**6. Screening of associated diseases**

**5. Monitoring disease progression**

16 Liver Research and Clinical Management

**Figure 1.** Practical approach to the management of patient with NAFLD.

of NASH and, especially, the stage of fibrosis.

A recent meta-analysis of 11 studies that evaluated the progression of NAFLD through the use of paired liver biopsies revealed that patients with NAFL and NASH presented a progression of fibrosis of 33.6% and an improvement of it of 22.3%, the rate of fibrosis progression being greater in patients with NASH than with NAFL (progression in a stage of 7.1 years compared to 14.3 years, respectively) [5]. However, there is a lack of homogenization in the speed of fibrosis progression in all these studies with paired biopsy, which is mostly due to the presence of characteristics of the metabolic syndrome in the patients [5–7, 62, 65, 138–144]. For this reason, due to the lack of studies that provide complete data about the differential progression of the disease in patients with different stages of NAFLD, there is no guide on the frequency of follow-up of these patients or on the means available to monitor the progression. Nevertheless, once the diagnosis of NAFLD is made, the follow-up will depend on the presence of metabolic risk factors and the severity of the hepatic disease, which will be determined by the presence

The principal metabolic factor of the risk of NAFLD progression is DM2 [1, 19, 145]. Patients with DM2 have a more severe grade of NAFLD than the patients without DM2, with rates of NASH up to 80% and of advanced fibrosis of 30–40% [146, 147]. These data confirm the need for closer monitoring in these patients. Bazick et al. [147] developed a clinical model to detect NASH and advanced fibrosis in patients with NAFLD and DM2 with a sensitivity and specificity of 57 and 90%, respectively. This model includes easily accessible parameters such as BMI, circumference at the waist, HbA1c, insulin resistance, ALT, AST, albumin and ferritin, for NASH; and age, BMI, waist/hip ratio, arterial hypertension, ALT/AST ratio, alkaline In recent years, several studies have confirmed that the morbimortality associated with NAFLD is not limited only to hepatic injury, yet it is a disease with multisystemic behavior with affectation of different organs.

#### **6.1. Insulin resistance and metabolic syndrome**

As was previously mentioned, the concurrent characteristics of metabolic syndrome increase the risk of developing NAFLD, and a recent study of the HepaMet group relates the severity of NAFLD with the number of factors of the metabolic syndrome present (publication pending). However, the presence of NAFLD in itself also increases the risk of developing complications such as dyslipidemia and insulin resistance [154–156]. In this sense, the diagnosis and quantification of hepatic fat can be useful in the prediction of future development of diabetes and other cardiovascular risk factors [56].

**6.3. Extrahepatic cancer**

neoplasms.

genesis [176, 177].

these patients.

**6.4. Other associated diseases**

The second most prevalent cause of death among patients with NAFLD is cancer, both gastrointestinal (colon, esophagus, stomach and pancreas) and extraintestinal (kidney and breast), which leads to the suspicion that this liver disease might promote the development of

Diagnosis and Characterization of Non-Alcoholic Fatty Liver Disease

http://dx.doi.org/10.5772/intechopen.72668

19

The association of insulin resistance/diabetes, obesity and metabolic syndrome with an increase in the risk of a large number of cancers is well established [166–171]. These three characteristics are closely related to NAFLD and contribute significantly to the risk of developing HCC; nevertheless, various recent studies indicate that NAFLD can be an additional and independent risk factor for extrahepatic cancers [172, 173], especially colorectal cancer (CRC) [127, 174]. In several studies, colorectal lesions, particularly tubular adenomas and carcinomas, were significantly more prevalent in NAFLD patients, regardless of age, sex and manifestations of metabolic syndrome; even the presence of NASH has been related to a greater risk in comparison with those with NAFL [174, 175]. This rise in the risk of CRC in NAFLD can be explained by the increase in insulin and pro-inflammatory cytokines and the alteration of the adipokines metabolism predominantly leptin versus adiponectin that exists in these patients and which promotes cellular proliferation, inhibition of apoptosis and angio-

Although these data clearly suggest more rigorous screening programmes for CRC in NAFLD patients, there are no well-designed prospective studies enabling the verification of a causal relation between NAFLD and CRC or studies that evaluate the usefulness of earlier screening in this liver disease, so no guidelines make a distinction with respect to CRC screening in

