**Pediatric Nonalcoholic Fatty Liver Disease**

Ebe D'Adamo, M. Loredana Marcovecchio, Tommaso de Giorgis, Valentina Chiavaroli, Cosimo Giannini, Francesco Chiarelli and Angelika Mohn

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53463

## **1. Introduction**

[159] E Andreotti FE, Sestito A, Riccardi P, Menini E, Crea F, Maseri A, Lanza GA. Mark‐ edly reduced insulin-like growth factor-1 associated with insulin resistance in syn‐

[160] Heald AH, Siddals KW, Fraser W, Taylor W, Kaushal K, Morris J, Young RJ, White A, Gibson JM. Low circulating levels of insulin-like growth factor binding protein-1 are closely associated with the presence of macrovascular disease and hypertension

drome X patients. American Journal of Cardiology 2002; 89:973–975

in type 2 diabetes. Diabetes 2002 Aug;51(8):2629-36.

220 Hot Topics in Endocrine and Endocrine-Related Diseases

Paralleling the burgeoning epidemics of childhood obesity, nonalcoholic fatty liver dis‐ ease (NAFLD) is now recognized as the most common cause of chronic liver disease in children [1,2].

NAFLD is a clinic-pathological condition defined by the accumulation of intrahepatic trigly‐ ceride fat (IHTF) content in the absence of alcohol consumption [1,2].

NAFLD encompasses a wide spectrum of liver damage, ranging from asymptomatic steato‐ sis with elevated or normal aminotransferases to steatosis with inflammation, ballooning de‐ generation and pericellular fibrosis (Nonalcoholic Steatohepatitis, NASH) to cirrhosis [2,3].

Although there are limited long-term data on the natural history of NAFLD in children, NASH is increasingly diagnosed in obese children [4] and it may progress to cirrhosis even in this age group [2,5]. In addition, children with NAFLD have a 13.6-fold higher risk of mortality or requiring a liver transplant as compared to age/sex matched controls [6].

During the last years there has been a growing interest in the relationship between NAFLD and the development of metabolic and cardiovascular diseases [7-9].

Several lines of evidence have shown that in obese children and adolescents excessive accumulation of IHTF is associated with important alterations in glucose, fatty acid (FA), lipoprotein metabolism and inflammation, suggesting that IHTF represents a strong risk factor for the development of the Metabolic Syndrome (MetS) and type 2 diabetes melli‐ tus (T2D) [7-10].

Although a multifactorial pathogenesis of NAFLD has been postulated [12-14], obesity and insulin resistance represent two important players in the development of the early stages of the disease [2,14]. Interestingly, although the insulin resistance state could explain the rela‐ tionship between NAFLD and the development of metabolic alterations [10,15], the presence of liver steatosis is also an important marker of multiorgan insulin resistance [16], opening a debate as to whether hepatic steatosis is a consequence or cause of insulin resistance.

transferase values [26]. Moreover, studies from autopsies of 742 children (ages 2–19 years) reported fatty liver prevalence at 9.6%, and in obese children this rate increased to an alarm‐

Pediatric Nonalcoholic Fatty Liver Disease http://dx.doi.org/10.5772/53463 223

NAFLD has been also described in obese prepubertal children. In the study by Manco et al.

The prevalence of NAFLD is around 30% in children with a Tanner pubertal stage I, signifi‐

Alarming data come from our study population of prepubertal Caucasian obese children [29]. Out of 100 severely obese prepubertal children, liver steatosis was found in 52% and

Although the pathogenetic mechanism of NAFLD is not completely understood, in accord‐ ance with the "two hit hypothesis", insulin resistance and oxidative stress represent two key

The "two-hit" model proposes that fat accumulation in the hepatocytes is a prerequisite for

Fat accumulation in the liver is likely to result from insulin resistance and concomitant im‐ pairment of fatty acid (FA) metabolism within liver, skeletal muscle and adipose tissue [31].

Insulin resistance seems to be responsible for abnormalities in lipid storage and lipolysis in insulin-sensitive tissues, leading to an increased fatty acids flux from adipose tissue to the liver and subsequent accumulation of triglycerides in the hepatocytes [31]. In particular, steatosis develops when the rate of FA input (uptake and synthesis with subsequent esterifi‐ cation to triglycerides (TG)) is greater than the rate of FA output (oxidation and secretion) [11]. The amount of TG in the hepatocytes represents a complex interaction among [11,31]: hepatic FA uptake, derived from plasma free fatty acid (FFA) released from hydrolysis of adipose tissue and FFA released from hydrolysis of circulating TG; de novo FA synthesis (de novo lipogenesis [DNL]); fatty acid oxidation (FAO); FA export within very low-density

Obesity is the most important cause in the development of insulin resistance and it has been demonstrated that the critical determinant of insulin sensitivity is not the degree of obesity

[27] NAFLD was detected in children as young as 3 years old.

was equally distributed between the two sexes [29].

**3. Pathogenesis and risk factors of NAFLD**

a second hit that induces fibrosis and inflammation [30].

*per se* but the distribution of fat partitioning [32,33].

**3.1. Insulin resistance and central obesity**

lipoprotein (VLDL)-TG.

cantly lower when compared to that found in the pubertal age [28].

Thus, NAFLD in an emerging health problem even in very young age groups.

factors for the development and progression of NAFLD/NASH [12,17,20].

ing 38% [25].

Therefore, it would be of paramount importance to identify children affected by NAFLD and to better understand the pathogenesis of this condition in order to prevent the develop‐ ment of the associated metabolic complications early in life.

## **2. Definition and prevalence of NAFLD**

Despite fatty liver is becoming one of the most common hepatic alterations in obese children [1,2], the prevalence of pediatric NAFLD is uncertain, mainly due to the methods used to assess fatty liver.

NAFLD is defined as an IHTF content > 5% of liver volume or weight and as a presence ≥5% of hepatocytes containing intracellular triglycerides, in the absence of alcohol con‐ sumption [17,18].

The gold standard for diagnosing NAFLD is liver biopsy [19,20]. Liver biopsy allows an ac‐ curate assessment of histopatological findings, providing information on the type of NAFLD (simple steatosis or steatohepatitis) and the various degrees of hepatic fibrosis [20]. Howev‐ er, the main limitation of the application of liver biopsy in the pediatric age group is due to the fact that it is an invasive procedure; thus, it is not considered as first line to screen the presence of liver disease [19,20].

