patients have increased levels of uridine adenosine, which can influence blood pressure, proliferation rate of vascular smooth

Lipoprotein has important physiologic functions within the human body. Many enzymes, enzyme activators, and protein parts, such as apolipoproteins and specific hepatic and extrahepatic receptors, are involved in their metabolism. Renal failure is associated with an increased risk of cardiovascular disease. One of the main mechanisms underlying this increased cardiovascular risk is dyslipidemia. Abnormal lipoprotein profiles are generally a combination of abnormalities of all fractions. Uremic lipoprotein profile includes increased triglyceride-rich lipoproteins, small dense LDL particles, increased lipoprotein (a), and decreased HDL. Enhanced oxidative stress and uremic environment can strongly modify plasma lipoproteins, changing their interactions with biological functions and especially cardiovascular physiology. This profound lipoprotein disorder has led to the formulation of an accelerated atherogenesis hypothesis and has been commonly

### **Chapter 9** Lipid Disorders in Uremia

*Valdete Topçiu-Shufta and Valdete Haxhibeqiri*

#### **Abstract**

Lipoprotein has important physiologic functions within the human body. Many enzymes, enzyme activators, and protein parts, such as apolipoproteins and specific hepatic and extrahepatic receptors, are involved in their metabolism. Renal failure is associated with an increased risk of cardiovascular disease. One of the main mechanisms underlying this increased cardiovascular risk is dyslipidemia. Abnormal lipoprotein profiles are generally a combination of abnormalities of all fractions. Uremic lipoprotein profile includes increased triglyceride-rich lipoproteins, small dense LDL particles, increased lipoprotein (a), and decreased HDL. Enhanced oxidative stress and uremic environment can strongly modify plasma lipoproteins, changing their interactions with biological functions and especially cardiovascular physiology. This profound lipoprotein disorder has led to the formulation of an accelerated atherogenesis hypothesis and has been commonly linked with their metabolic alteration associated with uremia.

**Keywords:** chronic uremia, lipoproteins, dyslipidemia, cardiovascular risk

#### **1. Introduction**

Urea cycle is one of the most important pathways in the human body. The continuous degradation and synthesis of cellular proteins occur in all forms of life. High rates of protein degradation occur in tissue undergoing structural rearrangements.

Approximately 75% of liberated amino acids are reutilized. Since the excess amino acids are not stored, those not immediately incorporated into new proteins are degraded rapidly. The excess nitrogen from amino acids forms urea. As a hydrosoluble compound, urea is excreted by the kidney. Uremia is a clinical syndrome marked by elevated concentrations of urea in the blood and is associated with many metabolic disorders such as acidosis, abnormalities in lipids, mineral and homocysteine metabolism, oxidative stress, chronic inflammation, insulin and erythropoietin resistance, vitamin D deficiency, and malnutrition. Uremia more commonly develops with chronic kidney disease (CKD), but it also may occur with acute kidney injury if loss of renal function is rapid. Nearly all body organs and systems are affected by the toxicity of uremic compounds retained in the course of renal dysfunction. According to the European Uremic Toxin Work Group, uremic toxins are defined as accumulated solutes, normally excreted by the kidneys, that interact negatively with biological functions [1]. This has shown the need for the search for new uremic compounds, combining them into panels of substances involved in the pathophysiological processes. As example we can mention uridine adenosine, a strong vasoconstrictor, which is considered as a new uremic toxin. It has been demonstrated that uremic patients have increased levels of uridine adenosine, which can influence blood pressure, proliferation rate of vascular smooth

muscle cells, and vascular calcification [2]. All these effects correlated with vascular dysfunctions and development of atherosclerosis. As uremic toxins are considered some components, which concentrations are not directly associated with glomerular filtration, but interacts negatively with vascular physiology. Several acute-phase proteins, IL-1, IL-6, IL-12, α2-macroglobulin, fibrinogen, and myeloperoxidase, together with endothelium-related proteins, such as vascular cell adhesion molecule 1, vascular endothelial growth factor 1, and soluble vascular endothelial growth factor receptor, increased in CKD and play a crucial role in endothelium dysfunction promoting the development of atherosclerosis. Renal failure is associated with an increased risk of cardiovascular disease [3, 4]. One of the main mechanisms underlying this increased cardiovascular risk is dyslipidemia [2]. In uremic environment lipids are affected by oxidative stress. The end products of lipid peroxidation process affect the circulating lipoproteins, lipidic and proteinic, leading to profound alterations of their biological properties, changing their interactions with biological functions and especially cardiovascular physiology. For this reason, lipoproteins, in renal failure, can be also considered as uremic toxins.

In the human body, dietary lipids absorbed from intestine and lipids synthesized by the liver and adipose tissue must be transported between the various tissues and organs for utilization and storage. Since lipids are insoluble in water, the problem on how to transport them in aqueous blood plasma is solved by associating nonpolar lipids (triacylglycerol and cholesterol esters) with amphipathic lipids (phospholipids and cholesterol) and proteins, to form water-soluble particle known as lipoproteins.

The plasma lipoproteins are classified as chylomicrons and very-low-density (VLDL), intermediate-density (IDL), low-density (LDL), and high-density (HDL) lipoproteins, according to their ultracentrifugation characteristics. Chylomicrons and VLDL serve as vehicles to transport triglycerides to the sites of consumption, as myocytes and suprarenal glands or storage in adipocytes. HDL fraction serves as a vehicle to transport surplus cholesterol from peripheral tissues to the liver for disposal. Many enzymes, enzyme activators, and protein parts, such as apolipoproteins and specific hepatic and extrahepatic receptors, are involved in lipoprotein metabolism.

Apolipoproteins (Apo), the protein part of lipoproteins, are present in each lipoprotein and carry out several roles. They can be part of the structure of lipoproteins, serve as an enzyme cofactors or inhibitors, and finally act as ligands for interaction with lipoprotein receptor in tissue. Apolipoproteins of HDL are designated as A (A-I, A-II, A-IV). Apo A-I is an activator of enzyme lecithin-cholesterol acyltransferase (LCAT) and serves as a ligand for HDL binding to specific scavenger receptor B1 (SR-B1). Apo A-II is an inhibitor of enzyme lipoprotein lipase. The main apolipoprotein of LDL and VLDL is Apo B-100, while the chylomicrons contain Apo B-48. Apo B-100 acts as ligand of LDL for LDL receptors in the liver and extrahepatic tissue. Apo B-48 is part of the structure of chylomicrons. Apo E is found in chylomicrons, VLDL, and HDL, and its role is to uptake the remnant of chylomicrons by a receptor specific for apolipoprotein E, in the liver. Apo C-I, Apo C-II, and Apo C-III are transferable between several different lipoproteins. Apo C-II is activator, whereas Apo C-III is an inhibitor for enzyme lipoprotein lipase. The Apo C-I is an inhibitor for enzyme cholesteryl ester transfer protein (CETP).

The main enzymes involved in lipoprotein metabolism are lipoprotein lipase (EC 3.1.1.34), hepatic lipase (EC 3.1.1.3), lecithin-cholesterol acyltransferase (EC 2.3.1.43), and acyl-CoA cholesterol acyltransferase (ACAT) (EC 2.3.1.26).

Lipoprotein lipase is located on the walls of blood capillaries of the heart, adipose tissue, spleen, lung, renal medulla, aorta, lactating mammary gland, and diaphragm. It is abundantly produced as an inactive enzyme by myocytes, adipocytes,

**145**

*Lipid Disorders in Uremia*

cron remnants and HDL.

liver and small intestine.

**2. Lipoprotein metabolism**

**2.1 The metabolism of chylomicrons**

their uptake by the liver and other tissues (**Figure 1**).

**2.2 The metabolism of VLDL, IDL and LDL**

*DOI: http://dx.doi.org/10.5772/intechopen.90043*

A-II and Apo C-III act as inhibitors.

HDL maturation and plasma HDL cholesterol level.

and several other cell types. The inactive enzyme requires sequential glycation and cleavage of a 27-amino acid peptide to become functionally active. The role of lipoprotein lipase is the hydrolysis of triglyceride-rich lipoproteins, as chylomicrons and VLDL. Apo C-II and phospholipids are cofactors for enzyme activity, while Apo

Hepatic lipase is bound to the surface of hepatic cells. Hepatic lipase catalyzes hydrolysis and removal of the triglyceride content of HDL and chylomicron remnant. Accordingly, hepatic lipase plays a central role in the metabolism of chylomi-

LCAT is the enzyme of HDL, which is activated by Apo A-I, the structural protein of HDL. The enzyme plays an important role in HDL-mediated cholesterol uptake from the extrahepatic tissues and, as such, serves as a main determinant of

The formation of cholesteryl esters from cholesterol and long-chain fatty-acylcoenzyme A catalyzes the enzyme called ACAT. It is a membrane-bound protein and, at the single-cell level, serves as a regulator of intracellular cholesterol homeostasis. In addition, ACAT supplies cholesteryl esters for lipoprotein assembly in the

Cholesteryl ester transfer protein is a hydrophobic glycoprotein that is secreted mainly from the liver and circulates in the plasma, bounded mainly to HDL [5]. It mediates cholesterol ester transfer from HDL to IDL in exchange for triglycerides. CETP promotes the transfer of cholesteryl esters from anti-atherogenic HDLs to proatherogenic Apo B-containing lipoproteins, including VLDL, VLDL remnants, IDL, and LDL. In this way CETP transfers lipids from one lipoprotein particle to another in a process that results in equilibration of lipids between lipoprotein fractions.

The exogenous pathway of lipid metabolism begins with chylomicrons. Chylomicrons are responsible for the transport of all dietary lipids into the circulation. They are produced within the enterocytes containing triglycerides, cholesterol ester, and phospholipids. Apo B-48 is essential for chylomicron formation. The nascent chylomicrons, from the small intestine, are released into the circulation via the lymphatic system. In the circulation, the nascent chylomicrons acquire Apo E and Apo C-II, which are in the surface of HDL. Apo C-II is an activator for enzyme lipoprotein lipase. The endothelium binding accommodates interaction of chylomicrons with the endothelium-bound lipoprotein lipase. Reaction with lipoprotein lipase results in the loss of approximately 90% of triglycerides in chylomicrons. The majority of fatty acids released diffuse into the adjacent myocytes for energy production or into adipocytes for energy storage. After hydrolysis chylomicron remnants are subsequently cleared by the liver and other tissues. Uptake is mediated by a receptor specific for Apo E. Both the LDL (Apo B-100 and Apo E) receptor and LDL receptor-related protein (LRP), specific for Apo E, are believed to take part. Chylomicron remnants return the borrowed Apo C- II and Apo E to HDL before

VLDL particles are produced by the liver and are precursor of IDL and LDL. VLDL serves as the vehicle for delivery of endogenous lipids, endogenous

#### *Lipid Disorders in Uremia DOI: http://dx.doi.org/10.5772/intechopen.90043*

*Cellular Metabolism and Related Disorders*

renal failure, can be also considered as uremic toxins.

