Non-alcoholic Fatty Liver Disease

*Advances in Hepatology*

2018;4:3

of a single center. Hepatoma Res

Fibrosis. Ann Hepatol. 2018 Oct

[101] Chen, CH., Chen, CH., Lin, CL. et al. Real-world safety and efficacy of paritaprevir/ritonavir/ombitasvir plus dasabuvir±ribavirin in patients with hepatitis C virus genotype 1 and advanced hepatic fibrosis or compensated cirrhosis: a multicenter pooled analysis. Sci Rep 9, 7086 (2019)

[102] Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S, Díaz A, Vilana R, Darnell A, Varela M, Sangro B, Calleja JL, Forns X, Bruix J. Unexpected high rate of early tumor recurrence in patients with HCVrelated HCC undergoing interferon-

free therapy. J Hepatol. 2016

[103] Dang H, Yeo YH, Yasuda S, Huang CF, Iio E, Landis C, et al. Cure with interferon free DAA is associated with increased survival in patients with HCV related HCC from both East and West. Hepatoology 2019 Oct 14;[Epub

[104] Ioannou GN, Beste LA, Green PK, Singal AG, Tapper EB, Waljee AK, et al. Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores. Gastroenterology 2019;157:1264-1278 e4

[105] Na SK, Song BC. Development and surveillance of hepatocellular carcinoma in patients with sustained virologic response after antiviral therapy for chronic hepatitis C. Clin Mol Hepatol

Oct;65(4):719-726

ahead of print]

16;17(6):959-968

[100] Pessoa MG, Ramalho-Madruga JV, Alves K, Nunes EP, Cheinquer H, Brandão-Mello CE, et al. Efficacy and Safety of Ombitasvir/Paritaprevir/ Ritonavir and Dasabuvir ± Ribavirin for HCV in Brazilian Adults with Advanced [106] Calvaruso V, Cabibbo G, Cacciola I, Petta S, Madonia S, Bellia A, et al. Incidence of

hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents. Gastroenterology 2018;155:411-421 e4

**124**

2019;25:234-244

**127**

the disease's activity.

**1. Introduction**

**Chapter 8**

**Abstract**

Steatohepatitis

*and Graciela Elia Castro-Narro*

Diagnosis of Nonalcoholic

*Eira Cerda-Reyes, Alicia Sarahi Ojeda-Yuren,* 

*Julián Torres-Vazquez, María del Rosario Herrero Maceda,* 

*Martín Uriel Vázquez-Medina, Perla Denice Flores-Rangel,* 

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased in the

last years up to 25% in the adult population. This disease includes a large spectrum of disorders, from simple fatty liver disease to cirrhosis and Hepatocellular Carcinoma (HCC), and they are related to chronic metabolic conditions. NAFLD is characterized by the presence of at least 5% of hepatic steatosis without evidence of hepatocellular injury. The diagnosis of this disease should be of exclusion and focused on its progression, treatment, and identification of the prognosis. The European Association for the Study of the Liver (EASL), the National Institute for Health and Care Excellence (NICE), the Italian Association for the Study of the Liver (AISF), and the American Association for the Study of the Liver (AASLD), published their Clinical Guidelines that have identified the criteria for the diagnosis of NAFLD, several, using imaging or histological diagnostic methods, although they imply a different approach and screening. The Fatty Liver Index and the NAFLD Liver Fat Score are used by 3 out of 5 Guidelines and they are easily calculated using blood tests and clinical information. Other non-invasive scales for NAFLD are the NAFLD fibrosis score (NFS), Fib-4, AST/ALT ratio index; also the ELF panel, Fibrometer, Fibrotest, Hepascore; and some imaging techniques that include transient elastography, magnetic resonance elastography (MRE), and shear wave elastography. Finally, proteomic's and glycomic's technologic biomarkers are currently under investigation and recent use, such as Cytokeratin 18 and Sirtuin 1. Still, liver biopsy remains the gold standard to distinguish between steatohepatitis and simple steatosis, using the histological classification and staging scoring systems of NAFLD Activity Score (NAS) and the Steatosis Activity Fibrosis (SAF), to evaluate

**Keywords:** non alcoholic liver disease, no invasive diagnosis, diagnosis

raised at a worldwide level, affecting up to 25% of the adult population [1].

In the last years, the prevalence of non-alcoholic fatty liver disease (NAFLD) has

*Yailin Fabiola Velásquez Palacios, Saraid Cerda-Reyes* 

#### **Chapter 8**

## Diagnosis of Nonalcoholic Steatohepatitis

*Eira Cerda-Reyes, Alicia Sarahi Ojeda-Yuren, Julián Torres-Vazquez, María del Rosario Herrero Maceda, Martín Uriel Vázquez-Medina, Perla Denice Flores-Rangel, Yailin Fabiola Velásquez Palacios, Saraid Cerda-Reyes and Graciela Elia Castro-Narro*

#### **Abstract**

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased in the last years up to 25% in the adult population. This disease includes a large spectrum of disorders, from simple fatty liver disease to cirrhosis and Hepatocellular Carcinoma (HCC), and they are related to chronic metabolic conditions. NAFLD is characterized by the presence of at least 5% of hepatic steatosis without evidence of hepatocellular injury. The diagnosis of this disease should be of exclusion and focused on its progression, treatment, and identification of the prognosis. The European Association for the Study of the Liver (EASL), the National Institute for Health and Care Excellence (NICE), the Italian Association for the Study of the Liver (AISF), and the American Association for the Study of the Liver (AASLD), published their Clinical Guidelines that have identified the criteria for the diagnosis of NAFLD, several, using imaging or histological diagnostic methods, although they imply a different approach and screening. The Fatty Liver Index and the NAFLD Liver Fat Score are used by 3 out of 5 Guidelines and they are easily calculated using blood tests and clinical information. Other non-invasive scales for NAFLD are the NAFLD fibrosis score (NFS), Fib-4, AST/ALT ratio index; also the ELF panel, Fibrometer, Fibrotest, Hepascore; and some imaging techniques that include transient elastography, magnetic resonance elastography (MRE), and shear wave elastography. Finally, proteomic's and glycomic's technologic biomarkers are currently under investigation and recent use, such as Cytokeratin 18 and Sirtuin 1. Still, liver biopsy remains the gold standard to distinguish between steatohepatitis and simple steatosis, using the histological classification and staging scoring systems of NAFLD Activity Score (NAS) and the Steatosis Activity Fibrosis (SAF), to evaluate the disease's activity.

**Keywords:** non alcoholic liver disease, no invasive diagnosis, diagnosis

#### **1. Introduction**

In the last years, the prevalence of non-alcoholic fatty liver disease (NAFLD) has raised at a worldwide level, affecting up to 25% of the adult population [1].

The prevalence of type 2 diabetes, cardiovascular diseases, cancer associated with obesity, and advanced hepatic diseases (liver cirrhosis and liver cancer), have increased together with the growth of the prevalence of NAFLD [1–4].

The broad spectrum of disorders that involve NAFLD range from simple fatty liver to nonalcoholic steatohepatitis, and the increasing of fibrosis that concludes in cirrhosis [5, 6]. Among the most relevant metabolic conditions related to this disease, are obesity, insulin resistance, dyslipidemia, and type 2 diabetes [5–7].

Furthermore, the European Association for the Study of the Liver (EASL) and the Asia-Pacific Guidelines point out the relation between Hepatocellular Carcinoma (HCC) and NAFLD, since it can occur in patients with NAFLD but without cirrhosis [8, 9].

#### **2. Definition**

Nonalcoholic fatty liver is characterized by the presence of at least 5% of hepatic steatosis without evidence of hepatocellular injury (ballooning). On the other hand, the definition of NASH (non-alcoholic steatohepatitis) is the appearance of at least 5% of hepatic steatosis and inflammation, hepatocytic injury (eg. ballooning) with or without fibrosis [10].

#### **3. Diagnosis**

The diagnosis' approach should focus on the non-invasive evaluation to first identify NAFLD in patients with metabolic risk factors, and then, monitor the progression of the disease, the treatment, and the response, in order to identify early patients with a worse prognosis [6, 11].

The risk with NAFLD is that it is a silent entity that is diagnosed incidentally, because abnormal liver enzymes are reported in liver biochemistry or through images, such as in ultrasound with steatosis reported. NAFLD is a diagnosis of exclusion, therefore once it is suspected, the diagnosis should be confirmed by ruling out other possible causes of steatosis; for example, alcoholic hepatitis and NASH are clinically indistinguishable. For this exclusion, it is necessary to evaluate if there is a significant consumption of alcohol, which is generally considered of more than 20 g per day [12]; also, it is important to carry out a good clinical record to identify risk factors for liver disease, such as the use of medications or a family history of liver disease. Several Clinical Guidelines have identified criteria for the diagnosis of NAFLD (**Table 1**).

All of these considerations imply a different approach to NAFLD detection by Scientific Societies. Only the recommendations of the Asia-Pacific Associations, EASL and NICE (National Institute for Health and Care Excellence) [13] recommend screening, in particular, of high-risk groups (**Table 2**). In contrast, the AASLD (American Association for the Study of the Liver) recommends a concept of surveillance in the metabolic risk factor populations since there is no cost-effectiveness evidence to support a test to determine NAFLD in adults [6, 14].

#### **3.1 Liver biochemistry**

The liver biochemistry of NAFLD usually presents within normal parameters, although a slight increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or gamma-glutamyl transpeptidase (γGT) can occur. However, since liver enzymes are not a sensitive screening test, all the recommendations agree that their normal values may not exclude NAFLD [13]. Besides, liver enzyme

**129**

**Table 2.**

autoimmune liver disease [6, 15, 16].

abnormalities can mask another cause of liver disease, in which steatosis is a coexisting condition. Also, abnormalities in laboratory tests (such as ferritin or autoantibodies) do not always diagnose the presence of another liver disease but could be an epiphenomenon of NAFLD with no other clinical consequence. In particular, according to the AASLD guidelines, elevated serum ferritin and low autoimmune antibody titers (especially antinuclear and smooth muscle antibodies) are frequent features in patients with NAFLD and may not demonstrate hemochromatosis or

*Translated from Leoni S. World J Gastroenterol. 2018 Aug 14;24(30):3361–3373. EASL: European Association for the Study of the Liver, NICE: National Institute for Health and Care Excellence, AISF: Italian Association for the* 

**EASL NICE Asia-Pacific AISF AASLD**

drinks / day 140 g / week

drink / day 70 g / week

**EASL NICE Asia-Pacific AISF AASLD**

Not mentioned

No No No No No

Yes Obesity Type 2 diabetes No, hepatic enzymes Yes, ultrasound If transient elastography

*Translated from Leoni S. World J Gastroenterol. 2018 Aug 14;24(30):3361–3373. EASL: European Association for the Study of the Liver, NICE: National Institute for Health and Care Excellence, AISF: Italian Association for the* 

Hepatic steatosis in images or histology. There are no other causes of steatosis. No significant alcohol consumption.