Although non-invasive methods, such as computer tomography, MRI, or ultrasonography are unable to distinguish between NASH and other forms of NAFLD [19,21], they have an acceptable sensitivity and specificity for the diagnosis of increased fat accumulation in the liver [21]. Furthermore, ultrasound has been shown to have a good correlation with the his‐ tological findings of liver biopsy, particularly macrovescicular steatosis [22].

In clinical practice, combining liver function tests, such as serum aminotransferases [18], with liver ultrasound represents a useful way of identifying the presence of liver steatosis in obese children.

In spite of the method used, it is clear that the prevalence of NAFDL is increasing in chil‐ dren and adolescence. NAFLD affects 2.6% of normal children [23] and up to 77% of obese individuals [24,25]. Pediatric NAFLD extends beyond North America according to centers in Europe, Asia, South America and Australia [2,3]. The prevalence of fatty liver in obese chil‐ dren in China, Italy, Japan, and the United States has been reported to be between 10% and 77% [2,3]. Data derived from the National Health and Nutrition Examination Survey III (1988-1994) suggest that approximately 3% of adolescents present abnormal serum amino‐ transferase values [26]. Moreover, studies from autopsies of 742 children (ages 2–19 years) reported fatty liver prevalence at 9.6%, and in obese children this rate increased to an alarm‐ ing 38% [25].

NAFLD has been also described in obese prepubertal children. In the study by Manco et al. [27] NAFLD was detected in children as young as 3 years old.

The prevalence of NAFLD is around 30% in children with a Tanner pubertal stage I, signifi‐ cantly lower when compared to that found in the pubertal age [28].

Alarming data come from our study population of prepubertal Caucasian obese children [29]. Out of 100 severely obese prepubertal children, liver steatosis was found in 52% and was equally distributed between the two sexes [29].

Thus, NAFLD in an emerging health problem even in very young age groups.

## **3. Pathogenesis and risk factors of NAFLD**

Although the pathogenetic mechanism of NAFLD is not completely understood, in accord‐ ance with the "two hit hypothesis", insulin resistance and oxidative stress represent two key factors for the development and progression of NAFLD/NASH [12,17,20].

#### **3.1. Insulin resistance and central obesity**

Although a multifactorial pathogenesis of NAFLD has been postulated [12-14], obesity and insulin resistance represent two important players in the development of the early stages of the disease [2,14]. Interestingly, although the insulin resistance state could explain the rela‐ tionship between NAFLD and the development of metabolic alterations [10,15], the presence of liver steatosis is also an important marker of multiorgan insulin resistance [16], opening a

Therefore, it would be of paramount importance to identify children affected by NAFLD and to better understand the pathogenesis of this condition in order to prevent the develop‐

Despite fatty liver is becoming one of the most common hepatic alterations in obese children [1,2], the prevalence of pediatric NAFLD is uncertain, mainly due to the methods used to

NAFLD is defined as an IHTF content > 5% of liver volume or weight and as a presence ≥5% of hepatocytes containing intracellular triglycerides, in the absence of alcohol con‐

The gold standard for diagnosing NAFLD is liver biopsy [19,20]. Liver biopsy allows an ac‐ curate assessment of histopatological findings, providing information on the type of NAFLD (simple steatosis or steatohepatitis) and the various degrees of hepatic fibrosis [20]. Howev‐ er, the main limitation of the application of liver biopsy in the pediatric age group is due to the fact that it is an invasive procedure; thus, it is not considered as first line to screen the

Although non-invasive methods, such as computer tomography, MRI, or ultrasonography are unable to distinguish between NASH and other forms of NAFLD [19,21], they have an acceptable sensitivity and specificity for the diagnosis of increased fat accumulation in the liver [21]. Furthermore, ultrasound has been shown to have a good correlation with the his‐

In clinical practice, combining liver function tests, such as serum aminotransferases [18], with liver ultrasound represents a useful way of identifying the presence of liver steatosis in

In spite of the method used, it is clear that the prevalence of NAFDL is increasing in chil‐ dren and adolescence. NAFLD affects 2.6% of normal children [23] and up to 77% of obese individuals [24,25]. Pediatric NAFLD extends beyond North America according to centers in Europe, Asia, South America and Australia [2,3]. The prevalence of fatty liver in obese chil‐ dren in China, Italy, Japan, and the United States has been reported to be between 10% and 77% [2,3]. Data derived from the National Health and Nutrition Examination Survey III (1988-1994) suggest that approximately 3% of adolescents present abnormal serum amino‐

tological findings of liver biopsy, particularly macrovescicular steatosis [22].

debate as to whether hepatic steatosis is a consequence or cause of insulin resistance.

ment of the associated metabolic complications early in life.

**2. Definition and prevalence of NAFLD**

222 Hot Topics in Endocrine and Endocrine-Related Diseases

assess fatty liver.

sumption [17,18].

obese children.

presence of liver disease [19,20].

The "two-hit" model proposes that fat accumulation in the hepatocytes is a prerequisite for a second hit that induces fibrosis and inflammation [30].

Fat accumulation in the liver is likely to result from insulin resistance and concomitant im‐ pairment of fatty acid (FA) metabolism within liver, skeletal muscle and adipose tissue [31].

Insulin resistance seems to be responsible for abnormalities in lipid storage and lipolysis in insulin-sensitive tissues, leading to an increased fatty acids flux from adipose tissue to the liver and subsequent accumulation of triglycerides in the hepatocytes [31]. In particular, steatosis develops when the rate of FA input (uptake and synthesis with subsequent esterifi‐ cation to triglycerides (TG)) is greater than the rate of FA output (oxidation and secretion) [11]. The amount of TG in the hepatocytes represents a complex interaction among [11,31]: hepatic FA uptake, derived from plasma free fatty acid (FFA) released from hydrolysis of adipose tissue and FFA released from hydrolysis of circulating TG; de novo FA synthesis (de novo lipogenesis [DNL]); fatty acid oxidation (FAO); FA export within very low-density lipoprotein (VLDL)-TG.