muscle cells, and vascular calcification [2]. All these effects correlated with vascular dysfunctions and development of atherosclerosis. As uremic toxins are considered some components, which concentrations are not directly associated with glomerular filtration, but interacts negatively with vascular physiology. Several acute-phase proteins, IL-1, IL-6, IL-12, α2-macroglobulin, fibrinogen, and myeloperoxidase, together with endothelium-related proteins, such as vascular cell adhesion molecule 1, vascular endothelial growth factor 1, and soluble vascular endothelial growth factor receptor, increased in CKD and play a crucial role in endothelium dysfunction promoting the development of atherosclerosis. Renal failure is associated with an increased risk of cardiovascular disease [3, 4]. One of the main mechanisms underlying this increased cardiovascular risk is dyslipidemia [2]. In uremic environment lipids are affected by oxidative stress. The end products of lipid peroxidation process affect the circulating lipoproteins, lipidic and proteinic, leading to profound alterations of their biological properties, changing their interactions with biological functions and especially cardiovascular physiology. For this reason, lipoproteins, in

In the human body, dietary lipids absorbed from intestine and lipids synthesized by the liver and adipose tissue must be transported between the various tissues and organs for utilization and storage. Since lipids are insoluble in water, the problem on how to transport them in aqueous blood plasma is solved by associating nonpolar lipids (triacylglycerol and cholesterol esters) with amphipathic lipids (phospholipids and cholesterol) and proteins, to form water-soluble particle known as

The plasma lipoproteins are classified as chylomicrons and very-low-density (VLDL), intermediate-density (IDL), low-density (LDL), and high-density (HDL) lipoproteins, according to their ultracentrifugation characteristics. Chylomicrons and VLDL serve as vehicles to transport triglycerides to the sites of consumption, as myocytes and suprarenal glands or storage in adipocytes. HDL fraction serves as a vehicle to transport surplus cholesterol from peripheral tissues to the liver for disposal. Many enzymes, enzyme activators, and protein parts, such as apolipoproteins and specific hepatic and extrahepatic receptors, are involved in lipoprotein

Apolipoproteins (Apo), the protein part of lipoproteins, are present in each lipoprotein and carry out several roles. They can be part of the structure of lipoproteins, serve as an enzyme cofactors or inhibitors, and finally act as ligands for interaction with lipoprotein receptor in tissue. Apolipoproteins of HDL are designated as A (A-I, A-II, A-IV). Apo A-I is an activator of enzyme lecithin-cholesterol acyltransferase (LCAT) and serves as a ligand for HDL binding to specific scavenger receptor B1 (SR-B1). Apo A-II is an inhibitor of enzyme lipoprotein lipase. The main apolipoprotein of LDL and VLDL is Apo B-100, while the chylomicrons contain Apo B-48. Apo B-100 acts as ligand of LDL for LDL receptors in the liver and extrahepatic tissue. Apo B-48 is part of the structure of chylomicrons. Apo E is found in chylomicrons, VLDL, and HDL, and its role is to uptake the remnant of chylomicrons by a receptor specific for apolipoprotein E, in the liver. Apo C-I, Apo C-II, and Apo C-III are transferable between several different lipoproteins. Apo C-II is activator, whereas Apo C-III is an inhibitor for enzyme lipoprotein lipase. The Apo C-I is an inhibitor for enzyme cholesteryl ester transfer protein (CETP). The main enzymes involved in lipoprotein metabolism are lipoprotein lipase (EC 3.1.1.34), hepatic lipase (EC 3.1.1.3), lecithin-cholesterol acyltransferase (EC

2.3.1.43), and acyl-CoA cholesterol acyltransferase (ACAT) (EC 2.3.1.26).

Lipoprotein lipase is located on the walls of blood capillaries of the heart, adipose tissue, spleen, lung, renal medulla, aorta, lactating mammary gland, and diaphragm. It is abundantly produced as an inactive enzyme by myocytes, adipocytes,

**144**

lipoproteins.

metabolism.

and several other cell types. The inactive enzyme requires sequential glycation and cleavage of a 27-amino acid peptide to become functionally active. The role of lipoprotein lipase is the hydrolysis of triglyceride-rich lipoproteins, as chylomicrons and VLDL. Apo C-II and phospholipids are cofactors for enzyme activity, while Apo A-II and Apo C-III act as inhibitors.

Hepatic lipase is bound to the surface of hepatic cells. Hepatic lipase catalyzes hydrolysis and removal of the triglyceride content of HDL and chylomicron remnant. Accordingly, hepatic lipase plays a central role in the metabolism of chylomicron remnants and HDL.

LCAT is the enzyme of HDL, which is activated by Apo A-I, the structural protein of HDL. The enzyme plays an important role in HDL-mediated cholesterol uptake from the extrahepatic tissues and, as such, serves as a main determinant of HDL maturation and plasma HDL cholesterol level.

The formation of cholesteryl esters from cholesterol and long-chain fatty-acylcoenzyme A catalyzes the enzyme called ACAT. It is a membrane-bound protein and, at the single-cell level, serves as a regulator of intracellular cholesterol homeostasis. In addition, ACAT supplies cholesteryl esters for lipoprotein assembly in the liver and small intestine.

Cholesteryl ester transfer protein is a hydrophobic glycoprotein that is secreted mainly from the liver and circulates in the plasma, bounded mainly to HDL [5]. It mediates cholesterol ester transfer from HDL to IDL in exchange for triglycerides. CETP promotes the transfer of cholesteryl esters from anti-atherogenic HDLs to proatherogenic Apo B-containing lipoproteins, including VLDL, VLDL remnants, IDL, and LDL. In this way CETP transfers lipids from one lipoprotein particle to another in a process that results in equilibration of lipids between lipoprotein fractions.

#### **2. Lipoprotein metabolism**

#### **2.1 The metabolism of chylomicrons**

The exogenous pathway of lipid metabolism begins with chylomicrons. Chylomicrons are responsible for the transport of all dietary lipids into the circulation. They are produced within the enterocytes containing triglycerides, cholesterol ester, and phospholipids. Apo B-48 is essential for chylomicron formation. The nascent chylomicrons, from the small intestine, are released into the circulation via the lymphatic system. In the circulation, the nascent chylomicrons acquire Apo E and Apo C-II, which are in the surface of HDL. Apo C-II is an activator for enzyme lipoprotein lipase. The endothelium binding accommodates interaction of chylomicrons with the endothelium-bound lipoprotein lipase. Reaction with lipoprotein lipase results in the loss of approximately 90% of triglycerides in chylomicrons. The majority of fatty acids released diffuse into the adjacent myocytes for energy production or into adipocytes for energy storage. After hydrolysis chylomicron remnants are subsequently cleared by the liver and other tissues. Uptake is mediated by a receptor specific for Apo E. Both the LDL (Apo B-100 and Apo E) receptor and LDL receptor-related protein (LRP), specific for Apo E, are believed to take part. Chylomicron remnants return the borrowed Apo C- II and Apo E to HDL before their uptake by the liver and other tissues (**Figure 1**).

#### **2.2 The metabolism of VLDL, IDL and LDL**

VLDL particles are produced by the liver and are precursor of IDL and LDL. VLDL serves as the vehicle for delivery of endogenous lipids, endogenous

#### **Figure 1.**

*Chylomicron metabolism. Chylomicrons, from the small intestine, are released into the circulation by apolipoprotein B-48 (B48). Nascent chylomicrons acquire apolipoprotein (Apo) E (green square) and C-II (purple circle), which are in the surface of HDL. Apo A-I (white triangle marked with a) is a main apolipoprotein of HDL. Apo E and Apo C-II are necessary for activation of lipoprotein lipase and for uptakes of remnant chylomicrons by an LDL receptor and LDL receptor-related protein. TG-triglycerides, C-cholesterol, P-phospholipids.*

triglycerol, and cholesterol, to the peripheral tissues. Nascent VLDL is formed within the hepatocyte and Apo B-100. Those are triglyceride-rich lipid droplet, followed by the addition of Apo E, Apo A-I, and Apo A-II. The triglycerides and cholesterol ester used by hepatocytes for incorporation into VLDL are generated by the enzymes acyl-CoA diacylglycerol acyltransferase (DGAT; EC 2.3.1.20) and ACAT. Apo C-II and Apo E, borrowed from HDL, are important for subsequent metabolism of VLDL by lipoprotein lipase and the VLDL receptor. Enzyme lipoprotein lipase is activated by the apolipoprotein C-II, and this is followed from the hydrolysis of VLDL triglycerides by the activated enzyme, leading to release fatty acids, which diffuse into the adjacent myocytes or adipocytes for energy production or storage. Lipolysis of VLDL results in reduction in their triglyceride content and detachment and release of a remnant particle, known as IDL. IDL particles may undergo further lipolysis via hepatic triglyceride lipase. Apo E serves as a ligand for remnant VLDL or IDL binding to specific receptors in the liver. This leads to the extraction of nearly all remaining triglycerides from IDL by the liver and formation of cholesterol-rich LDL. LDL particles are then removed via LDL (Apo B-100) receptor by the liver, as well as extrahepatic tissue (**Figure 2**).

#### **2.3 The metabolism of HDL**

HDL is synthesized and secreted from the liver and intestine. A major function of HDL is to act as a repository for the Apo C-II and Apo E, for metabolism of triglyceride-rich lipoproteins, chylomicrons, and VLDL. Also, the primary function of HDL is retrieval and transport of cholesterol from the tissue to the liver which is known as reverse cholesterol transport. This cycle is very important for cellular cholesterol homeostasis. The principal apolipoprotein constituents of HDL are Apo A-I and Apo A-II. As the main structural constituent of HDL, Apo A-I is the activator of enzyme LCAT. LCAT system is involved in HDL-mediated removal of excess unesterified cholesterol from triglyceride-rich lipoproteins and tissues. Apo A-II serves as an activator of hepatic lipase, which plays a central role in the removal of HDL triglycerides by the liver. HDL-mediated removal of surplus

**147**

**Figure 3.**

*transporter type I.*

cholesterol from extrahepatic tissues requires attachment of nascent HDL to the ATP-binding cassette transporter type I (ABCA1). Binding to ABCA1 appears to trigger active transfer of phospholipids to nascent HDL, a step which is necessary for efficient translocation of free cholesterol from adjacent caveolae to the surface of HDL. Free cholesterol reaching the surface of HDL moves to the core of HDL. In this process nascent discoidal HDL is transformed into spherical HDL 3. After being accepted by HDL3, the free cholesterol is then esterified by LCAT to

*High-density lipoprotein metabolism. As the main structural constituent of HDL, apolipoprotein A-I (Apo A-I), is the activator of enzyme lecithin-cholesterol acyltransferase. LCAT system is involved in HDL-mediated removal of excess unesterified cholesterol from tissues and its esterification. Scavenger receptor B1,and ATP-binding cassette* 

*Very-low-density lipoprotein metabolism. In circulation VLDL are transformed into intermediate-density lipoprotein after lipoprotein lipase activation by apolipoprotein C-II. IDL are removed by hepatic LDL receptors specific for apolipoprotein B and E. Apo E and Apo C-II are borrowed from high-density lipoprotein. A, Apolipoprotein a; B-100, Apolipoprotein B-100; C, Apolipoprotein C; E, Apolipoprotein E; LDL, low-*