Evidence of hepatic steatosis by imaging or histology. There are no other causes of steatosis. No significant alcohol consumption. Noncoexisting chronic liver disease.

30 g/d 21 standard

20 g/d 14 standard

No (active surveillance)

drink / week 294 g / week

drinks / week 196 g / week

Hepatic steatosis by imaging or histology. There are no other causes of steatosis. No significant alcohol consumption.

Excessive fat in the liver. There are no other causes of steatosis. No significant alcohol consumption.

30 g/d 30 g/d 2 standard

20 g/d 20 g/d 1 standard

*Study of the Liver, AASLD: American Association for the Study of the Liver.*

*Diagnostic criteria for NAFLD according to various clinical guidelines.*

Yes Obesity Type 2 diabetes No, hepatic enzymes. Yes, ultrasound.

*Study of the Liver, AASLD: American Association for the Study of the Liver.*

*Comparisons of recommendations for screening of NAFLD.*

Yes Obesity Metabolic syndrome Altered liver enzymes Yes, hepatic enzymes

*Diagnosis of Nonalcoholic Steatohepatitis DOI: http://dx.doi.org/10.5772/intechopen.96281*

> in>5% of hepatocytes by imaging or histology. There are no other causes of steatosis. Insulin resistance

Criteria Steatosis

Alcohol consumption limit (males)

Alcohol consumption limit (females)

**Table 1.**

Generalized screening

Screening in high-risk groups Screening type

#### *Diagnosis of Nonalcoholic Steatohepatitis DOI: http://dx.doi.org/10.5772/intechopen.96281*


*Translated from Leoni S. World J Gastroenterol. 2018 Aug 14;24(30):3361–3373. EASL: European Association for the Study of the Liver, NICE: National Institute for Health and Care Excellence, AISF: Italian Association for the Study of the Liver, AASLD: American Association for the Study of the Liver.*

#### **Table 1.**

*Diagnostic criteria for NAFLD according to various clinical guidelines.*


*Translated from Leoni S. World J Gastroenterol. 2018 Aug 14;24(30):3361–3373. EASL: European Association for the Study of the Liver, NICE: National Institute for Health and Care Excellence, AISF: Italian Association for the Study of the Liver, AASLD: American Association for the Study of the Liver.*

#### **Table 2.**

*Comparisons of recommendations for screening of NAFLD.*

abnormalities can mask another cause of liver disease, in which steatosis is a coexisting condition. Also, abnormalities in laboratory tests (such as ferritin or autoantibodies) do not always diagnose the presence of another liver disease but could be an epiphenomenon of NAFLD with no other clinical consequence. In particular, according to the AASLD guidelines, elevated serum ferritin and low autoimmune antibody titers (especially antinuclear and smooth muscle antibodies) are frequent features in patients with NAFLD and may not demonstrate hemochromatosis or autoimmune liver disease [6, 15, 16].

#### **3.2 Non-invasive techniques**

Currently, the absence of highly specific and sensitive non-invasive markers that can predict inflammation and fibrosis has increased the efforts in the identification of new markers of the disease's progression and the development of clinical scores of disease's severity. To evaluate steatosis, the Fatty Liver Index (FLI) and the NAFLD Liver Fat Score are used by the EASL, the Asia Pacific Association, and the Italian guidelines. These scores can be calculated easily by using common blood tests and simple clinical information. For instance, FLI is calculated from triglyceride levels, body mass index, waist circumference, and gamma-glutamyltransferase, while NAFLD liver fat score is determined by evaluating the presence/absence of the metabolic syndrome and type 2 diabetes, fasting serum insulin, and aminotransferases. Both of them have been validated in a cohort of severely obese patients and in the general population, which can predict the presence of steatosis, but not its severity [6, 17–19].

Respectively, there has been an increase in the investigation of different tools in this regard, that include non-invasive scales (NAFLD fibrosis score (NFS), FIB-4, AST/ALT ratio index), serum biomarkers (ELF panel, Fibrometer, Fibrotest, Hepascore), and techniques of imaging, such as transient elastography, magnetic resonance elastography (MRE), and shear wave elastography. According to the NICE guideline, the best cost–benefit ratio in identifying patients with advanced fibrosis stages was demonstrated by the liver fibrosis (ELF) blood test, and therefore, these tests should be offered to all patients with an incidental diagnosis of NAFLD. On the contrary, the EASL and Italian guidelines suggest the use of the NAFLD fibrosis score (NFS) and the FIB-4 as non-invasive scores to identify patients with different risks of advanced fibrosis. Both scores predict liver-related mortality and cardiovascular disease since they have been validated in several ethnically NAFLD patients. Furthermore, in a recent study of the AASLD is highlighted that both NFS and FIB-4 present the best predictive value for advanced fibrosis in NAFLD patients with histological diagnosis (**Table 3**) [20–22].

#### **3.3 Proteomics, glycomics and microRNA**

The new technology in proteomics, glycomics, and microRNA (miRNA) can tell us about the pathophysiology of NAFLD/NASH [23].

Sirtuin 1 (Sirt 1) is a heat shock protein that is related to toxic immune reactions, antimicrobial activity, and mitophagy. Mitophagy is very important in NAFLD along with other diseases, therefore there is an increasing interest in maintaining the regulation and homeostasis of the mitochondria, due that it is necessary for the survival of many tissues [ 24]. The nuclear receptor of Sirt 1 is a nicotinamide adenine dinucleotide (NAD+) dependent class III histone deacetylase (HDAC) that modifies the gene expression to the metabolic activity of transcription factors, such as p53, and deacetylation of nuclear receptors. Its functions involve the metabolism of cholesterol, fatty acids, glucose, and xenobiotics, as well as the expression of p450 in the hepatic metabolism [25]. This is why the regulation of the nuclear receptor Sirt 1 is crucial to prevent NAFLD and other metabolic diseases. The proteome blood clinical analysis for the proteomic biomarkers, especially Sirt 1, with its measurement in plasma, cytoplasm, and nucleus, is the key to detect, evaluate and determine mitochondrial apoptosis and the progression of the disease [24, 25].

The most studied biomarker is cytokeratin 18 that is used to evaluate the presence of inflammation. There is a lot of research about its circulating levels as a signal of hepatocellular apoptotic activity and as a specific feature of NASH [6, 26].

**131**

**Table 3.**

The Asia Pacific Association guidelines recommend that elevated levels of cytokeratin18 have a good predictive value for NAFLD in comparison to healthy livers, but it makes no difference between NASH versus simple steatosis. However, the EASL recommendations highlight that serum levels of cytokeratin 18 has an inverse relation with the histological improvement, although its predictive value is no better

than ALT in identifying histological responders [6, 27–29].

*Diagnosis of Nonalcoholic Steatohepatitis DOI: http://dx.doi.org/10.5772/intechopen.96281*

SteatoTest Poynard et.at,

FLI Bedogni et al.

NAFLD-LFS Kotronen

LAP Bedogni et al.

Nash Diagnosis

Apoptosis Panel

NAFLD fibrosis score

**Diagnostic dashboards to predict NASH** NASH Test Poynard et al.

**Validated diagnostic panels to predict hepatic steatosis**

2005

2006

et al. 2009

2010

2006

Younossi et al. 2008

Tamimi et.al 2011

> Angulo et al.2007

> > 2006

2008

2009

et al. 2011

*Different scores and models to predict steatosis, NASH, and fibrosis.*

*critical appraisal. J Hepatol 2013;58(5):1007–1019.*

**Diagnostic panels to predict fibrosis in NASH**

Fibrotest Ratziu et al.

BARD Harrison et al.

FibroMeter Cales et al.

FIB-A McPherson

**Panel Study Biomarkers Sensitivity** 

α-MG, Haptoglobin, Apolipoprotein A1, Total Bilirubin, GGT, Glucose, Triglycerides, Cholesterol, ALT, Age, Gender, and BMI

Triglycerides, BMI, GGT, waist circumference

NASH panels Undisclosed formula, α-MG, Haptoglobulin, Apoliprotein A1, Total Bilirubin, GGT, AST, Triglycerides, Cholesterol, ALT, Age, Gender, Weight and Height

Undisclosed formula, CK18-M30, CK 18-M65, adiponectin and resistin

Cytokeratin 18 fragments, Fas ligand, soluble Fas

Age, glucose, BMI, platelets, albumin, AST / ALT

Age,,α2-macroglobuline, Total bilirubin, GGT and apolipoprotein A1

DT2

Glucose, AST, ferritin, platelets, ALT, weight, age

, AST/ALT≥0.8,

Age, AST / platelets, ALT 85 65

BMI ≥ 28 Kg/m2

α*-MG: alpha 2 macroglobulin, FLI: liver fat index, LAP. Lipid accumulation product, NA: not applicable. Translated from Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A* 

**(%)**

Mets, DT2, AST, ALT, insulin 95 95

Waist circumference, triglycerides NA NA

90 70

87 86

33 94

72 91

88 89

82 98

77 98

NA NA

79 96

**Specificity (%)**


α*-MG: alpha 2 macroglobulin, FLI: liver fat index, LAP. Lipid accumulation product, NA: not applicable. Translated from Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J Hepatol 2013;58(5):1007–1019.*

#### **Table 3.**

*Different scores and models to predict steatosis, NASH, and fibrosis.*

The Asia Pacific Association guidelines recommend that elevated levels of cytokeratin18 have a good predictive value for NAFLD in comparison to healthy livers, but it makes no difference between NASH versus simple steatosis. However, the EASL recommendations highlight that serum levels of cytokeratin 18 has an inverse relation with the histological improvement, although its predictive value is no better than ALT in identifying histological responders [6, 27–29].

#### **3.4 Liver ultrasound and imaging techniques**

The first line of diagnosis of hepatic steatosis is liver ultrasound because it is inexpensive, non-invasive, and widely accessible. Also, it is used currently in clinical practice and is quite accurate with an overall sensitivity of 85% and a specificity of 94% [30]. On the ultrasound can be observed that there is usually a visual decrease in the vascular margins, a loss of definition of the diaphragm, hepatomegaly, and hyperechogenicity of the liver parenchyma, as well as focal fat deposition in the hyperechoic area. If hepatocyte steatosis is not inferior to 31%, the transabdominal ultrasound is very effective [31].

There is a consensus for the use of abdominal ultrasound (USA). On the other hand, it can miss the diagnosis when the fat hepatic content is <20% because the sensitivity of USA among patients with morbid obesity (BMI > 40 kg/m2) is low [6, 32, 33].