Obesity is the most important cause in the development of insulin resistance and it has been demonstrated that the critical determinant of insulin sensitivity is not the degree of obesity *per se* but the distribution of fat partitioning [32,33].

Several studies [32,33] have demonstrated that obese adolescents presenting increased intra‐ myocellular lipid content (IMCL) [32] and visceral fat and decreased subcutaneous fat depo‐ sition are more likely to develop insulin resistance.

visceral fat mass [11,15,36]. In particular, NAFLD has been found to be associated with insu‐ lin resistance in liver (impaired suppression of insulin-mediated glucose production) [39,40], skeletal muscle (reduced insulin stimulated glucose uptake) [40] and adipose tissue (de‐ crease inhibition of lipolysis by insulin) [41] in obese children and adolescents, independent‐

Pediatric Nonalcoholic Fatty Liver Disease http://dx.doi.org/10.5772/53463 225

Recently, Caprio et al. [16] reported that obese adolescents with high liver fat content, inde‐ pendent of visceral and IMCL had an impaired insulin action (as assessed by the hyperinsu‐ linemic-euglycemic clamp) in the liver and in the muscle and early defects in β-cell function [16]. These results suggest that the liver has a central role in the complex phenotype of the

Although it is clear that there is an important correlation between insulin resistance and hepatic steatosis, the mechanisms responsible for the interrelationships between fatty liver disease and insulin resistance are not clearly understood. In fact, it remains unclear whether hepatic steatosis is a consequence or the primary event leading to hepatic and subsequently

Petersen et al. [42] showed that the lack of adipose tissue in the congenital lipodystrophy is characterized by extreme insulin resistance associated with massive hepatic fat accumula‐ tion; intervention with subcutaneous leptin administration in these patients improved whole-body insulin sensitivity mainly due to the mobilization of the excessive fatty liver

Models of patients with liver cirrhosis in which hepatic dysfunction is known to be the pri‐ mary disturbance provide strong support that insulin resistance in peripheral tissues devel‐ ops secondary to liver disease [43]. 60-80% of patients with liver cirrhosis are glucose intolerant and in 10-15% diabetes occurs relatively rapidly (over a period of 5 years). Diabe‐ tes complicating liver cirrhosis, also known as hepatogenous diabetes, and the common form of T2D are the results of a marked reduction in insulin action and a β-cell secretion de‐ fect that is not able to compensate the severity of insulin resistance [43,44]. The important role of peripheral insulin resistance in the glucose tolerance of cirrhosis has been highlighted by the observation that liver transplantation, when the dosage of immunosuppressive agents was reduce and corticosteroids withdrawn, was able to restore normal insulin sensi‐ tivity not only in the liver but also at the level of the skeletal muscle and adipose tissue and

The mechanism by which IHTF has an important systemic consequence to adversely affect insulin sensitivity is unknown. However, it has been proposed that fatty liver might inter‐ fere with insulin degradation [45]; the resultant hyperinsulinemia may potentially be able to impair insulin action in peripheral tissues, as shown in benign insulinoma induced hyperin‐ sulinemia [43,44,46]. This hyperinsulinemia-induced mechanism may be justified also based on the finding of the reverse experiment: when the prolonged infusion of octreotide was ad‐ ministered to extremely insulin-resistant cirrhotic individuals, the correlation of hyperinsuli‐

insulin resistance state in obese adolescents with fatty liver.

normalizes glucose tolerance in most patients with diabetes [43,44].

nemia was paralleled by the restoration of normal insulin sensitivity [43,47].

ly of adiposity.

peripheral insulin resistance.

content.

There is extensive evidence indicating that central obesity is associated with an impaired in‐ sulin action in obese pediatric populations. Although controversy remains regarding the contribution of visceral and subcutaneous fat to the development of insulin resistance [33], a previous study by Cruz et al. [35] showed a direct impact of visceral fat accumulation on insulin sensitivity and secretion, independently of total body adiposity, in obese children with a family history of T2D. Indeed, by stratifying a multiethnic cohort of obese adoles‐ cents into tertiles based on the proportion of visceral fat in the abdomen (visceral/subcutane‐ ous fat ratio), insulin resistance (homeostasis model assessment) significantly increased and insulin sensitivity (Matsuda index) decreased in obese adolescents with high proportion of visceral fat and relatively low abdominal subcutaneous fat [33].

These findings suggest that obese children and adolescents at risk for developing metabolic complications are not necessarily the most severely obese, but are characterized by an un‐ favorable lipid partitioning profile.

## **3.2. Insulin resistance and fatty liver disease: Which comes first?**

Despite the demonstrated relationship between IMCL, visceral fat and metabolic dysfunc‐ tion, the ectopic fat deposition in the liver is emerging as the most important marker of insu‐ lin resistance in adults [15] as well as in obese pediatric population [36].

In healthy nondiabetic humans the correlation between the IHTF content and peripheral in‐ sulin resistance was much stronger than the correlation with intramyocellular lipid content, visceral fat content or subcutaneous fat content [37]. The relationship between liver steatosis and insulin resistance has been clearly demonstrated in children [36,29]. In our cross section‐ al study, we evaluated insulin resistance indexes between obese prepubertal children with and without liver steatosis; furthermore insulin resistance indexes were compared to values of normal weight children. Our results showed that children with NAFLD not only present‐ ed severe obesity but also an increased degree of insulin resistance when compared to the sex- and age-matched normal weight children [29].

The relationship between insulin resistance and fatty liver disease is not only related to the presence of liver steatosis, but also to the degree of fatty liver. In a multiethnic cohort of obese adolescents, Calì et al. [36] clearly showed a significant decrease in insulin sensitivity and an imbalance between anti- and pro-inflammatory markers [adiponectin and interleu‐ kin 6 (IL-6)] paralleling the severity of hepatic steatosis [36]. In particular, adiponectin, the most abundant secretory protein produced by adipose tissue, is closely related with insulin action. Plasma adiponectin concentrations are inversely associated with hepatic steatosis and metabolic complications [37,38].