*density lipoproteins; TG, triglycerides; C, cholesterol; P, phospholipids.*

*Lipid Disorders in Uremia*

**Figure 2.**

*DOI: http://dx.doi.org/10.5772/intechopen.90043*

#### **Figure 2.**

*Cellular Metabolism and Related Disorders*

triglycerol, and cholesterol, to the peripheral tissues. Nascent VLDL is formed within the hepatocyte and Apo B-100. Those are triglyceride-rich lipid droplet, followed by the addition of Apo E, Apo A-I, and Apo A-II. The triglycerides and cholesterol ester used by hepatocytes for incorporation into VLDL are generated by the enzymes acyl-CoA diacylglycerol acyltransferase (DGAT; EC 2.3.1.20) and ACAT. Apo C-II and Apo E, borrowed from HDL, are important for subsequent metabolism of VLDL by lipoprotein lipase and the VLDL receptor. Enzyme lipoprotein lipase is activated by the apolipoprotein C-II, and this is followed from the hydrolysis of VLDL triglycerides by the activated enzyme, leading to release fatty acids, which diffuse into the adjacent myocytes or adipocytes for energy production or storage. Lipolysis of VLDL results in reduction in their triglyceride content and detachment and release of a remnant particle, known as IDL. IDL particles may undergo further lipolysis via hepatic triglyceride lipase. Apo E serves as a ligand for remnant VLDL or IDL binding to specific receptors in the liver. This leads to the extraction of nearly all remaining triglycerides from IDL by the liver and formation of cholesterol-rich LDL. LDL particles are then removed via LDL (Apo B-100)

*Chylomicron metabolism. Chylomicrons, from the small intestine, are released into the circulation by apolipoprotein B-48 (B48). Nascent chylomicrons acquire apolipoprotein (Apo) E (green square) and C-II (purple circle), which are in the surface of HDL. Apo A-I (white triangle marked with a) is a main apolipoprotein of HDL. Apo E and Apo C-II are necessary for activation of lipoprotein lipase and for uptakes of remnant chylomicrons by an LDL receptor and LDL receptor-related protein. TG-triglycerides,* 

receptor by the liver, as well as extrahepatic tissue (**Figure 2**).

HDL is synthesized and secreted from the liver and intestine. A major function of HDL is to act as a repository for the Apo C-II and Apo E, for metabolism of triglyceride-rich lipoproteins, chylomicrons, and VLDL. Also, the primary function of HDL is retrieval and transport of cholesterol from the tissue to the liver which is known as reverse cholesterol transport. This cycle is very important for cellular cholesterol homeostasis. The principal apolipoprotein constituents of HDL are Apo A-I and Apo A-II. As the main structural constituent of HDL, Apo A-I is the activator of enzyme LCAT. LCAT system is involved in HDL-mediated removal of excess unesterified cholesterol from triglyceride-rich lipoproteins and tissues. Apo A-II serves as an activator of hepatic lipase, which plays a central role in the removal of HDL triglycerides by the liver. HDL-mediated removal of surplus

**2.3 The metabolism of HDL**

**146**

**Figure 1.**

*C-cholesterol, P-phospholipids.*

*Very-low-density lipoprotein metabolism. In circulation VLDL are transformed into intermediate-density lipoprotein after lipoprotein lipase activation by apolipoprotein C-II. IDL are removed by hepatic LDL receptors specific for apolipoprotein B and E. Apo E and Apo C-II are borrowed from high-density lipoprotein. A, Apolipoprotein a; B-100, Apolipoprotein B-100; C, Apolipoprotein C; E, Apolipoprotein E; LDL, lowdensity lipoproteins; TG, triglycerides; C, cholesterol; P, phospholipids.*

#### **Figure 3.**

*High-density lipoprotein metabolism. As the main structural constituent of HDL, apolipoprotein A-I (Apo A-I), is the activator of enzyme lecithin-cholesterol acyltransferase. LCAT system is involved in HDL-mediated removal of excess unesterified cholesterol from tissues and its esterification. Scavenger receptor B1,and ATP-binding cassette transporter type I.*

cholesterol from extrahepatic tissues requires attachment of nascent HDL to the ATP-binding cassette transporter type I (ABCA1). Binding to ABCA1 appears to trigger active transfer of phospholipids to nascent HDL, a step which is necessary for efficient translocation of free cholesterol from adjacent caveolae to the surface of HDL. Free cholesterol reaching the surface of HDL moves to the core of HDL. In this process nascent discoidal HDL is transformed into spherical HDL 3. After being accepted by HDL3, the free cholesterol is then esterified by LCAT to

cholesterol esters, increasing the size of the particles to form the less dense HDL2. In the next step, HDL2, released in circulation, participates in a series of elaborate exchanges of apoproteins and lipids with the Apo B-containing lipoproteins such as chylomicrons, VLDL, and IDL, before reaching the liver. Actually, HDL in circulation receives triglycerides from Apo B-containing lipoproteins in exchange for cholesterol esters, a process catalyzed by CETP. Finally, HDL-2, via Apo A-I, binds to the scavenger receptor B1, which has been identified as a HDL receptor in the liver. The cycle is completed by the reformation of HDL 3, either after selective delivery of cholesteryl esters to the liver via SR-B1 or by hydrolysis of HDL2 phospholipids and triglycerides by hepatic lipase. Released, free Apo A-I forms preβ-HDL with the minimum amount of phospholipid and cholesterol. Preβ-HDL is considered the most potent form of HDL in inducing cholesterol efflux from the tissues to form discoidal HDL (**Figure 3**).

#### **3. Oxidative stress, lipid peroxidation, and lipoprotein modifications**

CKD is associated with increased oxidative stress, which promotes covalent modifications of lipids and lipoproteins. Oxidative stress is an imbalance in the reactive oxygen species (ROS) production and their degradation ratio. ROS include various compounds such as superoxide anions, hydroperoxide, and hydroxyl radical. These compounds are produced under physiologic conditions, during energy production in mitochondria by reducing oxygen during aerobic respiration.

But excessive ROS levels may have a harmful effect on tissue function and structure, because of their interaction with different biomolecules in the human body, such as nucleic acids, proteins, and lipids. This interaction results with oxidative modifications of these biomolecules.

Under physiologic conditions, the production of ROS is balanced by antioxidant mechanisms that protect the cells from oxidative damages. The antioxidant mechanisms include enzymes; superoxide dismutase (SOD, EC 1.15.1.1) which catalyzes the dismutation of O2•<sup>−</sup> into H2O2; and glutathione peroxidase (GPX, EC 1.11.1.9), which detoxifies H2O2 and other hydroperoxides. Reduced glutathione (GSH), as a non-enzymatic antioxidant, allows the scavenging of OH. The redox reactions are catalyzed by glutathione peroxidase. In antioxidant mechanisms also included several compounds such as HDL, albumin, tocopherols, ferritin, ceruloplasmin, transferrin, ubiquinol, flavonoids, and carotenoids.

HDL is well known for its protective antioxidant properties. Protein paraoxonase-1 (PON1, EC 3.1.8.1), bound to HDL, exhibited antioxidant effects, against lipid peroxidation. Selenium Glutathione-peroxidase 3, also known as glutathione peroxidase 3 (GPX3, EC 1.11.1.9), is another antioxidant enzyme, which is associated with HDL. Besides many functions in the human body, albumins are known for the antioxidant function too. In the first place concerning the lipid peroxidation, albumin can scavenge hypochlorous acid, responsible for chlorination of proteins mediated by myeloperoxidase, and through its reduced cysteine residue can scavenge hydroxyl radicals. One of the physiological functions of albumins is the transportation of insoluble components, through the blood plasma. In this way, albumins bind the long-chain fatty acids (LCFA), polyunsaturated fatty acids (PUFAs), and cholesterol and in the circulation, preventing them from oxidative modifications. Albumins bind also the ligands such as copper, iron, α-tocopherol, bilirubin, and homocysteine and prevent their antioxidant damages. Tocopherol is an important antioxidant in the human body, because of its ability to intercept intermediary radicals during the lipid peroxidation process. Most antioxidant mechanisms described above are decreased in patients with renal failure, leading to

**149**

*Lipid Disorders in Uremia*

*DOI: http://dx.doi.org/10.5772/intechopen.90043*

radical can create lipid peroxyl radicals (LOO•

**4. Lipid disorders in chronic uremia**

associated with uremia.

**4.1 Chylomicrons and VLDL**

MDA induce mutations and base-pair substitutions [6].

a higher sensitivity to oxidative stress. These patients have low activity and concentration of Glutathione, low concentration of HDL, PON-1 and GPX3 enzymes, albumins and antioxidant vitamins such as vitamin E, D and C. This decreased antioxidant status, enhanced oxidative stress, and affected lipids and proteins leading to lipoproteins modifications and dysfunction. Lipids are one of the compounds mostly attached to oxidative stress. The peroxidation of lipids began with the reaction between a free radical with a polyunsaturated fatty acid containing more than two double bounds and formation of a lipid radical. In the next reaction, lipid

further react with other lipids forming new lipid radicals and lipid hydroperoxide (LOOH). Malondialdehyde (MDA) and 4-OH-2,3 alkenals are the end products of lipid hydroperoxide degradation. MDA covalently binds to proteins and nucleic acids, interfering with their normal biological functions. Binding to nucleic acids,

Binding to lysine amino group of protein part of lipoproteins, MDA created toxic adducts known as advanced lipoxidation end products (ALEs). In general, ALEs exhibit several pro-inflammatory effects and are involved in atherosclerosis [7]. These ALEs on Apo B result with oxidative modification of [8]. 4-OH-2,3 alkenals can also react with proteins, exactly with histidine, cysteine, and lysine residues and, create ALEs [9], which generate modified LDL. In this modified form, LDL can activate macrophages and increase the upregulation of class A scavenger receptors involved in the transformation of LDL into foam cells [10]. Another end product of lipid peroxidation is F2α-isoprostanes. Oxidation of arachidonic acid by a cyclooxygenase-independent pathway generates F2α-isoprostanes, known for atherogenic properties, because of their implication on platelet aggregation via Thromboxane A2 receptor, vasoconstrictive effects on smooth muscle cells, and endothelial cell proliferation and endothelin-1 secretion [11]. These three end products are routinely used for in vivo evaluation of lipid peroxidation level [12].