Transient elastography has been recently approved by the United States (US) Food and Drug Administration (FDA) as a diagnostic tool for adult and pediatric patients with liver disease. Its cut-off value for advanced fibrosis in adults with NAFLD has been established at 9.9 KpA with a sensitivity of 95% and a specificity of 77%. Particularly, for clinically significant fibrosis, the elastography score has been shown to have good diagnostic accuracy with an AUROC of 0.93 (95% CI: 0.890.096) for advanced fibrosis (F3) and cirrhosis, and a negative predictive value of 90% in ruling out cirrhosis when a cutoff of 7.9 kPa is used. Although, it has a weaker capacity to make a difference between F2 and F3. Due to this high rate of false positive results, the EASL and the Asia Pacific recommendations mention that its low specificity limits its use in daily practice in the diagnosis of the advanced degree of fibrosis and cirrhosis, as well as a high failure rate. Moreover, the EASL highlights that it should not be used only as a first-line screening tool to identify advanced fibrosis or cirrhosis because of the unreliable results among patients with high BMI and thoracic fold thickness. However, by using M or XLprobe, the performance can improve and increase the success rate. For the identification of different degrees in fibrosis in NAFLD patients, especially in the intermediate stage, the US guidelines recommend magnetic resonance elastography (MRE), since it has a better performance than transient elastography in this regard, but shows the same predictive value for advanced stages of fibrosis. As a result, the AASLD concludes that ERM and transient elastography are useful tools to identify NAFLD patients with advanced liver fibrosis. Although, like transient elastography, shear wave elastography seems to be inadequate to distinguish between intermediate stages of fibrosis and to provide reliable results in 73% of patients with a BMI of 30 kg/m<sup>2</sup> [34–37].

Nevertheless, the gold standard for evaluating and quantifying hepatic steatosis and detecting the amount of liver fat as low as 5%–10% is magnetic resonance imaging (MRI), either by proton density fat fraction (1H-MRS) or by spectroscopy, although it is not commonly used in the clinical practice. This MRI is not recommended in the daily clinical setting despite its accurate precision, because of its limited availability, high costs, and long execution time [6, 38].

Another imaging technique used to quantify the fat content in the liver is transient ultrasound-based ultrasound (TE) using the continuous attenuation parameter (CAP). Due to that it simultaneously measures liver stiffness and evaluates the severity of NAFLD in the same setting, it has become a promising tool with good sensitivity [39]. However, despite its low cost and speed of implementation, its role in clinical practice has not yet been defined. In fact, according to the EASL, it has never been compared to hepatic steatosis as measured by 1H-MRS and there is limited data on its ability to discriminate different histological patterns.

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*Diagnosis of Nonalcoholic Steatohepatitis DOI: http://dx.doi.org/10.5772/intechopen.96281*

bodyweight [6].

NAFLD [23].

**3.5 Liver biopsy**

activity [6].

wire fibrosis [6, 41].

**4. Conclusions**

asymptomatic.

fibrosis and cirrhosis.

intensive approach is needed.

On the other hand, the Asia Pacific Association proposes the CAP as a useful screening tool for the diagnosis of NAFLD, as well as to demonstrate an improvement in hepatic steatosis after the intervention in lifestyle and the reduction of the

The stiffness of the liver measured by the M probe is not always successful in obese patients. The XL probe, an improved FibroScan probe, has been demostrated to achieve better diagnostic accuracy. The cutoff values, compared to the M probe values, are approximately 1.5 to 2 kPa lower. In conclusion, in the diagnosis of fibrosis and cirrhosis, a strong alternative to liver biopsy can be ET in patients with

The optimal strategy for stratifying patients with NAFLD and monitoring disease progression has yet to be established. The EASL and the Italian guidelines mention that the combination of noninvasive scores (NFS and FIB4) and transient elastography should be used to identify patients at low risk for advanced liver disease and clinical decision making. Also, in combination, they can identify patients who must undergo a liver biopsy to confirm advanced fibrosis, and in whom a more

The gold standard remains the liver biopsy, although it may not always be required to diagnose NAFLD, because it can distinguish steatohepatitis from simple steatosis, provide an evaluation of the degree of necroinflammatory activity, visualize fibrosis, and architectural alterations. The most widely used histological classification and staging system for NAFLD [23, 40] is the NAFLD Activity Score (NAS) and the Steatosis Activity Fibrosis (SAF) scoring systems to assess disease

The SAF score simplified the identification of a subset of NAFLD, which includes the assessment of steatosis (S), activity (A), and fibrosis (F): NASH. The histopathologic features of NAFLD include lobular and portal inflammation, steatosis, hepatocellular ballooning, glycogenated nuclei, apoptotic hepatocytes (acidophilic bodies), deposition, megamitochondria, Mallory-Denk bodies, and fibrosis, with the characteristic pattern centered on the perisinusoidal/pericellular area. This fibrotic pattern typically originated in the adult zone, is known as chicken

A score of ≥5 with steatosis and ballooning of hepatocytes is generally considered diagnostic of NASH, although patients may have NASH with lower NAS scores

The incidence and prevalence of NAFLD are increasing. Clinical guidelines agree that noninvasive tests are currently not available to detect NAFLD and

distinguish it from simple steatosis. Identifying people at risk of disease progression to NASH, fibrosis, and cirrhosis is extremely important because most patients are

The current gold standard for the diagnosis of NAFLD / NASH is liver biopsy.

The most validated diagnostic panels include the NAFLD fibrosis score, FIB-4, and FibroMeter. Transient elastography is very useful in the evaluation of advanced

Noninvasive tests such as proteomic biomarkers, transient elastography, and

elastoMR to evaluate NAFLD/NASH are promising.

if there is the presence of steatosis and ballooning of hepatocytes [6, 40].

#### *Diagnosis of Nonalcoholic Steatohepatitis DOI: http://dx.doi.org/10.5772/intechopen.96281*

On the other hand, the Asia Pacific Association proposes the CAP as a useful screening tool for the diagnosis of NAFLD, as well as to demonstrate an improvement in hepatic steatosis after the intervention in lifestyle and the reduction of the bodyweight [6].

The stiffness of the liver measured by the M probe is not always successful in obese patients. The XL probe, an improved FibroScan probe, has been demostrated to achieve better diagnostic accuracy. The cutoff values, compared to the M probe values, are approximately 1.5 to 2 kPa lower. In conclusion, in the diagnosis of fibrosis and cirrhosis, a strong alternative to liver biopsy can be ET in patients with NAFLD [23].

The optimal strategy for stratifying patients with NAFLD and monitoring disease progression has yet to be established. The EASL and the Italian guidelines mention that the combination of noninvasive scores (NFS and FIB4) and transient elastography should be used to identify patients at low risk for advanced liver disease and clinical decision making. Also, in combination, they can identify patients who must undergo a liver biopsy to confirm advanced fibrosis, and in whom a more intensive approach is needed.

#### **3.5 Liver biopsy**

The gold standard remains the liver biopsy, although it may not always be required to diagnose NAFLD, because it can distinguish steatohepatitis from simple steatosis, provide an evaluation of the degree of necroinflammatory activity, visualize fibrosis, and architectural alterations. The most widely used histological classification and staging system for NAFLD [23, 40] is the NAFLD Activity Score (NAS) and the Steatosis Activity Fibrosis (SAF) scoring systems to assess disease activity [6].

The SAF score simplified the identification of a subset of NAFLD, which includes the assessment of steatosis (S), activity (A), and fibrosis (F): NASH. The histopathologic features of NAFLD include lobular and portal inflammation, steatosis, hepatocellular ballooning, glycogenated nuclei, apoptotic hepatocytes (acidophilic bodies), deposition, megamitochondria, Mallory-Denk bodies, and fibrosis, with the characteristic pattern centered on the perisinusoidal/pericellular area. This fibrotic pattern typically originated in the adult zone, is known as chicken wire fibrosis [6, 41].

A score of ≥5 with steatosis and ballooning of hepatocytes is generally considered diagnostic of NASH, although patients may have NASH with lower NAS scores if there is the presence of steatosis and ballooning of hepatocytes [6, 40].

#### **4. Conclusions**

The incidence and prevalence of NAFLD are increasing. Clinical guidelines agree that noninvasive tests are currently not available to detect NAFLD and distinguish it from simple steatosis. Identifying people at risk of disease progression to NASH, fibrosis, and cirrhosis is extremely important because most patients are asymptomatic.

The current gold standard for the diagnosis of NAFLD / NASH is liver biopsy. Noninvasive tests such as proteomic biomarkers, transient elastography, and elastoMR to evaluate NAFLD/NASH are promising.

The most validated diagnostic panels include the NAFLD fibrosis score, FIB-4, and FibroMeter. Transient elastography is very useful in the evaluation of advanced fibrosis and cirrhosis.

### **Author details**

Eira Cerda-Reyes1 \*, Alicia Sarahi Ojeda-Yuren<sup>2</sup> , Julián Torres-Vazquez3 , María del Rosario Herrero Maceda4 , Martín Uriel Vázquez-Medina5 , Perla Denice Flores-Rangel6 , Yailin Fabiola Velásquez Palacios7 , Saraid Cerda-Reyes8 and Graciela Elia Castro-Narro9

1 Head of Academic Coordination, Central Military Hospital, Mexico

2 Anahuac University, Mexico

3 Chief Resident of Internal Medicine, Central Military Hospital, Mexico

4 Appointed Physician at the Gastroenterology Section, Central Military Hospital, Mexico

5 National Polytechnic Institute, Mexico

6 Gastroenterology Resident, Central Military Hospital, Mexico

7 Internal Medicine Resident, Central Military Hospital, Mexico


\*Address all correspondence to: arieirace@yahoo.com.mx

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

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[1] Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology

[2] GBD 2016 Disease and Injury

Global, regional, and national

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017; 390: 1345-422.

[4] Pearson-Stuttard J, Zhou B, Kontis V, Bentham J, Gunter MJ, Ezzati M. Worldwide burden of cancer attributable to diabetes and high body-mass index: a comparative risk assessment. Lancet Diabetes Endocrinol

[5] De Minicis S, Day C, Svegliati-Baroni G. From NAFLD to NASH and HCC: pathogenetic mechanisms and therapeutic insights. Curr Pharm Des

[6] Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L. Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis World J Gastroenterol. 2018 Aug

[7] Schwimmer JB, Deutsch R, Kahen T,

Lavine JE, Stanley C, Behling C.

Incidence and Prevalence Collaborators.

Prevalence of fatty liver in children and adolescents. Pediatrics 2006; 118:

[8] Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, Bedossa P, Belghiti J. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.