Although these findings support the central role of insulin resistance in the development of fatty liver, several studies have demonstrated that the presence of liver steatosis is an impor‐ tant marker of multiorgan insulin resistance, independently of BMI, percent body fat, and visceral fat mass [11,15,36]. In particular, NAFLD has been found to be associated with insu‐ lin resistance in liver (impaired suppression of insulin-mediated glucose production) [39,40], skeletal muscle (reduced insulin stimulated glucose uptake) [40] and adipose tissue (de‐ crease inhibition of lipolysis by insulin) [41] in obese children and adolescents, independent‐ ly of adiposity.

Several studies [32,33] have demonstrated that obese adolescents presenting increased intra‐ myocellular lipid content (IMCL) [32] and visceral fat and decreased subcutaneous fat depo‐

There is extensive evidence indicating that central obesity is associated with an impaired in‐ sulin action in obese pediatric populations. Although controversy remains regarding the contribution of visceral and subcutaneous fat to the development of insulin resistance [33], a previous study by Cruz et al. [35] showed a direct impact of visceral fat accumulation on insulin sensitivity and secretion, independently of total body adiposity, in obese children with a family history of T2D. Indeed, by stratifying a multiethnic cohort of obese adoles‐ cents into tertiles based on the proportion of visceral fat in the abdomen (visceral/subcutane‐ ous fat ratio), insulin resistance (homeostasis model assessment) significantly increased and insulin sensitivity (Matsuda index) decreased in obese adolescents with high proportion of

These findings suggest that obese children and adolescents at risk for developing metabolic complications are not necessarily the most severely obese, but are characterized by an un‐

Despite the demonstrated relationship between IMCL, visceral fat and metabolic dysfunc‐ tion, the ectopic fat deposition in the liver is emerging as the most important marker of insu‐

In healthy nondiabetic humans the correlation between the IHTF content and peripheral in‐ sulin resistance was much stronger than the correlation with intramyocellular lipid content, visceral fat content or subcutaneous fat content [37]. The relationship between liver steatosis and insulin resistance has been clearly demonstrated in children [36,29]. In our cross section‐ al study, we evaluated insulin resistance indexes between obese prepubertal children with and without liver steatosis; furthermore insulin resistance indexes were compared to values of normal weight children. Our results showed that children with NAFLD not only present‐ ed severe obesity but also an increased degree of insulin resistance when compared to the

The relationship between insulin resistance and fatty liver disease is not only related to the presence of liver steatosis, but also to the degree of fatty liver. In a multiethnic cohort of obese adolescents, Calì et al. [36] clearly showed a significant decrease in insulin sensitivity and an imbalance between anti- and pro-inflammatory markers [adiponectin and interleu‐ kin 6 (IL-6)] paralleling the severity of hepatic steatosis [36]. In particular, adiponectin, the most abundant secretory protein produced by adipose tissue, is closely related with insulin action. Plasma adiponectin concentrations are inversely associated with hepatic steatosis

Although these findings support the central role of insulin resistance in the development of fatty liver, several studies have demonstrated that the presence of liver steatosis is an impor‐ tant marker of multiorgan insulin resistance, independently of BMI, percent body fat, and

sition are more likely to develop insulin resistance.

224 Hot Topics in Endocrine and Endocrine-Related Diseases

visceral fat and relatively low abdominal subcutaneous fat [33].

**3.2. Insulin resistance and fatty liver disease: Which comes first?**

sex- and age-matched normal weight children [29].

and metabolic complications [37,38].

lin resistance in adults [15] as well as in obese pediatric population [36].

favorable lipid partitioning profile.

Recently, Caprio et al. [16] reported that obese adolescents with high liver fat content, inde‐ pendent of visceral and IMCL had an impaired insulin action (as assessed by the hyperinsu‐ linemic-euglycemic clamp) in the liver and in the muscle and early defects in β-cell function [16]. These results suggest that the liver has a central role in the complex phenotype of the insulin resistance state in obese adolescents with fatty liver.

Although it is clear that there is an important correlation between insulin resistance and hepatic steatosis, the mechanisms responsible for the interrelationships between fatty liver disease and insulin resistance are not clearly understood. In fact, it remains unclear whether hepatic steatosis is a consequence or the primary event leading to hepatic and subsequently peripheral insulin resistance.

Petersen et al. [42] showed that the lack of adipose tissue in the congenital lipodystrophy is characterized by extreme insulin resistance associated with massive hepatic fat accumula‐ tion; intervention with subcutaneous leptin administration in these patients improved whole-body insulin sensitivity mainly due to the mobilization of the excessive fatty liver content.

Models of patients with liver cirrhosis in which hepatic dysfunction is known to be the pri‐ mary disturbance provide strong support that insulin resistance in peripheral tissues devel‐ ops secondary to liver disease [43]. 60-80% of patients with liver cirrhosis are glucose intolerant and in 10-15% diabetes occurs relatively rapidly (over a period of 5 years). Diabe‐ tes complicating liver cirrhosis, also known as hepatogenous diabetes, and the common form of T2D are the results of a marked reduction in insulin action and a β-cell secretion de‐ fect that is not able to compensate the severity of insulin resistance [43,44]. The important role of peripheral insulin resistance in the glucose tolerance of cirrhosis has been highlighted by the observation that liver transplantation, when the dosage of immunosuppressive agents was reduce and corticosteroids withdrawn, was able to restore normal insulin sensi‐ tivity not only in the liver but also at the level of the skeletal muscle and adipose tissue and normalizes glucose tolerance in most patients with diabetes [43,44].

The mechanism by which IHTF has an important systemic consequence to adversely affect insulin sensitivity is unknown. However, it has been proposed that fatty liver might inter‐ fere with insulin degradation [45]; the resultant hyperinsulinemia may potentially be able to impair insulin action in peripheral tissues, as shown in benign insulinoma induced hyperin‐ sulinemia [43,44,46]. This hyperinsulinemia-induced mechanism may be justified also based on the finding of the reverse experiment: when the prolonged infusion of octreotide was ad‐ ministered to extremely insulin-resistant cirrhotic individuals, the correlation of hyperinsuli‐ nemia was paralleled by the restoration of normal insulin sensitivity [43,47].

Although these data showed a clear possibility that intrahepatic fat accumulation plays a key role in the onset of insulin resistance and insulin resistance syndrome, longitudinal data are needed in order to clarify which abnormality comes first.