Renal failure is characterized by specific metabolic abnormalities of plasma lipoproteins [13]. These abnormalities involve all lipoprotein classes and show variations depending on the degree of renal impairment. Uremic lipid profile includes increased VLDL, IDL, small dense LDL particles, lipoprotein (a), and decreased HDL. Besides the changes in their concentration and structure, as stated above, uremic environment can strongly modified circulating lipoproteins leading to profound alterations of their biological properties and toxic effects in different cells and tissues. This has led to the formulation of an accelerated atherogenesis hypothesis and has been commonly linked with the lipid metabolic alteration

Hypertriglyceridemia is common a disorder in uremic patients. Several studies have shown increased concentration of triglycerides even though serum creatinine levels are within normal range [14]. The predominant mechanism responsible for increased concentration of triglyceride-rich lipoproteins, including chylomicrons, VLDL, and their remains, is delayed catabolism and increased synthesis Apo B-48, the essential for chylomicrons metabolism. There are evidences that Apo B-48 levels are increased and inversely correlated with glomerular filtration and proteinuria [15]. In circulation, triglyceride-rich lipoproteins acquire Apo E and Apo C-II,

) in reaction with oxygen, which can

#### *Lipid Disorders in Uremia DOI: http://dx.doi.org/10.5772/intechopen.90043*

*Cellular Metabolism and Related Disorders*

tissues to form discoidal HDL (**Figure 3**).

modifications of these biomolecules.

transferrin, ubiquinol, flavonoids, and carotenoids.

cholesterol esters, increasing the size of the particles to form the less dense HDL2. In the next step, HDL2, released in circulation, participates in a series of elaborate exchanges of apoproteins and lipids with the Apo B-containing lipoproteins such as chylomicrons, VLDL, and IDL, before reaching the liver. Actually, HDL in circulation receives triglycerides from Apo B-containing lipoproteins in exchange for cholesterol esters, a process catalyzed by CETP. Finally, HDL-2, via Apo A-I, binds to the scavenger receptor B1, which has been identified as a HDL receptor in the liver. The cycle is completed by the reformation of HDL 3, either after selective delivery of cholesteryl esters to the liver via SR-B1 or by hydrolysis of HDL2 phospholipids and triglycerides by hepatic lipase. Released, free Apo A-I forms preβ-HDL with the minimum amount of phospholipid and cholesterol. Preβ-HDL is considered the most potent form of HDL in inducing cholesterol efflux from the

**3. Oxidative stress, lipid peroxidation, and lipoprotein modifications**

CKD is associated with increased oxidative stress, which promotes covalent modifications of lipids and lipoproteins. Oxidative stress is an imbalance in the reactive oxygen species (ROS) production and their degradation ratio. ROS include various compounds such as superoxide anions, hydroperoxide, and hydroxyl radical. These compounds are produced under physiologic conditions, during energy production in mitochondria by reducing oxygen during aerobic respiration.

But excessive ROS levels may have a harmful effect on tissue function and structure, because of their interaction with different biomolecules in the human body, such as nucleic acids, proteins, and lipids. This interaction results with oxidative

Under physiologic conditions, the production of ROS is balanced by antioxidant mechanisms that protect the cells from oxidative damages. The antioxidant mechanisms include enzymes; superoxide dismutase (SOD, EC 1.15.1.1) which catalyzes the dismutation of O2•<sup>−</sup> into H2O2; and glutathione peroxidase (GPX, EC 1.11.1.9), which detoxifies H2O2 and other hydroperoxides. Reduced glutathione (GSH), as a non-enzymatic antioxidant, allows the scavenging of OH. The redox reactions are catalyzed by glutathione peroxidase. In antioxidant mechanisms also included several compounds such as HDL, albumin, tocopherols, ferritin, ceruloplasmin,

HDL is well known for its protective antioxidant properties. Protein paraoxonase-1 (PON1, EC 3.1.8.1), bound to HDL, exhibited antioxidant effects, against lipid peroxidation. Selenium Glutathione-peroxidase 3, also known as glutathione peroxidase 3 (GPX3, EC 1.11.1.9), is another antioxidant enzyme, which is associated with HDL. Besides many functions in the human body, albumins are known for the antioxidant function too. In the first place concerning the lipid peroxidation, albumin can scavenge hypochlorous acid, responsible for chlorination of proteins mediated by myeloperoxidase, and through its reduced cysteine residue can scavenge hydroxyl radicals. One of the physiological functions of albumins is the transportation of insoluble components, through the blood plasma. In this way, albumins bind the long-chain fatty acids (LCFA), polyunsaturated fatty acids (PUFAs), and cholesterol and in the circulation, preventing them from oxidative modifications. Albumins bind also the ligands such as copper, iron, α-tocopherol, bilirubin, and homocysteine and prevent their antioxidant damages. Tocopherol is an important antioxidant in the human body, because of its ability to intercept intermediary radicals during the lipid peroxidation process. Most antioxidant mechanisms described above are decreased in patients with renal failure, leading to

**148**

a higher sensitivity to oxidative stress. These patients have low activity and concentration of Glutathione, low concentration of HDL, PON-1 and GPX3 enzymes, albumins and antioxidant vitamins such as vitamin E, D and C. This decreased antioxidant status, enhanced oxidative stress, and affected lipids and proteins leading to lipoproteins modifications and dysfunction. Lipids are one of the compounds mostly attached to oxidative stress. The peroxidation of lipids began with the reaction between a free radical with a polyunsaturated fatty acid containing more than two double bounds and formation of a lipid radical. In the next reaction, lipid radical can create lipid peroxyl radicals (LOO• ) in reaction with oxygen, which can further react with other lipids forming new lipid radicals and lipid hydroperoxide (LOOH). Malondialdehyde (MDA) and 4-OH-2,3 alkenals are the end products of lipid hydroperoxide degradation. MDA covalently binds to proteins and nucleic acids, interfering with their normal biological functions. Binding to nucleic acids, MDA induce mutations and base-pair substitutions [6].

Binding to lysine amino group of protein part of lipoproteins, MDA created toxic adducts known as advanced lipoxidation end products (ALEs). In general, ALEs exhibit several pro-inflammatory effects and are involved in atherosclerosis [7]. These ALEs on Apo B result with oxidative modification of [8]. 4-OH-2,3 alkenals can also react with proteins, exactly with histidine, cysteine, and lysine residues and, create ALEs [9], which generate modified LDL. In this modified form, LDL can activate macrophages and increase the upregulation of class A scavenger receptors involved in the transformation of LDL into foam cells [10]. Another end product of lipid peroxidation is F2α-isoprostanes. Oxidation of arachidonic acid by a cyclooxygenase-independent pathway generates F2α-isoprostanes, known for atherogenic properties, because of their implication on platelet aggregation via Thromboxane A2 receptor, vasoconstrictive effects on smooth muscle cells, and endothelial cell proliferation and endothelin-1 secretion [11]. These three end products are routinely used for in vivo evaluation of lipid peroxidation level [12].

#### **4. Lipid disorders in chronic uremia**

Renal failure is characterized by specific metabolic abnormalities of plasma lipoproteins [13]. These abnormalities involve all lipoprotein classes and show variations depending on the degree of renal impairment. Uremic lipid profile includes increased VLDL, IDL, small dense LDL particles, lipoprotein (a), and decreased HDL. Besides the changes in their concentration and structure, as stated above, uremic environment can strongly modified circulating lipoproteins leading to profound alterations of their biological properties and toxic effects in different cells and tissues. This has led to the formulation of an accelerated atherogenesis hypothesis and has been commonly linked with the lipid metabolic alteration associated with uremia.

#### **4.1 Chylomicrons and VLDL**

Hypertriglyceridemia is common a disorder in uremic patients. Several studies have shown increased concentration of triglycerides even though serum creatinine levels are within normal range [14]. The predominant mechanism responsible for increased concentration of triglyceride-rich lipoproteins, including chylomicrons, VLDL, and their remains, is delayed catabolism and increased synthesis Apo B-48, the essential for chylomicrons metabolism. There are evidences that Apo B-48 levels are increased and inversely correlated with glomerular filtration and proteinuria [15]. In circulation, triglyceride-rich lipoproteins acquire Apo E and Apo C-II,

which are in the surface of HDL. In uremic patients, concentrations of Apo E and Apo C-II, which are necessary for activation of lipoprotein lipase and for uptakes of remnant chylomicrons and VLDL by a receptor specific for Apo E, are reduced. Such defect leads to a reduced release of triglycerides in peripheral tissues and to an accumulation of triglycerides. Delayed catabolism of triglyceride-rich lipoproteins occurs probably because of a decreased activity of hepatic triglyceride lipase and lipoprotein lipase. Moreover, significant evidence showed that enzyme lipoprotein lipase is lacking in renal failure [16]. There are evidences that diminished activity of enzyme is a consequence of the downregulation of the enzyme gene [17]. There is also downregulation of hepatic lipase expression [18].

The presence of lipoprotein lipase inhibitors also contributes to delayed triglyceride-rich lipoprotein catabolism. Apolipoprotein C-II is an activator, whereas apolipoprotein C-III is a direct lipoprotein lipase inhibitor. A decrease in apolipoprotein C-II/ apolipoprotein C-III ratio due to a disproportionate increase in plasma apolipoprotein C-III may be the cause of lipoprotein lipase inactivation, which further contributes to hypertriglyceridemia [19].

As it is mentioned above, triglyceride-rich lipoproteins, chylomicrons, and VLDL,need apolipoprotein C-II and apolipoprotein E for their maturation, which are delivered by HDL-2. In uremic patients HDL metabolism is impaired and HDL-3 are not maturated into HDL-2 due to a LCAT deficiency [20].

In healthy persons, VLDL and chylomicrons are transformed into IDL and chylomicron remnants after lipolysis in peripheral tissue. Chylomicron remnants are removed by the specific receptors of the liver, via LDL (Apo B-100 and Apo E) receptor and LDL receptor-related protein. It has been demonstrated that LDL receptor protein is downregulated in uremic patients [21] which leads to increasing levels of exogenous triglycerides. In physiological conditions, surplus IDL is transformed into LDL by the removal of their triglycerides by the hepatic lipase and enrichment in cholesteryl esters from HDL-2 by CETP. But the lack of HDL-2 impedes this process and leads to the accumulation of pro-atherogenic IDL [22]. There is a downregulation of hepatic lipase expression [18]; thus hepatic lipase deficiency which decreased conversion of IDL to LDL and lack of HDL work in concert to rise plasma concentration of IDL. A part of VLDL is removed by VLDL receptors, but in chronic uremia, the expression of VLDL receptors in tissues is also downregulated [23]. This makes impossible the VLDL binding with VLDL receptors in adipocytes and myocytes and their removal from the circulation (**Figure 4**). Insulin resistance is often associated with chronic uremia and seems to be responsible for a hepatic VLDL overproduction [24]. Secondary hyperparathyroidism, in renal failure, may play an additional role in triglyceride-rich lipoprotein catabolism impairment.

The predominant mechanism responsible for delayed metabolism of chylomicrons and very-low-density lipoproteins is increased synthesis apolipoprotein (Apo B-48) and low activity of lipoprotein lipase (LPL). Decrease concentration of highdensity lipoproteins in renal failure results with decreased Apo E and Apo C-II, which are necessary for activation of LPL and for uptakes of remnant chylomicrons and intermediate-density lipoproteins by a receptor specific for Apo E. Such defect, together with the downregulation of LDL receptor protein and hepatic lipase (HL), leads to accumulation of chylomicron remnants and IDL, reducing the release of fatty acids into peripheral tissues. In physiological conditions, surplus IDL is transformed into LDL by the removal of their triglycerides and enrichment in cholesteryl esters from HDL-2 by CETP. But the lack of HDL-2 impedes this process and leads to the accumulation of pro-atherogenic IDL. Increased activity of CETP contributed in reducing HDL concentration. The presence of lipoprotein lipase inhibitor, Apo C-III, also contributes to delayed triglyceride-rich lipoprotein metabolism.

**151**

*Lipid Disorders in Uremia*

**4.2 HDL cholesterol**

**Figure 4.**

total ACAT activity [29].