*Hepatology* 2009; 49: 851-859

[9] Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, Tiribelli C, Bellentani S; HCC-NAFLD Italian Study Group. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. *Hepatology* 2016; 63: 827-838

[10] Naga Chalasani N, Younossi Z, Lavine, JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, and Sanyal AJ. Practice Guidance. The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From the American Association for the Study of Liver Diseases. Hepatology 2018;67: 328-357

[11] European Association for the Study of the Liver (EASL). European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64: 1388-1402

[12] Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30:

[13] Cheah MC, McCullough AJ,

Goh GB. Current Modalities of Fibrosis Assessment in Non-alcoholic Fatty Liver Disease. *J Clin Transl Hepatol* 2017; 5:

1356-1362.

261-271

1388-1393

[3] GBD 2016 Risk Factors Collaborators.

incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet

**References**

2016; 64: 73-84.

2017; 390: 1211-59.

2018; 6: e6-15. 7

2013; 19: 5239-5249

14;24(30):3361-3373

*Diagnosis of Nonalcoholic Steatohepatitis DOI: http://dx.doi.org/10.5772/intechopen.96281*

#### **References**

[1] Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64: 73-84.

[2] GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017; 390: 1211-59.

[3] GBD 2016 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017; 390: 1345-422.

[4] Pearson-Stuttard J, Zhou B, Kontis V, Bentham J, Gunter MJ, Ezzati M. Worldwide burden of cancer attributable to diabetes and high body-mass index: a comparative risk assessment. Lancet Diabetes Endocrinol 2018; 6: e6-15. 7

[5] De Minicis S, Day C, Svegliati-Baroni G. From NAFLD to NASH and HCC: pathogenetic mechanisms and therapeutic insights. Curr Pharm Des 2013; 19: 5239-5249

[6] Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L. Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis World J Gastroenterol. 2018 Aug 14;24(30):3361-3373

[7] Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C.

Prevalence of fatty liver in children and adolescents. Pediatrics 2006; 118: 1388-1393

[8] Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, Bedossa P, Belghiti J. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. *Hepatology* 2009; 49: 851-859

[9] Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, Tiribelli C, Bellentani S; HCC-NAFLD Italian Study Group. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. *Hepatology* 2016; 63: 827-838

[10] Naga Chalasani N, Younossi Z, Lavine, JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, and Sanyal AJ. Practice Guidance. The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From the American Association for the Study of Liver Diseases. Hepatology 2018;67: 328-357

[11] European Association for the Study of the Liver (EASL). European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64: 1388-1402

[12] Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30: 1356-1362.

[13] Cheah MC, McCullough AJ, Goh GB. Current Modalities of Fibrosis Assessment in Non-alcoholic Fatty Liver Disease. *J Clin Transl Hepatol* 2017; 5: 261-271

[14] Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. *Hepatology* 2018; 67: 328-357

[15] Valenti L, Fracanzani AL, Bugianesi E, Dongiovanni P, Galmozzi E, Vanni E, Canavesi E, Lattuada E, Roviaro G, Marchesini G, Fargion S. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. *Gastroenterology* 2010; 138: 905-912

[16] Vuppalanchi R, Gould RJ, Wilson LA, Unalp-Arida A, Cummings OW, Chalasani N, Kowdley KV; Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Clinical significance of serum autoantibodies in patients with NAFLD: results from the nonalcoholic steatohepatitis clinical research network. *Hepatol Int* 2012; 6: 379-385

[17] Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, Tiribelli C. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. *BMC Gastroenterol* 2006; 6: 33 [PMID: 17081293 DOI: 10.1186/1471-230X-6-33]

[18] Kotronen A, Peltonen M, Hakkarainen A, Sevastianova K, Bergholm R, Johansson LM, Lundbom N, Rissanen A, Ridderstråle M, Groop L, Orho-Melander M, Yki-Järvinen H. Prediction of non- alcoholic fatty liver disease and liver fat using metabolic and genetic factors. *Gastroenterology* 2009; 137: 865-872

[19] Fedchuk L, Nascimbeni F, Pais R, Charlotte F, Housset C, Ratziu V; LIDO Study Group. Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease. *Aliment Pharmacol Ther* 2014; 40: 1209-1222

[20] Kaswala DH, Lai M, Afdhal NH. Fibrosis Assessment in Nonalcoholic Fatty Liver Disease (NAFLD) in 2016. *Dig Dis Sci* 2016; 61: 1356-1364 [PMID: 27017224 DOI: 10.1007/ s10620-016-4079-4]

[21] Fagan KJ, Pretorius CJ, Horsfall LU, Irvine KM, Wilgen U, Choi K, Fletcher LM, Tate J, Melino M, Nusrat S, Miller GC, Clouston AD, Ballard E, O'Rourke P, Lampe G, Ungerer JP, Powell EE. ELF score �9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. *Liver Int* 2015; 35: 1673-1681

[22] Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, Kaye P, Burt AD, Ryder SD, Aithal GP, Day CP, Rosenberg WM. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers. *Hepatology* 2008; 47: 455-460

[23] Tsai E, Lee T-P. Diagnosis and Evaluation of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis, Including Noninvasive Biomarkers and Transient Elastography. Clin Liver Dis 22 (2018) 73-92

[24] Martins IJ. Evaluation of diagnostic tests in human health and disease. J Clin Path Lab Med. 2018;2(1):13-15.

[25] Martins IJ. "Sirtuin 1, a Diagnostic Protein Marker and its Relevance to Chronic Disease and Therapeutic Drug Interventions". EC Pharmacology and Toxicology 6.4. 2018: 209-215

[26] Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18

**137**

3: 165-174

*Diagnosis of Nonalcoholic Steatohepatitis DOI: http://dx.doi.org/10.5772/intechopen.96281*

steatohepatitis: a multicenter validation study. *Hepatology* 2009; 50: 1072-1078

[33] Ryan CK, Johnson LA, Germin BI, Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl 2002; 8:

[34] Tapper EB, Challies T, Nasser I, Afdhal NH, Lai M. The Performance of Vibration Controlled Transient Elastography in a US Cohort of

Patients With Nonalcoholic Fatty Liver Disease. Am J Gastroenterol 2016;

[35] Wong VW, Vergniol J, Wong GL, Foucher J, Chan AW, Chermak F, Choi PC, Merrouche W, Chu SH, Pesque S, Chan HL, de Lédinghen V. Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2012;

[36] Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, Choi PC, Kowo M, Chan AW, Merrouche W, Sung JJ, de Lédinghen V. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010;

[37] Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, Fujita K, Yoneda M, Taguri M,

[38] Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288: E462-E468

Hyogo H, Sumida Y, Ono M, Eguchi Y, Inoue T, Yamanaka T, Wada K, Saito S, Nakajima A. Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Than Transient Elastography. Gastroenterology 2016; 150: 626-637.e7

1114-1122

111: 677-684

107: 1862-1871

51: 454-462

[27] Chan WK, Sthaneshwar P, Nik Mustapha NR, Mahadeva S. Limited utility of plasma M30 in discriminating non-alcoholic steatohepatitis from steatosis--a comparison with routine biochemical markers. PLoS One 2014;

[28] Shen J, Chan HL, Wong GL, Chan AW, Choi PC, Chan HY, Chim AM, Yeung DK, Yu J, Chu WC, Wong VW. Assessment of non-alcoholic fatty liver disease using serum total cell death and apoptosis markers. Aliment Pharmacol Ther 2012; 36: 1057-1066 [PMID: 23066946 DOI: 10.1111/

[29] Vuppalanchi R, Jain AK, Deppe R, Yates K, Comerford M, Masuoka HC, Neuschwander-Tetri BA, Loomba R, Brunt EM, Kleiner DE, Molleston JP, Schwimmer JB, Lavine JE, Tonascia J, Chalasani N. Relationship between changes in serum levels of keratin 18 and changes in liver histology in children and adults with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014; 12: 2121-2130. e1-2

[30] Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action. Diabetes Care 2017; 40: 419-30

[31] Lucas C, Lucas G, Lucas N, Krzowska-Firych J, Tomasiewicz K. A systematic review of the present and future of non-alcoholic fatty liver disease. Clin Exp Hepatol 2018; 4,

Gramlich T, Ong JP, Hurley M, Mullen KD, Cooper JN, Sheridan MJ. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 745-750

[32] Saadeh S, Younossi ZM, Remer EM,

9: e105903

apt.12091]

fragment levels as noninvasive biomarkers for nonalcoholic

*Diagnosis of Nonalcoholic Steatohepatitis DOI: http://dx.doi.org/10.5772/intechopen.96281*

fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. *Hepatology* 2009; 50: 1072-1078

[27] Chan WK, Sthaneshwar P, Nik Mustapha NR, Mahadeva S. Limited utility of plasma M30 in discriminating non-alcoholic steatohepatitis from steatosis--a comparison with routine biochemical markers. PLoS One 2014; 9: e105903

[28] Shen J, Chan HL, Wong GL, Chan AW, Choi PC, Chan HY, Chim AM, Yeung DK, Yu J, Chu WC, Wong VW. Assessment of non-alcoholic fatty liver disease using serum total cell death and apoptosis markers. Aliment Pharmacol Ther 2012; 36: 1057-1066 [PMID: 23066946 DOI: 10.1111/ apt.12091]

[29] Vuppalanchi R, Jain AK, Deppe R, Yates K, Comerford M, Masuoka HC, Neuschwander-Tetri BA, Loomba R, Brunt EM, Kleiner DE, Molleston JP, Schwimmer JB, Lavine JE, Tonascia J, Chalasani N. Relationship between changes in serum levels of keratin 18 and changes in liver histology in children and adults with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014; 12: 2121-2130. e1-2

[30] Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action. Diabetes Care 2017; 40: 419-30

[31] Lucas C, Lucas G, Lucas N, Krzowska-Firych J, Tomasiewicz K. A systematic review of the present and future of non-alcoholic fatty liver disease. Clin Exp Hepatol 2018; 4, 3: 165-174

[32] Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, Mullen KD, Cooper JN, Sheridan MJ. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 745-750

[33] Ryan CK, Johnson LA, Germin BI, Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl 2002; 8: 1114-1122

[34] Tapper EB, Challies T, Nasser I, Afdhal NH, Lai M. The Performance of Vibration Controlled Transient Elastography in a US Cohort of Patients With Nonalcoholic Fatty Liver Disease. Am J Gastroenterol 2016; 111: 677-684

[35] Wong VW, Vergniol J, Wong GL, Foucher J, Chan AW, Chermak F, Choi PC, Merrouche W, Chu SH, Pesque S, Chan HL, de Lédinghen V. Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2012; 107: 1862-1871

[36] Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, Choi PC, Kowo M, Chan AW, Merrouche W, Sung JJ, de Lédinghen V. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010; 51: 454-462

[37] Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, Fujita K, Yoneda M, Taguri M, Hyogo H, Sumida Y, Ono M, Eguchi Y, Inoue T, Yamanaka T, Wada K, Saito S, Nakajima A. Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Than Transient Elastography. Gastroenterology 2016; 150: 626-637.e7

[38] Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288: E462-E468 [39] Kwok R, Choi KC, Wong GL, Zhang Y, Chan HL, Luk AO, Shu SS, Chan AW, Yeung MW, Chan JC, Kong AP, Wong VW. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut 2016; 65: 1359-1368

[40] Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313-1321.