These findings have been recently supported by Santoro et al. [53]. By genotyping the *PNLPA3* SNP in a multiethnic group of 85 obese youths, the authors found that the *PNPLA3*

Pediatric Nonalcoholic Fatty Liver Disease http://dx.doi.org/10.5772/53463 227

Nutrition and physical activity are important *environmental factors* that determine risk in

Excess food intake and lack of exercise contribute to weight gain, which has been shown to contribute to the progression of liver fibrosis in patients with NAFLD [54]. Specific dietary factors may also play either protective or antagonistic roles in the development and progres‐ sion of NAFLD. An increased consumption of meat and soft drinks and low consumption of fish were found to be associated with NAFLD cases compared with controls [49]. Further‐ more, low intakes of polyunsaturated fatty acid (PUFA) and high intakes of saturated fat and cholesterol were also shown to be associated with NAFLD [49]. Other studies have shown higher-carbohydrate and lower-fat diets to be associated with more progressive dis‐ ease [49,55]. Notably, very recent animal data have shown that in both mice [49,56] and nonhuman primates [49] exposure to a maternal high-fat diet leads to a disturbing development

It has been proposed that increase consumption of fructose in soft drinks and fruit drinks may have a role in the pathogenesis of NAFLD [2]. In one study, children with biopsy-pro‐ ven NAFLD were shown to have significantly elevated plasma TG levels and oxidative stress levels after consumption of fructose as compared with glucose [57]. However, chil‐ dren without NAFLD were found to have no differences in TG or oxidative stress levels fol‐

Small intestinal bacterial overgrowth may be an additional environmental factor in‐ volved in NAFLD pathogenesis, and dietary supplements such as probiotics could have a beneficial effect [49]. Evidences from animal studies have shown that small intestinal bacterial overgrowth increases gut permeability leading to portal endotoxaemia and in‐ creased circulating inflammatory cytokines, both of which have been implicated in the

**4. NAFLD, metabolic and cardiovascular complications in obese children**

NAFLD is nowadays considered the hepatic manifestation of the MetS in adults as well as in children [60]. This is not surprising since NAFLD is closely associated with obesity, insulin

The association between NAFLD and MetS has been clearly demonstrated by Burgert et al. [61,62]. In 392 obese adolescents, elevated alanine aminotransferases (ALT) (>35 U/L) levels were found in 14% of participants, with a predominance of White/Hispanic. After adjusting

rs738409 SNP gene confers susceptibility to hepatic steatosis.

and progression of NAFLD in the offspring.

progression of NAFLD [58,59].

**4.1. NAFLD and metabolic complications**

**and adolescents**

lowing the consumption of glucose compared with fructose [2].

resistance, and alterations in glucose and lipid metabolism [44].

NAFLD.

#### **3.3. Oxidative stress**

In accordance with the "two hit hypothesis", dysfunction of various oxidation pathways within the hepatocytes and subsequent overproduction of reactive oxygen species (ROS), may result in the peroxidation of accumulated lipids, inflammation, hepatocellular apopto‐ sis and fibrogenesis [31].

Obese subjects affected by NAFLD present an impaired oxidant-antioxidant status than sub‐ jects without [12,48].

Interestingly, we recently observed [48] that obese prepubertal children affected by liver steatosis had impaired levels of receptors for advanced glycation endproducts (RAGEs), which has been demonstrated to be correlated with the progression of several metabolic and cardiovascular diseases. In particular, obese prepubertal children with liver steatosis pre‐ sented decreased RAGEs levels compared with children without liver disease, underling that oxidative stress could play a role even in the early stages of the disease [48].

#### **3.4. Genetic and environmental factors associated with fatty liver disease**

Several genetic and environmental factors are likely responsible for NAFLD and its progres‐ sion from simple steatosis to NASH.

In fact, although the development of NAFLD is strongly linked to obesity and insulin resist‐ ance, there are obese individuals who do not have NAFLD, and since NAFLD can occur in normal-weight individuals with normal metabolic profile, thus multiple genetic and envi‐ ronmental factors should be involved in its development [49].

Initial evidence for a *genetic component* of NAFLD comes from ethnic variation in NAFLD prevalence [50]. Children from certain ethnicities are predisposed to NAFLD, primarily His‐ panics, Asians and Native Americans [25,50].

Furthermore, a familial aggregation study of fatty liver in overweight children with and without NAFLD found that fatty liver is a highly heritable trait. Family members of children with biopsy-proven NAFLD and overweight children without NAFLD were evaluated by magnetic resonance imaging (MRI). Fatty liver was identified in 17% of siblings and 37% of parents of overweight children without NAFLD and in 59% of siblings and 78% of parents of children with NAFLD [51].

Interestingly, Romeo et al. [52] conducted the first genome-wide association scan conducted in a large multiethnic population. The authors demonstrated that the patatin-like phospholi‐ pase domain containing protein 3 (also known as adiponutrin) gene was strongly associated with IHTF content in adults [52].

These findings have been recently supported by Santoro et al. [53]. By genotyping the *PNLPA3* SNP in a multiethnic group of 85 obese youths, the authors found that the *PNPLA3* rs738409 SNP gene confers susceptibility to hepatic steatosis.

Nutrition and physical activity are important *environmental factors* that determine risk in NAFLD.

Excess food intake and lack of exercise contribute to weight gain, which has been shown to contribute to the progression of liver fibrosis in patients with NAFLD [54]. Specific dietary factors may also play either protective or antagonistic roles in the development and progres‐ sion of NAFLD. An increased consumption of meat and soft drinks and low consumption of fish were found to be associated with NAFLD cases compared with controls [49]. Further‐ more, low intakes of polyunsaturated fatty acid (PUFA) and high intakes of saturated fat and cholesterol were also shown to be associated with NAFLD [49]. Other studies have shown higher-carbohydrate and lower-fat diets to be associated with more progressive dis‐ ease [49,55]. Notably, very recent animal data have shown that in both mice [49,56] and nonhuman primates [49] exposure to a maternal high-fat diet leads to a disturbing development and progression of NAFLD in the offspring.