Uremic patients have decreased HDL in comparison with healthy population [25, 26]. Several mechanisms, working in concern, may underlie the reduction in HDL levels, which is usually indicative of impaired reverse cholesterol transport. Specifically, maturation of HDL is impaired and its composition is altered. Thus, uremic patients usually exhibit decreased levels of apolipoproteins A-I and A-II (the main protein constituents of HDL), diminished activity of LCAT, the enzyme responsible for the esterification of free cholesterol in HDL particles, as well as increased activity of CETP that facilitates the transfer of cholesterol esters from HDL to triglyceride-rich lipoproteins. One of the mechanisms for impaired HDL metabolism in uremia is the increased activity of enzyme ACAT which is responsible for intracellular cholesterol esterification. In physiological conditions, Apo A-I and Apo A-II, in the circulation, are loaded with cholesterol and phospholipids to form nascent HDL. Then, nascent HDL binds to the ABCA-1 receptor on circulating macrophages and activates cholesterol ester hydrolase allowing their loading with cholesterol. ACAT limits this reverse efflux of cholesterol from macrophages by catalyzing the esterification of intracellular cholesterol. Oxidative modification of Apo A-I can limit HDL binding on macrophages [27] and upregulation of hepatic ACAT [28] contributing in impaired cholesterol efflux. Therefore, an increase in ACAT activity can potentially limit HDL-mediated cholesterol uptake and contribute to the reduction in plasma HDL cholesterol and impaired maturation of HDL. Although the effect of chronic renal failure on ACAT expression and activity in the extrahepatic tissues is not known, chronic renal failure has been recently shown to markedly raise hepatic ACAT-2 mRNA and protein abundance, as well as

On the other hand, the activity of enzyme LCAT is decreased [30, 31]. Apo A-I is the activator of LCAT, the essential enzyme for the HDL-mediated cholesterol retrieval from extrahepatic tissues and as well as ligand for the SR-B1 and HDLbinding protein (ABCA1 transporter). Apo A-II serves as an activator of hepatic lipase, which plays a central role in the removal of HDL triglycerides by the liver. As mentioned above, in patients with impaired kidney function, Apo A-I and Apo A-II levels are decreased. This reduction contributes to diminished HDL concentration and impaired HDL maturation. Until recently, it was not clear whether the reported reduction in plasma LCAT activity is caused by the reduction in its hepatic production and plasma concentration or is a consequence of its inhibition by an

*DOI: http://dx.doi.org/10.5772/intechopen.90043*

*Changes in chylomicrons and VLDL metabolism in renal failure.*

*Cellular Metabolism and Related Disorders*

also downregulation of hepatic lipase expression [18].

further contributes to hypertriglyceridemia [19].

which are in the surface of HDL. In uremic patients, concentrations of Apo E and Apo C-II, which are necessary for activation of lipoprotein lipase and for uptakes of remnant chylomicrons and VLDL by a receptor specific for Apo E, are reduced. Such defect leads to a reduced release of triglycerides in peripheral tissues and to an accumulation of triglycerides. Delayed catabolism of triglyceride-rich lipoproteins occurs probably because of a decreased activity of hepatic triglyceride lipase and lipoprotein lipase. Moreover, significant evidence showed that enzyme lipoprotein lipase is lacking in renal failure [16]. There are evidences that diminished activity of enzyme is a consequence of the downregulation of the enzyme gene [17]. There is

The presence of lipoprotein lipase inhibitors also contributes to delayed triglyceride-rich lipoprotein catabolism. Apolipoprotein C-II is an activator, whereas apolipoprotein C-III is a direct lipoprotein lipase inhibitor. A decrease in apolipoprotein C-II/ apolipoprotein C-III ratio due to a disproportionate increase in plasma apolipoprotein C-III may be the cause of lipoprotein lipase inactivation, which

As it is mentioned above, triglyceride-rich lipoproteins, chylomicrons, and VLDL,need apolipoprotein C-II and apolipoprotein E for their maturation, which are delivered by HDL-2. In uremic patients HDL metabolism is impaired and

In healthy persons, VLDL and chylomicrons are transformed into IDL and chylomicron remnants after lipolysis in peripheral tissue. Chylomicron remnants are removed by the specific receptors of the liver, via LDL (Apo B-100 and Apo E) receptor and LDL receptor-related protein. It has been demonstrated that LDL receptor protein is downregulated in uremic patients [21] which leads to increasing levels of exogenous triglycerides. In physiological conditions, surplus IDL is transformed into LDL by the removal of their triglycerides by the hepatic lipase and enrichment in cholesteryl esters from HDL-2 by CETP. But the lack of HDL-2 impedes this process and leads to the accumulation of pro-atherogenic IDL [22]. There is a downregulation of hepatic lipase expression [18]; thus hepatic lipase deficiency which decreased conversion of IDL to LDL and lack of HDL work in concert to rise plasma concentration of IDL. A part of VLDL is removed by VLDL receptors, but in chronic uremia, the expression of VLDL receptors in tissues is also downregulated [23]. This makes impossible the VLDL binding with VLDL receptors in adipocytes and myocytes and their removal from the circulation (**Figure 4**). Insulin resistance is often associated with chronic uremia and seems to be responsible for a hepatic VLDL overproduction [24]. Secondary hyperparathyroidism, in renal failure, may play an additional role in triglyceride-rich lipoprotein catabolism

The predominant mechanism responsible for delayed metabolism of chylomicrons and very-low-density lipoproteins is increased synthesis apolipoprotein (Apo B-48) and low activity of lipoprotein lipase (LPL). Decrease concentration of highdensity lipoproteins in renal failure results with decreased Apo E and Apo C-II, which are necessary for activation of LPL and for uptakes of remnant chylomicrons and intermediate-density lipoproteins by a receptor specific for Apo E. Such defect, together with the downregulation of LDL receptor protein and hepatic lipase (HL), leads to accumulation of chylomicron remnants and IDL, reducing the release of fatty acids into peripheral tissues. In physiological conditions, surplus IDL is transformed into LDL by the removal of their triglycerides and enrichment in cholesteryl esters from HDL-2 by CETP. But the lack of HDL-2 impedes this process and leads to the accumulation of pro-atherogenic IDL. Increased activity of CETP contributed in reducing HDL concentration. The presence of lipoprotein lipase inhibitor, Apo C-III, also contributes to delayed triglyceride-rich lipoprotein metabolism.

HDL-3 are not maturated into HDL-2 due to a LCAT deficiency [20].

**150**

impairment.

**Figure 4.** *Changes in chylomicrons and VLDL metabolism in renal failure.*

#### **4.2 HDL cholesterol**

Uremic patients have decreased HDL in comparison with healthy population [25, 26]. Several mechanisms, working in concern, may underlie the reduction in HDL levels, which is usually indicative of impaired reverse cholesterol transport. Specifically, maturation of HDL is impaired and its composition is altered. Thus, uremic patients usually exhibit decreased levels of apolipoproteins A-I and A-II (the main protein constituents of HDL), diminished activity of LCAT, the enzyme responsible for the esterification of free cholesterol in HDL particles, as well as increased activity of CETP that facilitates the transfer of cholesterol esters from HDL to triglyceride-rich lipoproteins. One of the mechanisms for impaired HDL metabolism in uremia is the increased activity of enzyme ACAT which is responsible for intracellular cholesterol esterification. In physiological conditions, Apo A-I and Apo A-II, in the circulation, are loaded with cholesterol and phospholipids to form nascent HDL. Then, nascent HDL binds to the ABCA-1 receptor on circulating macrophages and activates cholesterol ester hydrolase allowing their loading with cholesterol. ACAT limits this reverse efflux of cholesterol from macrophages by catalyzing the esterification of intracellular cholesterol. Oxidative modification of Apo A-I can limit HDL binding on macrophages [27] and upregulation of hepatic ACAT [28] contributing in impaired cholesterol efflux. Therefore, an increase in ACAT activity can potentially limit HDL-mediated cholesterol uptake and contribute to the reduction in plasma HDL cholesterol and impaired maturation of HDL. Although the effect of chronic renal failure on ACAT expression and activity in the extrahepatic tissues is not known, chronic renal failure has been recently shown to markedly raise hepatic ACAT-2 mRNA and protein abundance, as well as total ACAT activity [29].

On the other hand, the activity of enzyme LCAT is decreased [30, 31]. Apo A-I is the activator of LCAT, the essential enzyme for the HDL-mediated cholesterol retrieval from extrahepatic tissues and as well as ligand for the SR-B1 and HDLbinding protein (ABCA1 transporter). Apo A-II serves as an activator of hepatic lipase, which plays a central role in the removal of HDL triglycerides by the liver. As mentioned above, in patients with impaired kidney function, Apo A-I and Apo A-II levels are decreased. This reduction contributes to diminished HDL concentration and impaired HDL maturation. Until recently, it was not clear whether the reported reduction in plasma LCAT activity is caused by the reduction in its hepatic production and plasma concentration or is a consequence of its inhibition by an

unknown uremic toxin [32]. Another enzyme with diminished activity is CETP. The enzyme mediates transfer of cholesterol ester from HDL to IDL in exchange for triglycerides. Increased activity of CETP in uremic patients facilitates the transfer of cholesterol esters from HDL to triglyceride-rich lipoproteins, reducing the HDL cholesterol ester and elevation of HDL triglycerides. The mechanism responsible for the elevation of CETP is unknown, but some investigation connected its increased synthesis with proteinuria. Probably the same mechanism is responsible for the dysregulation of hepatic SR-B1. Hepatic SR-B1 is the primary pathway for the disposal of HDL-borne cholesterol ester and triglycerides, and dysregulation of this protein can impact HDL metabolism. Heavy glomerular proteinuria has been shown to significantly reduce hepatic SR-B1 protein expression in experimental animals [29]. HDL has a protective effect against inflammation, platelet adhesion, and LDL oxidation. Those protective functions of HDL can be attributed to HDL-associated enzymes on its surface. Paraoxonase-1 is considered as the main antioxidant enzyme bound to HDL. Mainly expressed in the liver and the kidney, this enzyme exhibited antioxidant properties against lipid peroxidation as it binds to HDL and in a minor part to VLDL [33]. Glutathione seleno-peroxidase 3, also known as glutathione peroxidase 3, is another antioxidant enzyme associated with HDL [34].

One of main anti-atherogenic properties of HDL is a reverse cholesterol transport from circulating macrophages. HDL also increases the production of nitric oxide (NO), through the activation of the endothelial NO synthase in endothelial cells resulting in a vasorelaxant phenotype. In CKD the production of NO by endothelial cells is significantly reduced with HDL [28]. HDL also inhibits the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1), which prevent the attachment of circulating monocytes to endothelial cells. In uremic patients, HDL promotes an enhanced expression of VCAM-1 and ICAM-1 on endothelial cells [35, 36]. Moreover, CKD-HDL upregulates the expression of pro-inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1), interleukin-1ß (IL-1ß), and tumor necrosis factor α (TNF-α) [36, 37]. And finally normal HDL exhibit anti-apoptotic effects on endothelial cells through the downregulation of caspase-3 (a member of the cysteine-aspartic acid protease) activity [38]. All these diminished protective functions of HDL can contribute to accelerated atherogenesis [39]. HDL is very sensitive in oxidative stress and posttranslational modifications. Renal failure is associated with an enhanced activity of enzyme myeloperoxidase (MPO, EC 1.11.2.2) that plays a crucial role in the generation of posttranslational modification derived products (PTMDPs). MPO catalyzed the oxidative reactions and formation of a variety of chlorinated protein and lipid adducts. MPO-modified ApoA-1 results in decreased reverse cholesterol efflux and a reduced binding with ABCA-1 receptor, which disturbed cholesterol homeostasis (**Figure 5**). 3-chlorotyrosine, an oxidation product of MPO, impairs the activity of enzymes, LCAT, and PON-1, resulting with decreased anti-inflammatory effects of HDL. And through the activation of SR-B1 in macrophages, MPO-modified HDL directly contributes in atherosclerosis (**Figure 5**).