[41] Valenti L, Fracanzani AL, Bugianesi E, et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2010; 138: 905-912.

**139**

barrier, targeted treatment

**1. Introduction**

**Chapter 9**

**Abstract**

Treatment of Nonalcoholic Fatty

Liver Disease through Changes in

Nonalcoholic fatty liver disease (NAFLD) is a leading liver disease worldwide with a prevalence of approximately 25% among adult population. The highest prevalence is observed in Middle East and the lowest prevalence in Africa. NAFLD is a spectrum of liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Pro-inflammatory diet, overweight/obesity, inflammation, insulin resistance, prediabetes, type 2 diabetes, dyslipidemia, disrupted gut microbiome, and impaired intestinal barrier function are important risk factors associated with and/or contributing to NAFLD. Gut microbiome is a complex and diverse microbial ecosystem essential for the maintenance of human health. It is influenced by several factors including diet and medications. Gut microbiome can be disrupted in NAFLD. Intestinal epithelial barrier is the largest and most important barrier against the external environment and plays an important role in health and disease. Several factors including diet and gut microbiome impact intestinal barrier function. NAFLD can be associated with impaired intestinal barrier function (increased intestinal permeability). There are no specific drugs that directly treat NAFLD. The first-line therapy of NAFLD is currently lifestyle intervention. Weight loss is an important component in the treatment of NAFLD subjects who have excess body weight. Gut microbiome and intestinal epithelial barrier are becoming promising targets for the treatment of several diseases including NAFLD. In the absence of approved pharmacotherapy for the treatment of NAFLD/NASH, in addition to lifestyle intervention and weight loss (in case of excess body weight), focus should also be on correcting gut microbiome and intestinal permeability (directly and/or through gut microbiome modulation) using diet (e.g., low-fat diet, high-fiber diet, and Mediterranean diet), prebiotics (nondigestible food ingredients), probiotics (nonpathogenic living microorganisms), synbiotics (combination of prebiotics and

probiotics), and fecal microbiota transplantation (transfer of healthy stool).

**Keywords:** nonalcoholic fatty liver disease, gut microbiome, intestinal epithelial

NAFLD is a leading liver disease worldwide with a prevalence of approximately 25% among adult population. It is the most common cause of chronic

Gut Microbiome and Intestinal

Epithelial Barrier

*Hassan M. Heshmati*

#### **Chapter 9**

## Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome and Intestinal Epithelial Barrier

*Hassan M. Heshmati*

### **Abstract**

Nonalcoholic fatty liver disease (NAFLD) is a leading liver disease worldwide with a prevalence of approximately 25% among adult population. The highest prevalence is observed in Middle East and the lowest prevalence in Africa. NAFLD is a spectrum of liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Pro-inflammatory diet, overweight/obesity, inflammation, insulin resistance, prediabetes, type 2 diabetes, dyslipidemia, disrupted gut microbiome, and impaired intestinal barrier function are important risk factors associated with and/or contributing to NAFLD. Gut microbiome is a complex and diverse microbial ecosystem essential for the maintenance of human health. It is influenced by several factors including diet and medications. Gut microbiome can be disrupted in NAFLD. Intestinal epithelial barrier is the largest and most important barrier against the external environment and plays an important role in health and disease. Several factors including diet and gut microbiome impact intestinal barrier function. NAFLD can be associated with impaired intestinal barrier function (increased intestinal permeability). There are no specific drugs that directly treat NAFLD. The first-line therapy of NAFLD is currently lifestyle intervention. Weight loss is an important component in the treatment of NAFLD subjects who have excess body weight. Gut microbiome and intestinal epithelial barrier are becoming promising targets for the treatment of several diseases including NAFLD. In the absence of approved pharmacotherapy for the treatment of NAFLD/NASH, in addition to lifestyle intervention and weight loss (in case of excess body weight), focus should also be on correcting gut microbiome and intestinal permeability (directly and/or through gut microbiome modulation) using diet (e.g., low-fat diet, high-fiber diet, and Mediterranean diet), prebiotics (nondigestible food ingredients), probiotics (nonpathogenic living microorganisms), synbiotics (combination of prebiotics and probiotics), and fecal microbiota transplantation (transfer of healthy stool).

**Keywords:** nonalcoholic fatty liver disease, gut microbiome, intestinal epithelial barrier, targeted treatment

#### **1. Introduction**

NAFLD is a leading liver disease worldwide with a prevalence of approximately 25% among adult population. It is the most common cause of chronic liver disease in Western countries. NAFLD is a spectrum of liver disorders ranging from simple steatosis to NASH [1–9].

Pro-inflammatory diet, overweight/obesity, inflammation, insulin resistance, prediabetes, type 2 diabetes, dyslipidemia, disrupted gut microbiome, and impaired intestinal barrier function are important risk factors associated with and/or contributing to NAFLD [2, 4–27].

In the absence of approved drugs for the treatment of NAFLD/NASH, management relies mainly on lifestyle intervention and weight loss (in case of excess body weight) [1, 2, 8, 28–30].

Gut microbiome and intestinal epithelial barrier are becoming promising targets for the treatment of several diseases including NAFLD [4, 17, 18, 20–22, 24, 25, 31–43].

#### **2. Physiology**

#### **2.1 Liver**

The liver is the largest visceral organ. It weighs approximately 1.5 kg. Macroscopically, the liver is divided into four lobes. The basic functional unit of the liver is the liver lobule which includes the hepatocytes. Approximately 30% of the liver volume is made up by blood (**Figure 1**) [44].

The liver is a vital organ. It has numerous important roles including secretion of bile (700–1,200 mL/day), metabolism of bilirubin, metabolism of nutrients (e.g., glucose homeostasis, fat synthesis, and albumin synthesis), endocrine function (e.g., production of angiotensinogen and activation of vitamin D), storage of minerals and vitamins (e.g., iron, copper, vitamin A, vitamin B12, and vitamin D), hematologic and vascular functions (e.g., hemostatic function and capacity to store/release large volume of blood), immunologic and protective functions, and metabolic inactivation and detoxification (e.g., catabolism or alteration of hormones, toxins, and drugs) [44].

**Figure 1.** *Normal liver.*

#### **2.2 Gut microbiome**

Gut microbiome is a complex and diverse microbial ecosystem living in the digestive tract, mainly in the colon. It is established within the few first years of life and contains up to 100 trillion microbes, mainly bacteria (more than 1,000 species) but also fungi, protozoa, archaea, and viruses (**Figure 2**) [45–51].

Gut microbiome is involved in multiple physiological functions and is essential for the maintenance of human health [50–57]. It is influenced by several factors including diet and medications [31, 32, 50, 53, 58–69].

**141**

**3. NAFLD**

**Figure 3.**

**3.1 Definition**

*Intestinal epithelial barrier.*

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome…*

The intestine is lined by layer of epithelial cells that are connected by cell–cell junctions (tight junction, adherens junction, desmosome). These junctions are responsible for maintenance of tissue integrity, creation of a barrier, and signaling. The barrier, which is important for tissue homeostasis, controls the passage of water, ions, molecules, cells, and pathogens across the epithelial layer. Intestinal epithelial barrier is the largest and most important barrier against the external environment (barrier between luminal contents and the underlying immune system).

Intestinal epithelial barrier is constantly challenged by gut microbiome. It plays an important role in health and disease [23, 41–43, 70, 71]. Several factors including diet and gut microbiome impact intestinal barrier function [20, 41–43]. A highfiber diet has a beneficial effect while a high-fructose diet and a high-fat diet have a

NAFLD is a liver disease characterized by hepatic steatosis (≥ 5% fat deposit) on either imaging or histology, with no excessive alcohol consumption (< 30 g/day for men and < 20 g/day for women), in the absence of other causes of steatosis (e.g.,

and requires approximately 40% of the

*DOI: http://dx.doi.org/10.5772/intechopen.97568*

**2.3 Intestinal epithelial barrier**

**Figure 2.** *Gut microbiome.*

It covers a surface of approximately 400 m2

deleterious effect on intestinal barrier function.

body energy expenditure (**Figure 3**) [23, 41–43, 70, 71].

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome… DOI: http://dx.doi.org/10.5772/intechopen.97568*

**Figure 2.** *Gut microbiome.*

*Advances in Hepatology*

ing from simple steatosis to NASH [1–9].

liver volume is made up by blood (**Figure 1**) [44].

mones, toxins, and drugs) [44].

**2.2 Gut microbiome**

**Figure 1.** *Normal liver.*

tributing to NAFLD [2, 4–27].

weight) [1, 2, 8, 28–30].

**2. Physiology**

**2.1 Liver**

liver disease in Western countries. NAFLD is a spectrum of liver disorders rang-

Pro-inflammatory diet, overweight/obesity, inflammation, insulin resistance, prediabetes, type 2 diabetes, dyslipidemia, disrupted gut microbiome, and impaired intestinal barrier function are important risk factors associated with and/or con-

In the absence of approved drugs for the treatment of NAFLD/NASH, management relies mainly on lifestyle intervention and weight loss (in case of excess body

Gut microbiome and intestinal epithelial barrier are becoming promising targets for the treatment of several diseases including NAFLD [4, 17, 18, 20–22, 24, 25, 31–43].

The liver is the largest visceral organ. It weighs approximately 1.5 kg.

Macroscopically, the liver is divided into four lobes. The basic functional unit of the liver is the liver lobule which includes the hepatocytes. Approximately 30% of the

The liver is a vital organ. It has numerous important roles including secretion of bile (700–1,200 mL/day), metabolism of bilirubin, metabolism of nutrients (e.g., glucose homeostasis, fat synthesis, and albumin synthesis), endocrine function (e.g., production of angiotensinogen and activation of vitamin D), storage of minerals and vitamins (e.g., iron, copper, vitamin A, vitamin B12, and vitamin D), hematologic and vascular functions (e.g., hemostatic function and capacity to store/release large volume of blood), immunologic and protective functions, and metabolic inactivation and detoxification (e.g., catabolism or alteration of hor-

Gut microbiome is a complex and diverse microbial ecosystem living in the digestive tract, mainly in the colon. It is established within the few first years of life and contains up to 100 trillion microbes, mainly bacteria (more than 1,000 species)

Gut microbiome is involved in multiple physiological functions and is essential for the maintenance of human health [50–57]. It is influenced by several factors

but also fungi, protozoa, archaea, and viruses (**Figure 2**) [45–51].

including diet and medications [31, 32, 50, 53, 58–69].