It has been proposed that increase consumption of fructose in soft drinks and fruit drinks may have a role in the pathogenesis of NAFLD [2]. In one study, children with biopsy-pro‐ ven NAFLD were shown to have significantly elevated plasma TG levels and oxidative stress levels after consumption of fructose as compared with glucose [57]. However, chil‐ dren without NAFLD were found to have no differences in TG or oxidative stress levels fol‐ lowing the consumption of glucose compared with fructose [2].

Small intestinal bacterial overgrowth may be an additional environmental factor in‐ volved in NAFLD pathogenesis, and dietary supplements such as probiotics could have a beneficial effect [49]. Evidences from animal studies have shown that small intestinal bacterial overgrowth increases gut permeability leading to portal endotoxaemia and in‐ creased circulating inflammatory cytokines, both of which have been implicated in the progression of NAFLD [58,59].

## **4. NAFLD, metabolic and cardiovascular complications in obese children and adolescents**

#### **4.1. NAFLD and metabolic complications**

Although these data showed a clear possibility that intrahepatic fat accumulation plays a key role in the onset of insulin resistance and insulin resistance syndrome, longitudinal data

In accordance with the "two hit hypothesis", dysfunction of various oxidation pathways within the hepatocytes and subsequent overproduction of reactive oxygen species (ROS), may result in the peroxidation of accumulated lipids, inflammation, hepatocellular apopto‐

Obese subjects affected by NAFLD present an impaired oxidant-antioxidant status than sub‐

Interestingly, we recently observed [48] that obese prepubertal children affected by liver steatosis had impaired levels of receptors for advanced glycation endproducts (RAGEs), which has been demonstrated to be correlated with the progression of several metabolic and cardiovascular diseases. In particular, obese prepubertal children with liver steatosis pre‐ sented decreased RAGEs levels compared with children without liver disease, underling

Several genetic and environmental factors are likely responsible for NAFLD and its progres‐

In fact, although the development of NAFLD is strongly linked to obesity and insulin resist‐ ance, there are obese individuals who do not have NAFLD, and since NAFLD can occur in normal-weight individuals with normal metabolic profile, thus multiple genetic and envi‐

Initial evidence for a *genetic component* of NAFLD comes from ethnic variation in NAFLD prevalence [50]. Children from certain ethnicities are predisposed to NAFLD, primarily His‐

Furthermore, a familial aggregation study of fatty liver in overweight children with and without NAFLD found that fatty liver is a highly heritable trait. Family members of children with biopsy-proven NAFLD and overweight children without NAFLD were evaluated by magnetic resonance imaging (MRI). Fatty liver was identified in 17% of siblings and 37% of parents of overweight children without NAFLD and in 59% of siblings and 78% of parents

Interestingly, Romeo et al. [52] conducted the first genome-wide association scan conducted in a large multiethnic population. The authors demonstrated that the patatin-like phospholi‐ pase domain containing protein 3 (also known as adiponutrin) gene was strongly associated

that oxidative stress could play a role even in the early stages of the disease [48].

**3.4. Genetic and environmental factors associated with fatty liver disease**

ronmental factors should be involved in its development [49].

are needed in order to clarify which abnormality comes first.

**3.3. Oxidative stress**

226 Hot Topics in Endocrine and Endocrine-Related Diseases

sis and fibrogenesis [31].

sion from simple steatosis to NASH.

panics, Asians and Native Americans [25,50].

of children with NAFLD [51].

with IHTF content in adults [52].

jects without [12,48].

NAFLD is nowadays considered the hepatic manifestation of the MetS in adults as well as in children [60]. This is not surprising since NAFLD is closely associated with obesity, insulin resistance, and alterations in glucose and lipid metabolism [44].

The association between NAFLD and MetS has been clearly demonstrated by Burgert et al. [61,62]. In 392 obese adolescents, elevated alanine aminotransferases (ALT) (>35 U/L) levels were found in 14% of participants, with a predominance of White/Hispanic. After adjusting for potential confounders, rising ALT levels were associated with deterioration in insulin sensitivity and glucose tolerance, as well as increasing FFA and TG levels. Furthermore, in‐ creased hepatic fat accumulation was found in 32% of obese adolescents and was associated with decreased insulin sensitivity and increased lipid levels and visceral fat [61]. These re‐ sults demonstrate that in obese children and adolescents, hepatic fat accumulation is associ‐ ated with insulin resistance, dyslipidemia and altered glucose metabolism.

NAFLD in youth may be considered not only a strong risk factor for MetS, but also for T2D [36]. In a cohort of 118 obese adolescents [36] stratifyied according to tertiles of hepatic fat content (as assessed by fat gradient MRI), independently of obesity, the severity of fatty liv‐ er was associated with the presence of prediabetes [impaired glucose tolerance (IGT) and impaired fasting glucose (IFG)/IGT]. In fact, paralleling the severity of hepatic steatosis, there was a significant decrease in insulin sensitivity and impairment in β-cell function, as indicated by the fall in the disposition index (DI). Furthermore, paralleling the severity of fatty liver, there was a significant increase in the prevalence of MetS, suggesting that hepatic

Pediatric Nonalcoholic Fatty Liver Disease http://dx.doi.org/10.5772/53463 229

The important role of intrahepatic fat content in the development of metabolic complications in obese subject has been recently underlined by Fabbrini et al. [15]. The authors showed that in adults with high IHTF insulin action in liver, skeletal muscle and adipose tissue was impaired and hepatic VLDL-TG secretion rate was increased. In contrast, they were not able to observe these metabolic alterations in subjects with high visceral fat volume and matched for IHTF. Therefore, the authors demonstrated that IHTF and not visceral fat is a better

Recent evidences suggests that individuals with NAFLD are also at high risk for coronary heart disease [3,43]. In adults, elevated serum ALT have been associated with increased risk

A study in Turkish children [66] showed that carotid artery intima-media thickness is signif‐ icantly higher in obese children with fatty liver than in obese children without fatty liver or

In addition, Pacifico et al. [67] reported that carotid artery intima-media thickness was high‐ est in obese children with echogenic liver and severity of liver fat was an independent pre‐

However, given the lack of long-term longitudinal cohort studies in pediatric fatty liver dis‐ ease, the relationship between the natural history of the disease and the actual risk for future

dictor of intima-media thickness after adjustment for known cardiovascular factors.