There is increasing interest in the possible contribution of NAFLD to the development and progression of chronic kidney disease (CKD) [178–181]. A recent meta-analysis has revealed that the presence and severity of NAFLD are associated with an increase in the risk and severity of CKD [181]. However, it is difficult to establish NAFLD as an independent risk factor of CKD given the close relation between NAFLD and other known risk factors of CKD such as obesity and IR. Obstructive sleep apnea syndrome (OSAS) is strongly associated with NAFLD independently of other traditional factors; it is a consequence of the decrease in the lipid metabolism provoked by intermittent hypoxia [182–185]. Other described diseases associated with NAFLD include osteoporosis [186], psoriasis [187], polycystic syndrome [188] and other endocrinopathies such as hypothyroidism [189], hypopituitarism [190] and hypogonadism [191]. Until now, there is no evidence for screening of all these pathologies for the mere fact that the subject presents NAFLD, so all that needs to be studied is the presence of them if the patient has clinical manifestations related to them. Moreover, a recent study by our group has demonstrated that psychotic patients with specific pharmacological treatment have a high risk of developing NAFLD in the first years, so its early detection will enable better prevention

of cardiovascular events, which are so increased in this population [192].

Insulin resistance is a key in the physiopathology of NAFLD, associated with the increase in the deposit of fat and fibrosis, and it substantially increases the risk of developing DM2, which indicates that NAFLD can precede the development of diabetes. Moreover, and as it was mentioned earlier, several studies have demonstrated that, especially in patients with insulin resistance and/or diabetes, liver fibrosis can progress even when a baseline hepatic histology described only simple steatosis without hepatocellular damage [62, 141]. All in all, in daily clinical practice the use of screening tools is necessary to detect the presence of diabetes (fasting blood glucose levels, HbA1c or, if available, the oral glucose tolerance test) or insulin resistance. The reference technique for the diagnosis of IR in non-diabetic patients is the hyperinsulinemic-euglycemic clamp test, although this procedure is expensive and complicated, so it is not routinely used in daily clinical practice [157]. In these cases, the calculation of HOMA-IR (*homeostatic model assessment*) is an acceptable alternative to evaluate the IR, although there is no agreement on the threshold that defines insulin resistance using this formula [158]. Nevertheless, HOMA-IR can help us during the follow-up to identify patients at risk of fibrosis progression [6, 62]. The next question once the patients with IR are identified is whether it is necessary to treat them pharmacologically or not; and, whether in diabetic patients is necessary to intensify the anti-diabetic treatment to avoid liver disease progression or not. As expected, several insulin-sensitizing agents have demonstrated an improvement in the hepatic histology [159–161], even in patients without DM2 [162, 163], given that both entities share multiple physiopathological mechanisms, so this treatment can be considered in patients with NASH and/or multiple factors of progression in which a decrease of IR cannot be achieved with diet and exercise, although the EASL and AASLD guidelines do not contemplate it. Given that IR plays an essential role in NAFLD progression but not the only one, we do not believe that it is necessary to treat DM2 differently/intensely in patients with NAFLD, independently of the grade, provided that the IR is controlled.

#### **6.2. Cardiovascular disease**

Cardiovascular disease is quantitatively the main cause of death in NAFLD patients. Besides the risk itself of the characteristics of the metabolic syndrome, multiple pathogenic conditions of NAFLD contribute to the development of cardiovascular disease. In fact, patients with NAFLD often present elevation in the markers implicated in the development of atherosclerosis, such as CD36 in its soluble form (sCD36), a membrane receptor responsible for, among other things, the transport of fatty acids [164]. The spectrum of CVD in NAFLD includes atherosclerotic coronary heart disease, heart failure and cardiac arrhythmias. This necessitates the study of probable CVD, especially subclinical atherosclerosis, in all these patients [10]. There are little data to define the optimal means of screening NAFLD patients with CVD, but it is important to be aware that there are different techniques for the detection of subclinical atherosclerosis that are bloodless and some of which are very easily performed. Among these, the measurement of ankle-brachial index and carotid ultrasound are assessments especially useful for patients with intermediate cardiovascular risk, situation affecting a very important part of the population with NAFLD [165].

#### **6.3. Extrahepatic cancer**

quantification of hepatic fat can be useful in the prediction of future development of diabetes

Insulin resistance is a key in the physiopathology of NAFLD, associated with the increase in the deposit of fat and fibrosis, and it substantially increases the risk of developing DM2, which indicates that NAFLD can precede the development of diabetes. Moreover, and as it was mentioned earlier, several studies have demonstrated that, especially in patients with insulin resistance and/or diabetes, liver fibrosis can progress even when a baseline hepatic histology described only simple steatosis without hepatocellular damage [62, 141]. All in all, in daily clinical practice the use of screening tools is necessary to detect the presence of diabetes (fasting blood glucose levels, HbA1c or, if available, the oral glucose tolerance test) or insulin resistance. The reference technique for the diagnosis of IR in non-diabetic patients is the hyperinsulinemic-euglycemic clamp test, although this procedure is expensive and complicated, so it is not routinely used in daily clinical practice [157]. In these cases, the calculation of HOMA-IR (*homeostatic model assessment*) is an acceptable alternative to evaluate the IR, although there is no agreement on the threshold that defines insulin resistance using this formula [158]. Nevertheless, HOMA-IR can help us during the follow-up to identify patients at risk of fibrosis progression [6, 62]. The next question once the patients with IR are identified is whether it is necessary to treat them pharmacologically or not; and, whether in diabetic patients is necessary to intensify the anti-diabetic treatment to avoid liver disease progression or not. As expected, several insulin-sensitizing agents have demonstrated an improvement in the hepatic histology [159–161], even in patients without DM2 [162, 163], given that both entities share multiple physiopathological mechanisms, so this treatment can be considered in patients with NASH and/or multiple factors of progression in which a decrease of IR cannot be achieved with diet and exercise, although the EASL and AASLD guidelines do not contemplate it. Given that IR plays an essential role in NAFLD progression but not the only one, we do not believe that it is necessary to treat DM2 differently/intensely in patients with NAFLD,