**140**

#### **2.3 Intestinal epithelial barrier**

The intestine is lined by layer of epithelial cells that are connected by cell–cell junctions (tight junction, adherens junction, desmosome). These junctions are responsible for maintenance of tissue integrity, creation of a barrier, and signaling. The barrier, which is important for tissue homeostasis, controls the passage of water, ions, molecules, cells, and pathogens across the epithelial layer. Intestinal epithelial barrier is the largest and most important barrier against the external environment (barrier between luminal contents and the underlying immune system). It covers a surface of approximately 400 m2 and requires approximately 40% of the body energy expenditure (**Figure 3**) [23, 41–43, 70, 71].

Intestinal epithelial barrier is constantly challenged by gut microbiome. It plays an important role in health and disease [23, 41–43, 70, 71]. Several factors including diet and gut microbiome impact intestinal barrier function [20, 41–43]. A highfiber diet has a beneficial effect while a high-fructose diet and a high-fat diet have a deleterious effect on intestinal barrier function.

**Figure 3.** *Intestinal epithelial barrier.*

#### **3. NAFLD**

#### **3.1 Definition**

NAFLD is a liver disease characterized by hepatic steatosis (≥ 5% fat deposit) on either imaging or histology, with no excessive alcohol consumption (< 30 g/day for men and < 20 g/day for women), in the absence of other causes of steatosis (e.g.,

viral hepatitis and medications). It is a spectrum of liver disorders ranging from simple steatosis to NASH. Up to 30% of NAFLD subjects develop NASH. NASH is the aggressive form of NAFLD that can progress to fibrosis, cirrhosis, and hepatocellular cancer. The presence of fibrosis is the strongest predictor of mortality (**Figure 4**) [1–9].

Recently, a consensus of international experts proposed to change the acronym NAFLD to MAFLD (metabolic dysfunction-associated fatty liver disease) [72].

#### **3.2 Prevalence**

NAFLD is a pandemic with a prevalence of approximately 25% among adult population worldwide. The highest prevalence is observed in Middle East and the lowest prevalence in Africa. More than 1 billion people are affected by NAFLD worldwide (**Table 1**) [3, 8]. The differences in prevalence can be explained, at least partially, by genetic background and lifestyle. NAFLD prevalence continues to rise in all age groups, including in the adolescent population, especially in the setting of the obesity pandemic.

NAFLD is a sexual dimorphic disease. The prevalence of NAFLD is higher in men than in women (protective role of estrogen) [73, 74].


#### **Table 1.**

*Prevalence of NAFLD in adult population by region.*

#### **3.3 Pathophysiology**

The pathophysiology underlying NAFLD is complex with both non-genetic and genetic components [2, 4–27, 75–79].

**143**

**Table 2.**

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome…*

Pro-inflammatory diet, overweight/obesity, inflammation, insulin resistance, prediabetes, type 2 diabetes, dyslipidemia, disrupted gut microbiome, and impaired intestinal barrier function are important risk factors associated with and/or contributing to NAFLD [2, 4–27]. In addition, some miscellaneous endocrine disorders including growth hormone (GH) deficiency, hypothyroidism, polycystic ovary syndrome, and hypogonadism and deficiency in epigenetic regulators such as sirtuin 1 have been reported as possible contributing factors to

There are several genetic forms of NAFLD including variations in patatinlike phospholipase domain-containing protein 3 (*PNPLA3*), transmembrane 6 superfamily 2 (*TM6SF2*), membrane-bound O-acyltransferase domain-containing protein 7 (*MBOAT7*), and glucokinase regulatory protein (*GCKR*) genes [5, 6]. Excessive fat deposition in the liver (hepatocytes) leading to NAFLD can result from one or several combined mechanisms including increased delivery of lipids to the liver from diet or adipose tissue, increased *de novo* synthesis of lipids in the liver, decreased hepatic oxidation of fatty acids, and decreased export of triglycerides

Various common food components have pro-inflammatory potential and by contributing to chronic inflammation, can promote the development of NAFLD [10]. They can either directly alter liver metabolism or act through disruption of gut microbiome. The Western diet which is a diet rich in saturated fat, red meat, fructose, alcohol, and salt is associated with an increased risk

Excess body weight (overweight and obesity) is considered as the main cause of several abnormalities that are contributing to the pathogenesis of NAFLD (e.g., inflammation and insulin resistance). NAFLD is commonly associated with overweight/obesity [74]. It is independently associated with both subcutaneous and visceral obesity. The adipose tissue inflammation observed in overweight/obesity and characterized by increased cytokine production leads to systemic inflammation which is responsible for insulin resistance [10, 11, 80]. Clinical studies have shown that cellular and molecular adipose tissue inflammation correlate with the degree of

Based on body mass index (BMI), up to approximately 19% of NAFLD subjects

The prevalence of NAFLD by BMI in a Chinese population of Shanghai is

**BMI NAFLD Prevalence** < 18.5 (n = 445) 0.4% 18.5 to < 24.0 (n = 4,899) 12.7% 24.0 to < 28.0 (n = 2,801) 49.2% ≥ 28.0 (672) 82.4%

*DOI: http://dx.doi.org/10.5772/intechopen.97568*

NAFLD [75–79].

from the liver [7–9].

of NAFLD.

*3.3.1 Pro-inflammatory diet*

reported in **Table 2** [74].

*3.3.2 Overweight/obesity, inflammation*

liver inflammation and the importance of liver disease.

do not have excess body weight (lean NAFLD) [74, 81, 82].

*Prevalence of NAFLD by BMI in a Chinese population of Shanghai (n = 8,817).*

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome… DOI: http://dx.doi.org/10.5772/intechopen.97568*

Pro-inflammatory diet, overweight/obesity, inflammation, insulin resistance, prediabetes, type 2 diabetes, dyslipidemia, disrupted gut microbiome, and impaired intestinal barrier function are important risk factors associated with and/or contributing to NAFLD [2, 4–27]. In addition, some miscellaneous endocrine disorders including growth hormone (GH) deficiency, hypothyroidism, polycystic ovary syndrome, and hypogonadism and deficiency in epigenetic regulators such as sirtuin 1 have been reported as possible contributing factors to NAFLD [75–79].

There are several genetic forms of NAFLD including variations in patatinlike phospholipase domain-containing protein 3 (*PNPLA3*), transmembrane 6 superfamily 2 (*TM6SF2*), membrane-bound O-acyltransferase domain-containing protein 7 (*MBOAT7*), and glucokinase regulatory protein (*GCKR*) genes [5, 6].

Excessive fat deposition in the liver (hepatocytes) leading to NAFLD can result from one or several combined mechanisms including increased delivery of lipids to the liver from diet or adipose tissue, increased *de novo* synthesis of lipids in the liver, decreased hepatic oxidation of fatty acids, and decreased export of triglycerides from the liver [7–9].

#### *3.3.1 Pro-inflammatory diet*

*Advances in Hepatology*

(**Figure 4**) [1–9].

**3.2 Prevalence**

*Spectrum of NAFLD.*

**Figure 4.**

the obesity pandemic.

**3.3 Pathophysiology**

genetic components [2, 4–27, 75–79].

*Prevalence of NAFLD in adult population by region.*

viral hepatitis and medications). It is a spectrum of liver disorders ranging from simple steatosis to NASH. Up to 30% of NAFLD subjects develop NASH. NASH is the aggressive form of NAFLD that can progress to fibrosis, cirrhosis, and hepatocellular cancer. The presence of fibrosis is the strongest predictor of mortality

Recently, a consensus of international experts proposed to change the acronym NAFLD to MAFLD (metabolic dysfunction-associated fatty liver disease) [72].

NAFLD is a pandemic with a prevalence of approximately 25% among adult population worldwide. The highest prevalence is observed in Middle East and the lowest prevalence in Africa. More than 1 billion people are affected by NAFLD worldwide (**Table 1**) [3, 8]. The differences in prevalence can be explained, at least partially, by genetic background and lifestyle. NAFLD prevalence continues to rise in all age groups, including in the adolescent population, especially in the setting of

NAFLD is a sexual dimorphic disease. The prevalence of NAFLD is higher in

**Region NAFLD Prevalence World 25%** Middle East 32% South America 30% Asia 27% North America 24% Europe 24% Africa 13%

The pathophysiology underlying NAFLD is complex with both non-genetic and

men than in women (protective role of estrogen) [73, 74].

**142**

**Table 1.**

Various common food components have pro-inflammatory potential and by contributing to chronic inflammation, can promote the development of NAFLD [10]. They can either directly alter liver metabolism or act through disruption of gut microbiome. The Western diet which is a diet rich in saturated fat, red meat, fructose, alcohol, and salt is associated with an increased risk of NAFLD.

#### *3.3.2 Overweight/obesity, inflammation*

Excess body weight (overweight and obesity) is considered as the main cause of several abnormalities that are contributing to the pathogenesis of NAFLD (e.g., inflammation and insulin resistance). NAFLD is commonly associated with overweight/obesity [74]. It is independently associated with both subcutaneous and visceral obesity. The adipose tissue inflammation observed in overweight/obesity and characterized by increased cytokine production leads to systemic inflammation which is responsible for insulin resistance [10, 11, 80]. Clinical studies have shown that cellular and molecular adipose tissue inflammation correlate with the degree of liver inflammation and the importance of liver disease.

Based on body mass index (BMI), up to approximately 19% of NAFLD subjects do not have excess body weight (lean NAFLD) [74, 81, 82].

The prevalence of NAFLD by BMI in a Chinese population of Shanghai is reported in **Table 2** [74].


#### **Table 2.**

*Prevalence of NAFLD by BMI in a Chinese population of Shanghai (n = 8,817).*

#### *3.3.3 Insulin resistance, prediabetes, type 2 diabetes*

Insulin resistance plays an important role in the in the development of NAFLD. Overweight/obesity and systemic inflammation are responsible for insulin resistance which in its turn is an important contributing factor to the pathogenesis of prediabetes, type 2 diabetes, and NAFLD [2, 10, 80]. NAFLD is highly correlated with prediabetes and type 2 diabetes. There is a reciprocal association between prediabetes/type 2 diabetes and NAFLD [13]. The global prevalence of NAFLD in subjects with prediabetes and type 2 diabetes is around 48% and more than 55%, respectively (**Figure 5**) [5, 10, 12, 15].

**Figure 5.** *There is a strong association between prediabetes/type 2 diabetes and NAFLD.*

#### *3.3.4 Dyslipidemia*

Dyslipidemia is a significant risk factor for NAFLD and associated cardiovascular disease. The mechanism by which dyslipidemia increases the risk of NAFLD may be related to an increased accumulation of lipids in the hepatocytes [16].