The prevalence of fatty liver disease is increasing in obese children and adolescence.

ing childhood and for exacerbated metabolic abnormalities later in life.

Although the exact pathogenetic mechanism is still unclear, there is an urgent need to screen obese children for this pathology. A misdiagnosis of fatty liver could represent a serious risk factor for the development of its associated metabolic and cardiovascular complications dur‐

of cardiovascular and all cause mortality (in addition to liver mortality) [3,65].

steatosis may probably be a predictive factor of MetS in children [36].

marker of metabolic derangements associated with obesity [15,16].

**4.2. NAFLD and cardiovascular disease**

normal weight control.

cardiac events is unclear.

**5. Conclusions**

In addition, the Korean National Health and Nutrition Examination Survey found partici‐ pants aged 10 – 19 years with three or more risk factors for MetS had an odds ratio that of 6.2 (95 % CI 2.3 – 16.8) for an elevated serum ALT, which they used as an indicator of fatty liver [62]. Furthermore, a case – control study of overweight children with biopsy-proven NAFLD and age-, sex-, and obesity-matched controls found that children with NAFLD were significantly more likely to have MetS than obese controls without evidence of fatty liver disease [9].

More recently, in a large histology-based study conducted in children with NAFLD [63], MetS was diagnosed in 25.6 % of the subjects, with central obesity and hypertension being the most common of the MetS features observed. In addition, a diagnosis of MetS was pre‐ dictive of steatosis severity, NASH, hepatocellular ballooning and NAFLD pattern [63].

In a recent study by our group [64], we assessed the role of liver steatosis in defining MetS in prepubertal children. The prevalence of the MetS was around 14% and increased to 20% when liver steatosis was included as an additional diagnostic criterion. These findings un‐ derline not only the relevance of the MetS even among prepubertal children but also empha‐ size the potential importance of testing for fatty liver as a component of the MetS already in this age group [64] (figure 1).

**Figure 1.** Prevalence of components of the MetS among obese prepubertal children [64].(TG, triglycerides; HDL-C, high density lipoprotein cholesterol; IGT, impaired glucose tolerance; NAFLD, non alcoholic fatty liver disease)

NAFLD in youth may be considered not only a strong risk factor for MetS, but also for T2D [36]. In a cohort of 118 obese adolescents [36] stratifyied according to tertiles of hepatic fat content (as assessed by fat gradient MRI), independently of obesity, the severity of fatty liv‐ er was associated with the presence of prediabetes [impaired glucose tolerance (IGT) and impaired fasting glucose (IFG)/IGT]. In fact, paralleling the severity of hepatic steatosis, there was a significant decrease in insulin sensitivity and impairment in β-cell function, as indicated by the fall in the disposition index (DI). Furthermore, paralleling the severity of fatty liver, there was a significant increase in the prevalence of MetS, suggesting that hepatic steatosis may probably be a predictive factor of MetS in children [36].

The important role of intrahepatic fat content in the development of metabolic complications in obese subject has been recently underlined by Fabbrini et al. [15]. The authors showed that in adults with high IHTF insulin action in liver, skeletal muscle and adipose tissue was impaired and hepatic VLDL-TG secretion rate was increased. In contrast, they were not able to observe these metabolic alterations in subjects with high visceral fat volume and matched for IHTF. Therefore, the authors demonstrated that IHTF and not visceral fat is a better marker of metabolic derangements associated with obesity [15,16].

#### **4.2. NAFLD and cardiovascular disease**

for potential confounders, rising ALT levels were associated with deterioration in insulin sensitivity and glucose tolerance, as well as increasing FFA and TG levels. Furthermore, in‐ creased hepatic fat accumulation was found in 32% of obese adolescents and was associated with decreased insulin sensitivity and increased lipid levels and visceral fat [61]. These re‐ sults demonstrate that in obese children and adolescents, hepatic fat accumulation is associ‐

In addition, the Korean National Health and Nutrition Examination Survey found partici‐ pants aged 10 – 19 years with three or more risk factors for MetS had an odds ratio that of 6.2 (95 % CI 2.3 – 16.8) for an elevated serum ALT, which they used as an indicator of fatty liver [62]. Furthermore, a case – control study of overweight children with biopsy-proven NAFLD and age-, sex-, and obesity-matched controls found that children with NAFLD were significantly more likely to have MetS than obese controls without evidence of fatty liver

More recently, in a large histology-based study conducted in children with NAFLD [63], MetS was diagnosed in 25.6 % of the subjects, with central obesity and hypertension being the most common of the MetS features observed. In addition, a diagnosis of MetS was pre‐ dictive of steatosis severity, NASH, hepatocellular ballooning and NAFLD pattern [63].

In a recent study by our group [64], we assessed the role of liver steatosis in defining MetS in prepubertal children. The prevalence of the MetS was around 14% and increased to 20% when liver steatosis was included as an additional diagnostic criterion. These findings un‐ derline not only the relevance of the MetS even among prepubertal children but also empha‐ size the potential importance of testing for fatty liver as a component of the MetS already in

**Figure 1.** Prevalence of components of the MetS among obese prepubertal children [64].(TG, triglycerides; HDL-C, high density lipoprotein cholesterol; IGT, impaired glucose tolerance; NAFLD, non alcoholic fatty liver disease)

ated with insulin resistance, dyslipidemia and altered glucose metabolism.

disease [9].

this age group [64] (figure 1).

228 Hot Topics in Endocrine and Endocrine-Related Diseases

Recent evidences suggests that individuals with NAFLD are also at high risk for coronary heart disease [3,43]. In adults, elevated serum ALT have been associated with increased risk of cardiovascular and all cause mortality (in addition to liver mortality) [3,65].

A study in Turkish children [66] showed that carotid artery intima-media thickness is signif‐ icantly higher in obese children with fatty liver than in obese children without fatty liver or normal weight control.

In addition, Pacifico et al. [67] reported that carotid artery intima-media thickness was high‐ est in obese children with echogenic liver and severity of liver fat was an independent pre‐ dictor of intima-media thickness after adjustment for known cardiovascular factors.