In renal failure, decreased activity of lecithin-cholesterol acyltransferase impaired the transformation of nascent cholesterol into HDL3 and then into HDL2. Increased activity of cholesteryl ester transfer protein facilitates the transfer of cholesterol esters from HDL to triglyceride-rich lipoproteins, reducing HDL concentration. Removal of free cholesterol from macrophages proceeds by scavenger receptor 1. Nascent HDL is generated when Apo A-I interacts with ATP-binding cassette transporter type 1 (ABCA1). Than nascent HDL activates cholesterol ester hydrolase allowing their loading with cholesterol. ACAT limits this reverse efflux of cholesterol from macrophages by catalyzing the esterification of intracellular

**153**

*Lipid Disorders in Uremia*

**4.3 LDL cholesterol**

*HDL metabolism in renal failure.*

**Figure 5.**

*DOI: http://dx.doi.org/10.5772/intechopen.90043*

cholesterol. Increased activity of ACAT, in renal failure, participates in impaired cholesterol efflux. Antioxidative and anti-inflammatory functions of HDL are impaired due to reduced activity of HDL enzyme PON1. HDL from patients with renal failure loses its vasoprotective properties, inhibiting nitric oxide production. Oxidative modification of Apo A-I decreases HDLs binding to macrophages. Myeloperoxidase-modified Apo A-I decrease reverse cholesterol efflux, reduce

Beyond atherogenic risk of LDL level itself, renal failure leads to various structural modifications of LDL particles. The lipoproteins found in uremic patients are disproportionately modified, with LDL that is enriched in triglycerides. These modified LDL particles tend to be smaller and denser in their form. Small dense LDL is believed to be markedly pro-atherogenic, and this is attributed to its ability to infiltrate the vessel wall and its increased susceptibility to oxidative modification. Because of the significantly modified lipid subfraction turnover, residence time of lipoproteins in the circulation is prolonged. Thus, lipoproteins are at risk of posttranslational modification. LDL receptor-mediated cholesterol uptake plays an important role in cholesterol homeostasis. Modified LDL have reduced affinity for the classic LDL receptors and are taken up by the scavenger receptors on the surface of the macrophages. These receptors are increased in chronic uremia. High affinity for macrophages results in the accumulation of cholesterol and the formation of foam cells in the vascular walls, resulting in the development of atherosclerotic plaques [40, 41]. Heavy proteinuria alone or in combination with chronic uremic state results in acquired LDL receptor deficiency and plays a central role in the genesis of the atherosclerosis and cardiovascular diseases. Several levels of LDL oxidation can coexist in the bloodstream and lead to the activation of several pathways involved in atherosclerosis through their binding to scavenger receptors [42] and smooth muscle cell proliferation. There is an evidence that OxLDL are accumulated in uremic patients and are correlated with the intensity of peripheral arterial disease [43]. Oxidized epitopes of LDL can activate immunity and then lead to the formation of antibodies directed against OxLDL. OxLDL/ antibodies against OxLDL ratio were also correlated with carotid atherosclerosis

binding with ABCA1, and impair HDLs anti-apoptotic properties.

*Cellular Metabolism and Related Disorders*

unknown uremic toxin [32]. Another enzyme with diminished activity is CETP. The enzyme mediates transfer of cholesterol ester from HDL to IDL in exchange for triglycerides. Increased activity of CETP in uremic patients facilitates the transfer of cholesterol esters from HDL to triglyceride-rich lipoproteins, reducing the HDL cholesterol ester and elevation of HDL triglycerides. The mechanism responsible for the elevation of CETP is unknown, but some investigation connected its increased synthesis with proteinuria. Probably the same mechanism is responsible for the dysregulation of hepatic SR-B1. Hepatic SR-B1 is the primary pathway for the disposal of HDL-borne cholesterol ester and triglycerides, and dysregulation of this protein can impact HDL metabolism. Heavy glomerular proteinuria has been shown to significantly reduce hepatic SR-B1 protein expression in experimental animals [29]. HDL has a protective effect against inflammation, platelet adhesion, and LDL oxidation. Those protective functions of HDL can be attributed to HDL-associated enzymes on its surface. Paraoxonase-1 is considered as the main antioxidant enzyme bound to HDL. Mainly expressed in the liver and the kidney, this enzyme exhibited antioxidant properties against lipid peroxidation as it binds to HDL and in a minor part to VLDL [33]. Glutathione seleno-peroxidase 3, also known as glutathione peroxidase 3, is another antioxidant enzyme associated with HDL [34]. One of main anti-atherogenic properties of HDL is a reverse cholesterol transport from circulating macrophages. HDL also increases the production of nitric oxide (NO), through the activation of the endothelial NO synthase in endothelial cells resulting in a vasorelaxant phenotype. In CKD the production of NO by endothelial cells is significantly reduced with HDL [28]. HDL also inhibits the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1), which prevent the attachment of circulating monocytes to endothelial cells. In uremic patients, HDL promotes an enhanced expression of VCAM-1 and ICAM-1 on endothelial cells [35, 36]. Moreover, CKD-HDL upregulates the expression of pro-inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1), interleukin-1ß (IL-1ß), and tumor necrosis factor α (TNF-α) [36, 37]. And finally normal HDL exhibit anti-apoptotic effects on endothelial cells through the downregulation of caspase-3 (a member of the cysteine-aspartic acid protease) activity [38]. All these diminished protective functions of HDL can contribute to accelerated atherogenesis [39]. HDL is very sensitive in oxidative stress and posttranslational modifications. Renal failure is associated with an enhanced activity of enzyme myeloperoxidase (MPO, EC 1.11.2.2) that plays a crucial role in the generation of posttranslational modification derived products (PTMDPs). MPO catalyzed the oxidative reactions and formation of a variety of chlorinated protein and lipid adducts. MPO-modified ApoA-1 results in decreased reverse cholesterol efflux and a reduced binding with ABCA-1 receptor, which disturbed cholesterol homeostasis (**Figure 5**). 3-chlorotyrosine, an oxidation product of MPO, impairs the activity of enzymes, LCAT, and PON-1, resulting with decreased anti-inflammatory effects of HDL. And through the activation of SR-B1 in macrophages, MPO-modified HDL directly contributes

**152**

in atherosclerosis (**Figure 5**).

In renal failure, decreased activity of lecithin-cholesterol acyltransferase impaired the transformation of nascent cholesterol into HDL3 and then into HDL2. Increased activity of cholesteryl ester transfer protein facilitates the transfer of cholesterol esters from HDL to triglyceride-rich lipoproteins, reducing HDL concentration. Removal of free cholesterol from macrophages proceeds by scavenger receptor 1. Nascent HDL is generated when Apo A-I interacts with ATP-binding cassette transporter type 1 (ABCA1). Than nascent HDL activates cholesterol ester hydrolase allowing their loading with cholesterol. ACAT limits this reverse efflux of cholesterol from macrophages by catalyzing the esterification of intracellular

#### **Figure 5.** *HDL metabolism in renal failure.*

cholesterol. Increased activity of ACAT, in renal failure, participates in impaired cholesterol efflux. Antioxidative and anti-inflammatory functions of HDL are impaired due to reduced activity of HDL enzyme PON1. HDL from patients with renal failure loses its vasoprotective properties, inhibiting nitric oxide production. Oxidative modification of Apo A-I decreases HDLs binding to macrophages. Myeloperoxidase-modified Apo A-I decrease reverse cholesterol efflux, reduce binding with ABCA1, and impair HDLs anti-apoptotic properties.

#### **4.3 LDL cholesterol**

Beyond atherogenic risk of LDL level itself, renal failure leads to various structural modifications of LDL particles. The lipoproteins found in uremic patients are disproportionately modified, with LDL that is enriched in triglycerides. These modified LDL particles tend to be smaller and denser in their form. Small dense LDL is believed to be markedly pro-atherogenic, and this is attributed to its ability to infiltrate the vessel wall and its increased susceptibility to oxidative modification. Because of the significantly modified lipid subfraction turnover, residence time of lipoproteins in the circulation is prolonged. Thus, lipoproteins are at risk of posttranslational modification. LDL receptor-mediated cholesterol uptake plays an important role in cholesterol homeostasis. Modified LDL have reduced affinity for the classic LDL receptors and are taken up by the scavenger receptors on the surface of the macrophages. These receptors are increased in chronic uremia. High affinity for macrophages results in the accumulation of cholesterol and the formation of foam cells in the vascular walls, resulting in the development of atherosclerotic plaques [40, 41]. Heavy proteinuria alone or in combination with chronic uremic state results in acquired LDL receptor deficiency and plays a central role in the genesis of the atherosclerosis and cardiovascular diseases. Several levels of LDL oxidation can coexist in the bloodstream and lead to the activation of several pathways involved in atherosclerosis through their binding to scavenger receptors [42] and smooth muscle cell proliferation. There is an evidence that OxLDL are accumulated in uremic patients and are correlated with the intensity of peripheral arterial disease [43]. Oxidized epitopes of LDL can activate immunity and then lead to the formation of antibodies directed against OxLDL. OxLDL/ antibodies against OxLDL ratio were also correlated with carotid atherosclerosis

and cardiovascular events [44]. Formation of OxLDL is a consequence of oxidative stress. As mentioned above, the breakdown of polyunsaturated fatty acids produces highly reactive molecules, such as MDA and 4-OH-2,3 alkenals. MDA and 4-OH-2,3 alkenals can form Schiff bases and covalent Michael-type adducts, with lysine residues of Apo B-100, in LDL (**Figure 6**). The oxidized fatty acid fragments which can remain attached via ester bridges, may also contain terminal reactive phospholipids which may form adducts with Schiff base lysine residues of Apo B-100. Similarly with HDL modifications, increased levels of MPO are involved in LDL modifications. MPO can modify LDL through several mechanisms. MPO initiated the reaction between hypochlorous acid and tyrosine residues of Apo B-100, protein part of LDL, resulting with 3-chlorotyrosine formation, which is known for pro-atherogenic properties through its binding with lectin-like oxidized LDL receptor 1. MPO also generated reactive nitrogen species, converting LDL into a nitrosilated-LDL form. This reaction resulted in nitration of Apo B-100 tyrosyl residues of LDL. Carbamylated LDL (cLDL) is another modified form of LDL, initiated by MPO. In this reaction MPO catalyzed the addition of thiocyanate, derived from the decomposition of urea to the lysine residues of LDL, and leads to the formation of carbamylated LDL [45, 46]. The carbamylation occurs by spontaneous, nonenzymatic chemical modification of Apo B-100, by thiocyanate. It is a irreversibly reaction of thiocyanate with free amino groups and ε-NH2 of lysine residues in protein part of LDL (**Figure 7**). cLDL have pro-atherogenic effects such as the transformation of macrophages into foam cells [47] through their binding to the pro-atherogenic CD36 receptor [48, 49]. cLDL are associated with endothelial toxicity [50, 51] through lectin-like oxidized LDL receptor 1 [52] (**Figure 8**). cLDL levels are raised by chronic uremia [53, 54].