#### *3.3.5 Disrupted gut microbiome*

Profound changes affecting the diversity and the abundance of gut microbiome (dysbiosis) are associated with several metabolic disorders including NAFLD [4, 10, 17–25, 83]. Gut microbiome plays a major role in the pathogenesis of NAFLD. Disrupted gut microbiome (e.g., increase in pro-inflammatory bacteria and decrease in protective bacteria) can promote or aggravate NAFLD through several mechanisms including change in intestinal permeability and change in the amount of absorbed energy (this can cause overweight/obesity, an important risk factor for NAFLD). Microbial metabolites and cell components contribute to the development of inflammation and hepatic steatosis.

Several clinical studies have shown the association of qualitative and quantitative changes in gut microbiome (e.g., increased *Lactobacillus* and Gram-negative bacteria) with NAFLD and its severity [4, 17–19, 24, 25]. The increased gut microbiome taxa may produce more short-chain fatty acids (SCFAs), alcohol, and lipopolysaccharides (LPS). Increased supply of SCFAs, alcohol, and LPS (endotoxins) into the portal circulation is implicated in the pathogenesis of NAFLD and its evolution to NASH (promotion of overweight/obesity and inflammation) [17, 20–23].

#### *3.3.6 Impaired intestinal barrier function*

Impaired intestinal barrier function causes increased intestinal permeability ("leaky gut") and is associated with several metabolic disorders including NAFLD [20, 23, 26, 27, 41–43, 70, 71].

**145**

**Figure 6.**

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome…*

Increased intestinal permeability is most likely caused by the disruption of intercellular tight junctions of the intestinal epithelium [26, 71]. It promotes translocation of bacteria-derived products (e.g., SCFAs, alcohol, and LPS) into the portal circulation, exposing the liver to substances capable of inducing hepatic steatosis and fibrosis [17, 20–23]. Several studies have reported that serum zonulin, a marker of intestinal permeability, correlates significantly with the severity of hepatic

Several miscellaneous endocrine disorders may contribute to the development of secondary NAFLD [75]. GH deficiency through different mechanisms including inflammation and insulin resistance may promote NAFLD. Hypothyroidism by causing impaired glucose and lipid metabolism and altered energy homeostasis can be linked to NAFLD. Polycystic ovary syndrome through multiple factors (e.g., obesity, inflammation, insulin resistance, and hyperandrogenism) may promote NAFLD. Hypogonadism can be associated with NAFLD through several mechanisms including obesity, insulin resistance, dyslipidemia, estrogen deficiency, and

Sirtuins are a group of proteins belonging to the family of silent information regulator 2. Humans have seven sirtuins. Sirtuin 1 is widely recognized as an important epigenetic regulator involved in multiple biological processes and its deficiency contributes to the pathogenesis of several diseases including NAFLD [76–79]. Exposure to sirtuin 1 inhibitors (e.g., fructose, alcohol, and LPS) leads to defective

Common genetic forms of NAFLD include variations in *PNPLA3*, *TM6SF2*, *MBOAT7*, and *GCKR* genes (**Figure 6**). These genetic forms of NAFLD are not associated with insulin resistance, type 2 diabetes, and dyslipidemia but can progress to

*DOI: http://dx.doi.org/10.5772/intechopen.97568*

steatosis in subjects with NAFLD [43].

*3.3.7 Miscellaneous endocrine disorders*

dehydroepiandrosterone deficiency.

sirtuin 1 function and can promote NAFLD.

NASH, cirrhosis, and hepatocellular cancer [5, 6].

*Several gene variants can contribute to the pathogenesis of NAFLD.*

*3.3.8 Sirtuin 1 deficiency*

*3.3.9 Genetic predisposition*

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome… DOI: http://dx.doi.org/10.5772/intechopen.97568*

Increased intestinal permeability is most likely caused by the disruption of intercellular tight junctions of the intestinal epithelium [26, 71]. It promotes translocation of bacteria-derived products (e.g., SCFAs, alcohol, and LPS) into the portal circulation, exposing the liver to substances capable of inducing hepatic steatosis and fibrosis [17, 20–23]. Several studies have reported that serum zonulin, a marker of intestinal permeability, correlates significantly with the severity of hepatic steatosis in subjects with NAFLD [43].

#### *3.3.7 Miscellaneous endocrine disorders*

*Advances in Hepatology*

*3.3.4 Dyslipidemia*

**Figure 5.**

*3.3.5 Disrupted gut microbiome*

*3.3.3 Insulin resistance, prediabetes, type 2 diabetes*

Insulin resistance plays an important role in the in the development of NAFLD. Overweight/obesity and systemic inflammation are responsible for insulin resistance which in its turn is an important contributing factor to the pathogenesis of prediabetes, type 2 diabetes, and NAFLD [2, 10, 80]. NAFLD is highly correlated with prediabetes and type 2 diabetes. There is a reciprocal association between prediabetes/type 2 diabetes and NAFLD [13]. The global prevalence of NAFLD in subjects with prediabetes and type 2 diabetes is around 48% and more than 55%, respectively (**Figure 5**) [5, 10, 12, 15].

Dyslipidemia is a significant risk factor for NAFLD and associated cardiovascular disease. The mechanism by which dyslipidemia increases the risk of NAFLD may

Profound changes affecting the diversity and the abundance of gut microbiome (dysbiosis) are associated with several metabolic disorders including NAFLD [4, 10, 17–25, 83]. Gut microbiome plays a major role in the pathogenesis of NAFLD. Disrupted gut microbiome (e.g., increase in pro-inflammatory bacteria and decrease in protective bacteria) can promote or aggravate NAFLD through several mechanisms including change in intestinal permeability and change in the amount of absorbed energy (this can cause overweight/obesity, an important risk factor for NAFLD). Microbial metabolites and cell components contribute to the

Several clinical studies have shown the association of qualitative and quantitative changes in gut microbiome (e.g., increased *Lactobacillus* and Gram-negative bacteria) with NAFLD and its severity [4, 17–19, 24, 25]. The increased gut microbiome taxa may produce more short-chain fatty acids (SCFAs), alcohol, and lipopolysaccharides (LPS). Increased supply of SCFAs, alcohol, and LPS (endotoxins) into the portal circulation is implicated in the pathogenesis of NAFLD and its evolution

to NASH (promotion of overweight/obesity and inflammation) [17, 20–23].

Impaired intestinal barrier function causes increased intestinal permeability ("leaky gut") and is associated with several metabolic disorders including NAFLD

be related to an increased accumulation of lipids in the hepatocytes [16].

*There is a strong association between prediabetes/type 2 diabetes and NAFLD.*

development of inflammation and hepatic steatosis.

*3.3.6 Impaired intestinal barrier function*

[20, 23, 26, 27, 41–43, 70, 71].

**144**

Several miscellaneous endocrine disorders may contribute to the development of secondary NAFLD [75]. GH deficiency through different mechanisms including inflammation and insulin resistance may promote NAFLD. Hypothyroidism by causing impaired glucose and lipid metabolism and altered energy homeostasis can be linked to NAFLD. Polycystic ovary syndrome through multiple factors (e.g., obesity, inflammation, insulin resistance, and hyperandrogenism) may promote NAFLD. Hypogonadism can be associated with NAFLD through several mechanisms including obesity, insulin resistance, dyslipidemia, estrogen deficiency, and dehydroepiandrosterone deficiency.

#### *3.3.8 Sirtuin 1 deficiency*

Sirtuins are a group of proteins belonging to the family of silent information regulator 2. Humans have seven sirtuins. Sirtuin 1 is widely recognized as an important epigenetic regulator involved in multiple biological processes and its deficiency contributes to the pathogenesis of several diseases including NAFLD [76–79]. Exposure to sirtuin 1 inhibitors (e.g., fructose, alcohol, and LPS) leads to defective sirtuin 1 function and can promote NAFLD.

#### *3.3.9 Genetic predisposition*

Common genetic forms of NAFLD include variations in *PNPLA3*, *TM6SF2*, *MBOAT7*, and *GCKR* genes (**Figure 6**). These genetic forms of NAFLD are not associated with insulin resistance, type 2 diabetes, and dyslipidemia but can progress to NASH, cirrhosis, and hepatocellular cancer [5, 6].

**Figure 6.** *Several gene variants can contribute to the pathogenesis of NAFLD.*

#### *3.3.10 Combination of several factors*

Several of the above-mentioned factors can be present in subjects with NAFLD, especially when they are interrelated. For example, a subject with obesity may have inflammation, insulin resistance (with prediabetes or type 2 diabetes), gut microbiome dysbiosis, and leaky gut.

#### **3.4 Diagnosis**

NAFLD is a liver disease characterized by hepatic steatosis (≥ 5% fat deposit) on either imaging or histology. Several tests (non-invasive and invasive) can be performed to support and/or confirm the diagnosis of NAFLD and the presence of fibrosis, and optimize the intervention [1, 5, 6, 9, 84–88]. There are several national and international guidelines related to the diagnosis and the management of NAFLD (e.g., American Association for the Study of Liver Diseases "AASLD", National Institute for Health and Care Excellence "NICE", European Association for the Study of the Liver "EASL", Italian Association for the Study of the Liver "AISF", and Asia-Pacific guidelines) [1, 89].

#### *3.4.1 Non-invasive tests*

Non-invasive tests of NAFLD include liver biochemistry and imaging examination [1, 5, 6, 9, 84–88].

To establish the diagnosis of NAFLD, conventional liver biochemistry is used first. It may show an increase in liver enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT). However, up to approximately 75% of subjects with NAFLD may have normal liver enzymes. Additional biomarkers and scores have been proposed (e.g., cytokeratin-18 fragment, fatty liver index, Zhejiang University index, and NAFLD liver fat score) (non-exhaustive list).

Imaging of the liver can be obtained with several tools including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) (**Figure 7**). Based on most guidelines, abdominal ultrasound should be the first-line examination for the identification of hepatic steatosis. Although ultrasound has some limitations in morbidly obese subjects and in subjects with liver fat content below 20%, it has the advantage of being widely available with low cost. MRI remains the gold standard for assessing and quantifying hepatic steatosis since it can detect a liver fat content as low as 5%. However, its use is limited due to high cost and a long time of execution. Another promising imaging technique is the ultrasonography-based transient elastography using continuous attenuation parameter.