However, given the lack of long-term longitudinal cohort studies in pediatric fatty liver dis‐ ease, the relationship between the natural history of the disease and the actual risk for future cardiac events is unclear.

## **5. Conclusions**

The prevalence of fatty liver disease is increasing in obese children and adolescence.

Although the exact pathogenetic mechanism is still unclear, there is an urgent need to screen obese children for this pathology. A misdiagnosis of fatty liver could represent a serious risk factor for the development of its associated metabolic and cardiovascular complications dur‐ ing childhood and for exacerbated metabolic abnormalities later in life.

## **Author details**

Ebe D'Adamo1,2\*, M. Loredana Marcovecchio1,2, Tommaso de Giorgis1,2, Valentina Chiavaroli1,2, Cosimo Giannini1,2, Francesco Chiarelli1,2 and Angelika Mohn1,2 [10] Fabbrini E, deHaseth D, Deivanayagam S, Mohammed BS, Vitola BE, Klein S. Altera‐ tions in fatty acid kinetics in obese adolescents with increased intrahepatic triglycer‐

Pediatric Nonalcoholic Fatty Liver Disease http://dx.doi.org/10.5772/53463 231

[11] D'Adamo E, Northrup V, Weiss R, Santoro N, Pierpont B, Savoye M, O'Malley G, Caprio S. Ethnic differences in lipoprotein subclasses in obese adolescents: impor‐

[12] Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J

[13] Sinatra FR. Nonalcoholic fatty liver disease in pediatric patients. JPEN J Parenter En‐

[14] Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hep‐

[15] Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, Oku‐ nade A et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications

[16] D'Adamo E, Cali AMG, Weiss R, Santoro N, Pierpont B, Northrup V, Caprio S. Cen‐ tral Role of Fatty Liver in the Pathogenesis of Insulin Resistance in Obese Adoles‐

[17] Manco M. Metabolic syndrome in childhood from impaired carbohydrate metabo‐ lism to nonalcoholic fatty liver disease. J Am Coll Nutr 2011;30(5):295-303. [18] Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221-1231.

[19] Pais R, Lupşor M, Poantă L, Silaghi A, Rusu ML, Badea R, Dumitraşcu DL. Liver Bi‐ opsy versus Noninvasive Methods – Fibroscan and Fibrotest in the Diagnosis of Non-alcoholic Fatty Liver Disease: A Review of the Literature. Rom J Intern Med.

[20] Janczyk W, Socha P. Non-alcoholic fatty liver disease in children. Clin Res Hepatol

[21] Joseph AE, Saverymuttu SH, Al-Sam S, Cook MG, Maxwell JD. Comparison of liver histology with ultrasonography in assessing diffuse parechymal liver disease. Clin

[22] Tominaga K, Kurata JH, Chen YK, Fujimoto E, Miyagawa S, Abe I, Kusano Y. Preva‐ lence of fatty liver in Japanese children and relationship to obesity. An epidemiologi‐

[23] Agawal N, Sharma BC. Insulin resistance and clinical aspects of non-alcoholic steato‐

[24] Franzese A, Vajro P, Argenziano A, Puzziello A, Iannucci MP, Saviano MC, Brunetti F, Rubino A. Liver involvement in obese children. Ultrasonography and liver en‐

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hepatitis (NASH). Hepatol Res 2005;33:92-96.

of obesity. Proc Natl Acad Sci U S A 2009;106:15430-15435.

cents. Diabetes Care 2012;33:1817–1822.

tance of liver and intraabdominal fat accretion. Am J Clin Nutr 2010:92:500-8.

ide content. Obesity (Silver Spring) 2009;17:25-29.

Clin Invest. 2004;114:147-52.

teral Nutr 2012;36:43S-8S.

atol 2010;7:195-203.

2009;47(4):331-40.

Radiol 1991: 43:26-31.

Gastroenterol 2012;36:297-300.

\*Address all correspondence to: ebe.dadamo@yahoo.com

1 Department of Pediatrics, University of Chieti, Chieti, Italy

2 Center of Excellence on Aging, "G. D'Annunzio" University Foundation, University of Chieti, Italy

## **References**


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**Author details**

230 Hot Topics in Endocrine and Endocrine-Related Diseases

Chieti, Italy

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234 Hot Topics in Endocrine and Endocrine-Related Diseases


**Chapter 10**

**Anabolic/Androgenic Steroids in Skeletal Muscle and**

Testosterone exerts significant effect on muscle cells, and abnormalities of plasma concentra‐ tions can cause both skeletal muscle and cardiovascular diseases. Low levels are known to be associated with hypogonadism and have recently been linked to sarcopenia and metabol‐ ic syndrome; high levels are associated with hypertrophy. However, most evidence of the link between testosterone and metabolic actions is observational. Studies targeted to estab‐ lish the mechanisms for such effects at the cell level and their correlation with *in vivo* models will broaden our understanding of the role played by these male steroid hormones in the

Anabolic/androgenic steroid hormones are part of the male reproductive endocrine axis. Androgens are the male sex hormones responsible for development of the male reproduc‐ tive system. Testosterone is the main androgen circulating in the blood and it is secreted from the testes, while other androgens, such as androstenedione and dehydroepiandroste‐ nedione (DHEA) come mainly from the adrenal gland. In some tissues the androgen actions require that testosterone can be converted to dihydrotestosterone by action of 5α-reductase, and in other tissues, including adipose tissue, testosterone can also be converted into estra‐

Endocrine actions of testosterone are under control of the hypothalamus-pituitary-gonad ax‐ is. The hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the secretion of luteinizing hormone (LH) from the anterior pituitary (adenohypophysis). In

and reproduction in any medium, provided the original work is properly cited.

© 2013 Basualto-Alarcón et al.; licensee InTech. This is an open access article 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.

© 2013 The Author(s). Licensee InTech. 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,

**Cardiovascular Diseases**

http://dx.doi.org/10.5772/53080

**1. Introduction**

Carla Basualto-Alarcón, Rodrigo Maass, Enrique Jaimovich and Manuel Estrada

Additional information is available at the end of the chapter

pathophysiology of muscular and metabolic diseases.

**1.1. Physiology of the androgens**

diol by aromatization of the androgen ring.