Cardiovascular disease is quantitatively the main cause of death in NAFLD patients. Besides the risk itself of the characteristics of the metabolic syndrome, multiple pathogenic conditions of NAFLD contribute to the development of cardiovascular disease. In fact, patients with NAFLD often present elevation in the markers implicated in the development of atherosclerosis, such as CD36 in its soluble form (sCD36), a membrane receptor responsible for, among other things, the transport of fatty acids [164]. The spectrum of CVD in NAFLD includes atherosclerotic coronary heart disease, heart failure and cardiac arrhythmias. This necessitates the study of probable CVD, especially subclinical atherosclerosis, in all these patients [10]. There are little data to define the optimal means of screening NAFLD patients with CVD, but it is important to be aware that there are different techniques for the detection of subclinical atherosclerosis that are bloodless and some of which are very easily performed. Among these, the measurement of ankle-brachial index and carotid ultrasound are assessments especially useful for patients with intermediate cardiovascular risk, situation affecting a very important

and other cardiovascular risk factors [56].

18 Liver Research and Clinical Management

independently of the grade, provided that the IR is controlled.

**6.2. Cardiovascular disease**

part of the population with NAFLD [165].

The second most prevalent cause of death among patients with NAFLD is cancer, both gastrointestinal (colon, esophagus, stomach and pancreas) and extraintestinal (kidney and breast), which leads to the suspicion that this liver disease might promote the development of neoplasms.

The association of insulin resistance/diabetes, obesity and metabolic syndrome with an increase in the risk of a large number of cancers is well established [166–171]. These three characteristics are closely related to NAFLD and contribute significantly to the risk of developing HCC; nevertheless, various recent studies indicate that NAFLD can be an additional and independent risk factor for extrahepatic cancers [172, 173], especially colorectal cancer (CRC) [127, 174]. In several studies, colorectal lesions, particularly tubular adenomas and carcinomas, were significantly more prevalent in NAFLD patients, regardless of age, sex and manifestations of metabolic syndrome; even the presence of NASH has been related to a greater risk in comparison with those with NAFL [174, 175]. This rise in the risk of CRC in NAFLD can be explained by the increase in insulin and pro-inflammatory cytokines and the alteration of the adipokines metabolism predominantly leptin versus adiponectin that exists in these patients and which promotes cellular proliferation, inhibition of apoptosis and angiogenesis [176, 177].

Although these data clearly suggest more rigorous screening programmes for CRC in NAFLD patients, there are no well-designed prospective studies enabling the verification of a causal relation between NAFLD and CRC or studies that evaluate the usefulness of earlier screening in this liver disease, so no guidelines make a distinction with respect to CRC screening in these patients.

#### **6.4. Other associated diseases**

There is increasing interest in the possible contribution of NAFLD to the development and progression of chronic kidney disease (CKD) [178–181]. A recent meta-analysis has revealed that the presence and severity of NAFLD are associated with an increase in the risk and severity of CKD [181]. However, it is difficult to establish NAFLD as an independent risk factor of CKD given the close relation between NAFLD and other known risk factors of CKD such as obesity and IR. Obstructive sleep apnea syndrome (OSAS) is strongly associated with NAFLD independently of other traditional factors; it is a consequence of the decrease in the lipid metabolism provoked by intermittent hypoxia [182–185]. Other described diseases associated with NAFLD include osteoporosis [186], psoriasis [187], polycystic syndrome [188] and other endocrinopathies such as hypothyroidism [189], hypopituitarism [190] and hypogonadism [191]. Until now, there is no evidence for screening of all these pathologies for the mere fact that the subject presents NAFLD, so all that needs to be studied is the presence of them if the patient has clinical manifestations related to them. Moreover, a recent study by our group has demonstrated that psychotic patients with specific pharmacological treatment have a high risk of developing NAFLD in the first years, so its early detection will enable better prevention of cardiovascular events, which are so increased in this population [192].