Modified forms of LDL; carbamylated LDL and oxidized LDL; activated lectin-like oxidized LDL receptor 1, on endothelial cells; and initiated formation of macrophages and smooth muscle cell proliferation.

**155**

**4.4 Lipoprotein (a)**

*Formation of carbamylated LDL.*

**Figure 7.**

The contribution of cardiovascular events to the extraordinary high mortality in CKD has generated some interest in nontraditional atherosclerotic cardiovascular disease risk factors, which are prevalent in this population, such as Lipoprotein (a) [Lp (a)]. Lp (a) is an LDL-like lipoprotein containing a unique apolipoprotein called Apo(a). Serum levels of Lp(a) are determined largely by genetic variation in the gene encoding for Apo(a). Apo(a) is very homologous to plasminogen [55] and exhibits an extreme size polymorphism with the Apo(a) isoproteins, ranging in size from 420 to 840 kDa. Inherited in an autosomal codominant fashion, the Apo(a) isoprotein is closely correlated with serum Lp(a) concentrations, with an inverse correlation between the size of the Apo(a) isoprotein and the serum Lp(a) concentrations. Lp(a) has been implicated in the regulation of plasminogen activator inhibitor-1 expression in endothelial cells and shown to inhibit endothelial cell surface fibrinolysis to

*Lipid Disorders in Uremia*

*DOI: http://dx.doi.org/10.5772/intechopen.90043*

**Figure 6.** *Formation of oxidized LDL.*

*Lipid Disorders in Uremia DOI: http://dx.doi.org/10.5772/intechopen.90043*

*Cellular Metabolism and Related Disorders*

levels are raised by chronic uremia [53, 54].

macrophages and smooth muscle cell proliferation.

and cardiovascular events [44]. Formation of OxLDL is a consequence of oxidative stress. As mentioned above, the breakdown of polyunsaturated fatty acids produces highly reactive molecules, such as MDA and 4-OH-2,3 alkenals. MDA and 4-OH-2,3 alkenals can form Schiff bases and covalent Michael-type adducts, with lysine residues of Apo B-100, in LDL (**Figure 6**). The oxidized fatty acid fragments which can remain attached via ester bridges, may also contain terminal reactive phospholipids which may form adducts with Schiff base lysine residues of Apo B-100. Similarly with HDL modifications, increased levels of MPO are involved in LDL modifications. MPO can modify LDL through several mechanisms. MPO initiated the reaction between hypochlorous acid and tyrosine residues of Apo B-100, protein part of LDL, resulting with 3-chlorotyrosine formation, which is known for pro-atherogenic properties through its binding with lectin-like oxidized LDL receptor 1. MPO also generated reactive nitrogen species, converting LDL into a nitrosilated-LDL form. This reaction resulted in nitration of Apo B-100 tyrosyl residues of LDL. Carbamylated LDL (cLDL) is another modified form of LDL, initiated by MPO. In this reaction MPO catalyzed the addition of thiocyanate, derived from the decomposition of urea to the lysine residues of LDL, and leads to the formation of carbamylated LDL [45, 46]. The carbamylation occurs by spontaneous, nonenzymatic chemical modification of Apo B-100, by thiocyanate. It is a irreversibly reaction of thiocyanate with free amino groups and ε-NH2 of lysine residues in protein part of LDL (**Figure 7**). cLDL have pro-atherogenic effects such as the transformation of macrophages into foam cells [47] through their binding to the pro-atherogenic CD36 receptor [48, 49]. cLDL are associated with endothelial toxicity [50, 51] through lectin-like oxidized LDL receptor 1 [52] (**Figure 8**). cLDL

Modified forms of LDL; carbamylated LDL and oxidized LDL; activated lectin-like oxidized LDL receptor 1, on endothelial cells; and initiated formation of

**154**

**Figure 6.**

*Formation of oxidized LDL.*

**Figure 7.** *Formation of carbamylated LDL.*

#### **4.4 Lipoprotein (a)**

The contribution of cardiovascular events to the extraordinary high mortality in CKD has generated some interest in nontraditional atherosclerotic cardiovascular disease risk factors, which are prevalent in this population, such as Lipoprotein (a) [Lp (a)]. Lp (a) is an LDL-like lipoprotein containing a unique apolipoprotein called Apo(a). Serum levels of Lp(a) are determined largely by genetic variation in the gene encoding for Apo(a). Apo(a) is very homologous to plasminogen [55] and exhibits an extreme size polymorphism with the Apo(a) isoproteins, ranging in size from 420 to 840 kDa. Inherited in an autosomal codominant fashion, the Apo(a) isoprotein is closely correlated with serum Lp(a) concentrations, with an inverse correlation between the size of the Apo(a) isoprotein and the serum Lp(a) concentrations. Lp(a) has been implicated in the regulation of plasminogen activator inhibitor-1 expression in endothelial cells and shown to inhibit endothelial cell surface fibrinolysis to

**Figure 8.** *Oxidized LDL and carbamylated LDL effects.*

attenuate plasminogen binding to platelets and to bind to plaque matrix components. Autopsy studies in humans have documented the presence of Lp(a) in aortic and coronary atherosclerotic plaques and an apparent colocalization with fibrinogen [56]. Lp(a) levels are frequently elevated in uremic patients with CKD [57] and have been associated with a frequency distribution of apolipoprotein (a)-Lp(a) isoforms, similar to those found in general population. This indicates that elevated Lp(a) levels in these patients are not due to the genetic origin [58]. It has been suggested that kidneys have an important role in Lp(a) metabolism [59]. In CKD, Lp(a) occurs at high concentrations, largely because of reduced clearance or as a result of increased hepatic synthesis, induced by an acute-phase reaction or by protein losses from proteinuria [60]. Uremia can be considered to be a state of activated acute-phase response, and in the micro-inflammatory milieu, a number of atherogenic proteins like Lp(a) are acting as an acute-phase reactant. Based in all these properties, Lp(a) is a prototype candidate to be classified as a uremic toxin.

#### **5. Conclusion**

Chronic uremia causes profound alteration in lipoprotein metabolism, promoting the development of atherosclerosis and cardiovascular disease. Besides the changes in their concentration, enhanced oxidative stress and uremic environment can strongly modify circulating lipoproteins leading to profound alterations of their biological properties and can be considered as uremic toxins. Uremic lipoprotein profile is directly involve in glomerular capillary endothelial damage and in the progression of renal disease. This "reverse epidemiology" shows the importance of lipid control to prevent the progression of renal failure.

**157**

*Lipid Disorders in Uremia*

**Abbreviations**

*DOI: http://dx.doi.org/10.5772/intechopen.90043*

α-TNF alpha tumor necrosis factor

Apo A,B,C,E apolipoprotein A,B,C,E

CKD chronic kidney disease

GPX glutathione peroxidase GPX3 glutathione peroxidase 3 HDL high-density lipoproteins

LDL low-density lipoproteins

mRNA messenger ribonucleic acid

Apo (a) apolipoprotein

IL-1ß interleukin-1ß

Lp(a) lipoprotein (a) LRP LDL related protein

MDA malondialdehyde MPO myeloperoxidase NO nitric oxide OxLDL oxidized-LDL

LCFA long chains fatty acids LOO• peroxyl radicals LOOH lipid hydroperoxide PON1 paraoxonase 1

PUFAs polyunsaturated fatty acids ROS reactive oxygen species SOD superoxide dismutase SR-B1 scavenger receptor B1

VCAM vascular adhesion molecule-1 VLDL very-low-density lipoprotein

ABCA1 ATP-binding cassette transporter type I ACAT acyl-CoA cholesterol acyltransferase

ALEs advanced lipoxidation end products

CETP cholesteryl ester transfer protein

IDL intermediate-density lipoproteins ICAM-1 intercellular adhesion molecule-1

LCAT lecithin-cholesterol acyltransferase

MCP-1 monocyte chemoattractant protein-1

PTMDPs posttranslational modification derived products

cLDL carbamylated low-density lipoprotein DGAT acyl-CoA diacylglycerol acyltransferase

#### **Conflict of interest**

The authors declare no conflict of interest.

*Lipid Disorders in Uremia DOI: http://dx.doi.org/10.5772/intechopen.90043*

#### **Abbreviations**

*Cellular Metabolism and Related Disorders*

to be classified as a uremic toxin.

*Oxidized LDL and carbamylated LDL effects.*

lipid control to prevent the progression of renal failure.

The authors declare no conflict of interest.

**5. Conclusion**

**Figure 8.**

**Conflict of interest**

attenuate plasminogen binding to platelets and to bind to plaque matrix components. Autopsy studies in humans have documented the presence of Lp(a) in aortic and coronary atherosclerotic plaques and an apparent colocalization with fibrinogen [56]. Lp(a) levels are frequently elevated in uremic patients with CKD [57] and have been associated with a frequency distribution of apolipoprotein (a)-Lp(a) isoforms, similar to those found in general population. This indicates that elevated Lp(a) levels in these patients are not due to the genetic origin [58]. It has been suggested that kidneys have an important role in Lp(a) metabolism [59]. In CKD, Lp(a) occurs at high concentrations, largely because of reduced clearance or as a result of increased hepatic synthesis, induced by an acute-phase reaction or by protein losses from proteinuria [60]. Uremia can be considered to be a state of activated acute-phase response, and in the micro-inflammatory milieu, a number of atherogenic proteins like Lp(a) are acting as an acute-phase reactant. Based in all these properties, Lp(a) is a prototype candidate

Chronic uremia causes profound alteration in lipoprotein metabolism, promoting the development of atherosclerosis and cardiovascular disease. Besides the changes in their concentration, enhanced oxidative stress and uremic environment can strongly modify circulating lipoproteins leading to profound alterations of their biological properties and can be considered as uremic toxins. Uremic lipoprotein profile is directly involve in glomerular capillary endothelial damage and in the progression of renal disease. This "reverse epidemiology" shows the importance of

**156**


*Cellular Metabolism and Related Disorders*

#### **Author details**

Valdete Topçiu-Shufta and Valdete Haxhibeqiri\* Faculty of Medicine, Clinic of Medical Biochemistry, University Clinical Center of Kosova, University of Prishtina, Prishtina, Republic of Kosova

\*Address all correspondence to: valbera@yahoo.com

© 2019 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, provided the original work is properly cited.

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*Lipid Disorders in Uremia*

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[12] Grotto D, Santa Maria LD, Boeira S, Valentini J, Charão MF, Moro AM, et al. Rapid quantification of malondialdehyde in plasma by high performance liquid chromatography-

visible detection. Journal of Pharmaceutical and Biomedical Analysis. 2007;**43**:619-624. DOI: 10.1016/j.jpba.2006.07.030

[13] Tsimihodimos V, Dounousi E, Siamopoulos KC. Dyslipidemia in

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[6] VanderVeen LA, Hashim MF, Shyr Y, Marnett LJ. Induction of frameshift and base pair substitution mutations by the major DNA adduct of the endogenous carcinogen malondialdehyde. PNAS. 2003;**100**:14247-14252. DOI: 10.1073/

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**Author details**

Valdete Topçiu-Shufta and Valdete Haxhibeqiri\*

\*Address all correspondence to: valbera@yahoo.com

provided the original work is properly cited.

Kosova, University of Prishtina, Prishtina, Republic of Kosova

Faculty of Medicine, Clinic of Medical Biochemistry, University Clinical Center of

© 2019 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,

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[20] Moradi H, Pahl MV, Elahimehr R, Vaziri ND. Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Translational Research. 2009;**153**:77-85. DOI: 10.1016/j. trsl.2008.11.007

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[22] Hirowatari Y, Homma Y, Yoshizawa J, Homma K. Increase of electronegative-LDL-fraction ratio and IDL-cholesterol in chronic kidney disease patients with hemodialysis treatment. Lipids in Health and Disease. 2012;**11**(1). DOI: 10.1186/1476-511X-11-111

[23] Sato T, Liang K, Vaziri ND. Downregulation of lipoprotein lipase and VLDL receptor in rats with focal glomerulosclerosis. Kidney International. 2002;**64**:1780-1786. DOI: 10.1046/j.1523-1755.2003.00281.x

[24] Tsimihodimos V, Mitrogianni Z, Elisaf M. Dyslipidemia associated with chronic kidney disease. Open Cardiovascular Medicine Journal. 2011;**5**:41-48

[25] Attman PO, Samuelsson O, Alaupovic P. Lipoprotein metabolism and renal failure. American Journal of Kidney Diseases. 1993;**21**:573-592

[26] Vaziri ND, Deng G, Liang K. Hepatic HDL receptor, SR-B1 and Apo A-I expression in chronic renal failure. Nephrology, Dialysis, Transplantation. 1999;**14**:1462-1466

[27] Shao B, Oda MN, Oram JF, Heinecke JW. Myeloperoxidase: An inflammatory enzyme for generating dysfunctional high density lipoprotein. Current Opinion in Cardiology. 2006;**21**:322-328. DOI: 10.1097/01. hco.0000231402.87232.aa

[28] Liang K, Vaziri ND. Upregulation of acyl-CoA: Cholesterol acyltransferase in chronic renal failure. American Journal of Physiology. Endocrinology and Metabolism. 2002;**283**:676-681. DOI: 10.1152/ajpendo.00364.2001

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[37] Yamamoto S, Yancey PG, Ikizler TA, Jerome WG, Kaseda R, Cox B, et al. Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. Journal of the American College of Cardiology. 2012;**60**:2372-2379. DOI:

[38] Kimura T, Sato K, Malchinkhuu E, Tomura H, Tamama K, Kuwabara A, et al. High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors. Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;**23**:1283-1288. DOI: 10.1161/01.

10.1016/j.jacc.2012.09.013

ATV.0000079011.67194.5A

2007;**18**:1246-1261

[39] Kwan BCH, Kronenberg F, Beddhu S, Cheung AK. Lipoprotein metabolism and lipid management in chronic kidney disease. Journal of the American Society of Nephrology.

[40] Shurraw S, Tonelli M. Statins for treatment of dyslipidemia in chronic kidney disease. Peritoneal Dialysis International. 2006;**26**:523-539

[41] Piecha G, Adamczak M, Ritz E. Dyslipidemia in chronic kidney disease.

[42] Levitan I, Volkov S. Oxidized LDL: Diversity, patterns of recognition, and pathophysiology. Antioxidants and Redox Signaling. 2010;**13**:39-75. DOI:

Polskie Archiwum Medycyny Wewnętrznej. 2009;**119**:487-492

[43] Takenaka T, Takahashi K, Kobayashi T, Oshima E, Iwasaki S, Suzuki H. Oxidized low density lipoprotein (ox-LDL) as a marker of atherosclerosis in hemodialysis (HD) patients. Clinical Nephrology.

2002;**58**:33-37. DOI: 10.5414/

CNP58033

10.1089/ars.2009.2733

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[30] Shoji T, Nishizawa Y, Nishitani H, Yamakawa M. Impaired metabolism of high density lipoprotein in uremic patients. Kidney International. 1992;**41**:1653-1661. DOI: 10.1038/

[31] Vaziri ND, Liang K, Parks JS. Down-

regulation of hepatic lecithin: Cholesterol acyltransferase gene expression in chronic renal failure. Kidney International. 2001;**59**:2192-2196. DOI:

10.1046/j.1523-1755.2001.00734.x

ajprenal.00099.2005

2012;**4**:523-532

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Dysfunctional high-density lipoproteins

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#### *Lipid Disorders in Uremia DOI: http://dx.doi.org/10.5772/intechopen.90043*

*Cellular Metabolism and Related Disorders*

chronic kidney disease an approach to pathogenesis and treatment. American Journal of Nephrology. 2008;**28**:958-973 [21] Kim C, Vaziri ND. Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure. Kidney International. 2005;**67**:1028-1032. DOI: 10.1111/j.1523-1755.2005.00166.x

[23] Sato T, Liang K, Vaziri ND. Downregulation of lipoprotein lipase and VLDL receptor in rats with focal glomerulosclerosis. Kidney International. 2002;**64**:1780-1786. DOI: 10.1046/j.1523-1755.2003.00281.x

[24] Tsimihodimos V, Mitrogianni Z, Elisaf M. Dyslipidemia associated with chronic kidney disease. Open Cardiovascular Medicine Journal.

[25] Attman PO, Samuelsson O, Alaupovic P. Lipoprotein metabolism and renal failure. American Journal of Kidney Diseases. 1993;**21**:573-592

[26] Vaziri ND, Deng G, Liang K. Hepatic HDL receptor, SR-B1 and Apo A-I expression in chronic renal failure. Nephrology, Dialysis, Transplantation.

[27] Shao B, Oda MN, Oram JF, Heinecke JW. Myeloperoxidase: An inflammatory enzyme for generating dysfunctional high density lipoprotein.

Current Opinion in Cardiology. 2006;**21**:322-328. DOI: 10.1097/01.

[28] Liang K, Vaziri ND. Upregulation of acyl-CoA: Cholesterol acyltransferase in chronic renal failure. American Journal of Physiology. Endocrinology and Metabolism. 2002;**283**:676-681. DOI:

hco.0000231402.87232.aa

10.1152/ajpendo.00364.2001

2011;**5**:41-48

1999;**14**:1462-1466

[22] Hirowatari Y, Homma Y, Yoshizawa J, Homma K. Increase of electronegative-LDL-fraction ratio and IDL-cholesterol in chronic kidney disease patients with hemodialysis treatment. Lipids in Health and Disease. 2012;**11**(1). DOI: 10.1186/1476-511X-11-111

[14] Sechi LA, Catena C, Zingaro L, Melis A, De Marchi S. Abnormalities of glucose metabolism in patients with early renal failure. Diabetes.

[15] Okubo M, Hanada H, Matsui M, Hidaka Y, Masuda D, Sakata Y, et al. Serum apolipoprotein B-48 concentration is associated with a reduced estimated glomerular filtration rate and increased proteinuria. Journal of Atherosclerosis and Thrombosis. 2014;**21**:974-982. DOI:

2002;**51**:1226-1232

10.5551/jat.23309

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10.1007/s10157-011-0549-3

1996;**50**:1928-1935

[17] Vaziri ND, Liang K. Downregulation of tissue lipoprotein lipase expression in experimental chronic renal failure. Kidney International.

[18] Sato T, Liang K, Vaziri ND. Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in focal glomerulosclerosis. Kidney International. 2003;**64**:1780-1786. DOI: 10.1046/j.1523-1755.2003.00281.x

[19] Chan DT, Dogra GK, Irish AB, et al. Chronic kidney disease delays VLDL apoB-100 particle catabolism: Potential role of apo C-III. Journal of Lipid Research. 2009;**50**:2524-2531

[20] Moradi H, Pahl MV, Elahimehr R, Vaziri ND. Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Translational Research.

2009;**153**:77-85. DOI: 10.1016/j.

Nicholas SB, Norris KC. Lipoprotein lipase deficiency in chronic kidney disease is accompanied by downregulation of endothelial GPIHBP1 expression. Clinical and Experimental Nephrology. 2012;**16**:238-243. DOI:

**160**

trsl.2008.11.007

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[31] Vaziri ND, Liang K, Parks JS. Downregulation of hepatic lecithin: Cholesterol acyltransferase gene expression in chronic renal failure. Kidney International. 2001;**59**:2192-2196. DOI: 10.1046/j.1523-1755.2001.00734.x

[32] Vaziri ND. Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences. American Journal Of Physiology. Renal Physiology. 2006;**290**(2):F262-F272. DOI: 10.1152/ ajprenal.00099.2005

[33] Litvinov D, Mahini H, Garelnabi M. Antioxidant and anti-inflammatory role of paraoxonase 1: Implication in arteriosclerosis diseases. North American Journal of Medical Sciences. 2012;**4**:523-532

[34] Maddipati KR, Marnett LJ. Characterization of the major hydroperoxide-reducing activity of human plasma. Purification and properties of a seleniumdependent glutathione peroxidase. The Journal of Biological Chemistry. 1987;**262**(36):17398-17403

[35] Shroff R, Speer T, Colin S, Charakida M, Zewinger S, Staels B, et al. HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype. Journal of the American Society of Nephrology. 2014;**25**:2658-2668. DOI: 10.1681/ ASN.2013111212

[36] Kaseda R, Jabs K, Hunley TE, Jones D, Bian A, Allen RM, et al. Dysfunctional high-density lipoproteins in children with chronic kidney disease. Metabolism. 2015;**64**:263-273. DOI: 10.1016/j.metabol.2014.10.020

[37] Yamamoto S, Yancey PG, Ikizler TA, Jerome WG, Kaseda R, Cox B, et al. Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. Journal of the American College of Cardiology. 2012;**60**:2372-2379. DOI: 10.1016/j.jacc.2012.09.013

[38] Kimura T, Sato K, Malchinkhuu E, Tomura H, Tamama K, Kuwabara A, et al. High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors. Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;**23**:1283-1288. DOI: 10.1161/01. ATV.0000079011.67194.5A

[39] Kwan BCH, Kronenberg F, Beddhu S, Cheung AK. Lipoprotein metabolism and lipid management in chronic kidney disease. Journal of the American Society of Nephrology. 2007;**18**:1246-1261

[40] Shurraw S, Tonelli M. Statins for treatment of dyslipidemia in chronic kidney disease. Peritoneal Dialysis International. 2006;**26**:523-539

[41] Piecha G, Adamczak M, Ritz E. Dyslipidemia in chronic kidney disease. Polskie Archiwum Medycyny Wewnętrznej. 2009;**119**:487-492

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[43] Takenaka T, Takahashi K, Kobayashi T, Oshima E, Iwasaki S, Suzuki H. Oxidized low density lipoprotein (ox-LDL) as a marker of atherosclerosis in hemodialysis (HD) patients. Clinical Nephrology. 2002;**58**:33-37. DOI: 10.5414/ CNP58033

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10.1681/ASN.2010040365

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10.1053/j.jrn.2011.10.023

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10.1042/CS20130369

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Hofbauer R, Hartmann B, Kapiotis S, Gmeiner B. Thiocyanate catalyzes myeloperoxidase-initiated lipid oxidation in LDL. Free Radical Biology and Medicine. 2004;**37**:146-155. DOI: 10.1016/j.freeradbiomed.2004.04.039

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Section 7

Glycogen Storage Disease

Section 7