**147**

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome…*

For the assessment of liver fibrosis, several biomarkers, scores, and imaging techniques have been proposed (e.g., AST/ALT ratio, AST to platelet ratio index, enhanced liver fibrosis score, NAFLD fibrosis score, and magnetic resonance

All the non-imaging assessments of NAFLD have limitations and alone cannot

Liver biopsy is the gold standard test in the assessment of NAFLD to diagnose NASH and stage liver fibrosis. It is potentially harmful and carries a low risk of morbidity and extremely low risk of mortality. Therefore, it should be reserved to selected subjects (**Figure 8**) [1, 90]. One important limitation of liver biopsy is that it explores only a small portion of the liver (approximately 1/50,000), not represen-

Because NAFLD/NASH is associated with increased morbidity and higher risk of death mainly related to cardiovascular and liver diseases, it is essential to initiate a treatment as soon as the diagnosis is made. In the absence of approved pharmacotherapy for the treatment of NAFLD/NASH, the first-line therapy of NAFLD remains lifestyle intervention with weight loss (in case of excess body weight) [1, 2, 8, 28–30]. Gut microbiome and intestinal epithelial barrier are becoming promising targets for the treatment of several diseases including NAFLD [4, 17, 18, 20–22, 24, 25, 31–43]. When treating NAFLD/NASH, in addition to lifestyle changes and weight loss (in case of excess body weight), focus should also be on correcting gut microbiome and intestinal permeability directly and/or through gut microbiome modulation [4, 17, 18, 20–22, 24, 25, 35–40, 43]. Several drugs for the treatment of NAFLD/NASH are currently under investigation [6, 8, 91]. It is also important to treat the associated morbidities other than overweight/obesity (e.g., type 2 diabetes and dyslipidemia).

*Liver histology showing macrovesicular steatosis in a subject with NAFLD.*

Lifestyle intervention which includes diet and exercise is the first-line therapy in NAFLD but is difficult to maintain (**Table 3**) [1, 2, 8, 28–30]. Diet is a powerful tool in the management of NAFLD. Diet relates to the amount and the composition of food that is consumed on a daily basis. There are several types of

*DOI: http://dx.doi.org/10.5772/intechopen.97568*

replace liver biopsy.

tative of the entire organ.

**3.5 Treatment**

**Figure 8.**

*3.5.1 Lifestyle intervention*

*3.4.2 Invasive tests*

elastography) (non-exhaustive list) [6, 84, 88].

**Figure 7.** *Abdominal CT scan showing diffuse hepatic steatosis in a subject with NAFLD.*

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome… DOI: http://dx.doi.org/10.5772/intechopen.97568*

For the assessment of liver fibrosis, several biomarkers, scores, and imaging techniques have been proposed (e.g., AST/ALT ratio, AST to platelet ratio index, enhanced liver fibrosis score, NAFLD fibrosis score, and magnetic resonance elastography) (non-exhaustive list) [6, 84, 88].

All the non-imaging assessments of NAFLD have limitations and alone cannot replace liver biopsy.

#### *3.4.2 Invasive tests*

*Advances in Hepatology*

**3.4 Diagnosis**

*3.4.1 Non-invasive tests*

examination [1, 5, 6, 9, 84–88].

liver fat score) (non-exhaustive list).

*3.3.10 Combination of several factors*

ome dysbiosis, and leaky gut.

Several of the above-mentioned factors can be present in subjects with NAFLD, especially when they are interrelated. For example, a subject with obesity may have inflammation, insulin resistance (with prediabetes or type 2 diabetes), gut microbi-

NAFLD is a liver disease characterized by hepatic steatosis (≥ 5% fat deposit) on either imaging or histology. Several tests (non-invasive and invasive) can be performed to support and/or confirm the diagnosis of NAFLD and the presence of fibrosis, and optimize the intervention [1, 5, 6, 9, 84–88]. There are several national and international guidelines related to the diagnosis and the management of NAFLD (e.g., American Association for the Study of Liver Diseases "AASLD", National Institute for Health and Care Excellence "NICE", European Association for the Study of the Liver "EASL", Italian Association for the Study of the Liver "AISF", and Asia-Pacific guidelines) [1, 89].

Non-invasive tests of NAFLD include liver biochemistry and imaging

To establish the diagnosis of NAFLD, conventional liver biochemistry is used first. It may show an increase in liver enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT). However, up to approximately 75% of subjects with NAFLD may have normal liver enzymes. Additional biomarkers and scores have been proposed (e.g., cytokeratin-18 fragment, fatty liver index, Zhejiang University index, and NAFLD

Imaging of the liver can be obtained with several tools including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) (**Figure 7**). Based on most guidelines, abdominal ultrasound should be the first-line examination for the identification of hepatic steatosis. Although ultrasound has some limitations in morbidly obese subjects and in subjects with liver fat content below 20%, it has the advantage of being widely available with low cost. MRI remains the gold standard for assessing and quantifying hepatic steatosis since it can detect a liver fat content as low as 5%. However, its use is limited due to high cost and a long time of execution. Another promising imaging technique is the ultrasonography-based

transient elastography using continuous attenuation parameter.

*Abdominal CT scan showing diffuse hepatic steatosis in a subject with NAFLD.*

**146**

**Figure 7.**

Liver biopsy is the gold standard test in the assessment of NAFLD to diagnose NASH and stage liver fibrosis. It is potentially harmful and carries a low risk of morbidity and extremely low risk of mortality. Therefore, it should be reserved to selected subjects (**Figure 8**) [1, 90]. One important limitation of liver biopsy is that it explores only a small portion of the liver (approximately 1/50,000), not representative of the entire organ.

**Figure 8.** *Liver histology showing macrovesicular steatosis in a subject with NAFLD.*

#### **3.5 Treatment**

Because NAFLD/NASH is associated with increased morbidity and higher risk of death mainly related to cardiovascular and liver diseases, it is essential to initiate a treatment as soon as the diagnosis is made. In the absence of approved pharmacotherapy for the treatment of NAFLD/NASH, the first-line therapy of NAFLD remains lifestyle intervention with weight loss (in case of excess body weight) [1, 2, 8, 28–30]. Gut microbiome and intestinal epithelial barrier are becoming promising targets for the treatment of several diseases including NAFLD [4, 17, 18, 20–22, 24, 25, 31–43]. When treating NAFLD/NASH, in addition to lifestyle changes and weight loss (in case of excess body weight), focus should also be on correcting gut microbiome and intestinal permeability directly and/or through gut microbiome modulation [4, 17, 18, 20–22, 24, 25, 35–40, 43]. Several drugs for the treatment of NAFLD/NASH are currently under investigation [6, 8, 91]. It is also important to treat the associated morbidities other than overweight/obesity (e.g., type 2 diabetes and dyslipidemia).

#### *3.5.1 Lifestyle intervention*

Lifestyle intervention which includes diet and exercise is the first-line therapy in NAFLD but is difficult to maintain (**Table 3**) [1, 2, 8, 28–30]. Diet is a powerful tool in the management of NAFLD. Diet relates to the amount and the composition of food that is consumed on a daily basis. There are several types of

diets with different caloric content and different composition of macronutrients, fiber, minerals, and vitamins. They include hypocaloric diet, low-carbohydrate diet, low-fat, high-protein diet, high-fiber diet, and Mediterranean diet (nonexhaustive list) [8, 29, 30, 92]. In NAFLD subjects, hypocaloric diet is usually a deficit of 500–1,000 kcal/day. For macronutrient composition and according to most recommendations, carbohydrate intake should be between 40 and 50% (with exclusion of fructose from foods and beverages), fat intake no more than 30% (with saturated fat below 10%), and protein intake between 15 and 20% [28]. Even without significant weight loss, anti-inflammatory diets like Mediterranean diet (a mainly plant-based low-carbohydrate and high-unsaturated fat diet) have beneficial properties both in the prevention and treatment of NAFLD [8, 10, 25, 27–29, 93]. The omega-3 polyunsaturated fatty acids present in the Mediterranean diet may reduce hepatic steatosis. A diet containing sirtuin 1 activators (e.g., magnesium and zinc) can be beneficial in NAFLD subjects [79].

The objective in NAFLD subjects with excess body weight is a weight loss of 7–10%. To achieve weight loss, in addition to lifestyle intervention, other tools including drugs, medical devices, and bariatric surgery can also be used when needed and indicated [2, 28, 94–97]. Rapid sudden weight loss should be avoided (risk of aggravation of liver failure).

Lean NAFLD subjects may have visceral obesity that is not detected by BMI. These subjects may also benefit from diet and weight loss.

In addition to the type of diet, the timing and the frequency of the meals may also influence NAFLD. It is recommended to consume more daily calories in the morning versus the evening and avoid skipping meals [29].

Regular exercise including moderate intensity aerobic activities (3–5 weekly sessions with approximately 40 minutes per session) and resistance training can reduce hepatic steatosis even without significant weight loss [1, 8, 28, 29]. Combination of exercise and diet has greater benefit than exercise or diet alone.


**Table 3.**

*Lifestyle intervention for the treatment of NAFLD.*

#### *3.5.2 Gut microbiome modulation*

The prevention and management of NAFLD may benefit from modulation and correction of gut microbiome [4, 17, 18, 20–22, 24, 25, 35–40]. Gut microbiome can be modulated through diet, antibiotics, prebiotics, probiotics, synbiotics, and fecal microbiota transplantation [4, 17, 18, 20–22, 24, 25, 33–40, 58–65]. To optimize the efficacy of these therapies, focus should be on the altered gut microbiome (e.g., taxa responsible for high alcohol and LPS production) [17].

**149**

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome…*

decrease in Firmicutes-to-Bacteroidetes phyla ratio) [58–64].

beneficial bacterial species and cause antibiotic resistance.

Diet is an important tool for the modulation of gut microbiome. The amount of daily caloric intake and the content of food significantly affect gut microbiome. A diet that is low in calories (when weight loss is needed), low in fat, and high in fiber has a favorable effect on weight control and gut microbiome (increase in richness,

The diet, through the modulation of gut microbiome, could be beneficial in

Antibiotics are medications used to fight local or systemic infection [98]. Antibiotics affect gut microbiome [4, 24, 59, 65]. They can deplete or alter gut microbiome (e.g., increase in Firmicutes phylum) and reduce liver disease development. However, their clinical use is limited since they may eliminate important

Prebiotics are chemicals (nondigestible food ingredients) inducing growth and/or activity of intestinal bacteria (e.g., inulin, lactulose, and resistant starch) [31, 69]. Some dietary fibers are prebiotics [25]. Prebiotics can be found in many foods (e.g., leek, asparagus, onion, soybean, apple, and banana) (**Figure 9**). Prebiotics can positively modulate gut microbiome and improve NAFLD [4, 21, 24, 25, 35]. They lower the production of LPS. Treatment with oligofructose (16 g/day for 8 weeks) in subjects with NASH showed a significant decrease of

Probiotics are nonpathogenic living microorganisms with direct or indirect effect on gut microbiome [31, 32, 68]. Probiotics can be found in several foods

Probiotics can positively impact gut microbiome and improve NAFLD [4, 21, 24, 36–39]. They reduce the production of LPS. Administration of *Lactobacillus rhamnosus* strain GG (12 billion CFU/day) for 8 weeks in children with NAFLD showed a significant decrease of ALT [36]. Treatment with VSL#3 (a mixture of 8 probiotic strains) for 4 months in children with NAFLD demon-

*Prebiotics can be beneficial in the treatment of NAFLD by modulating gut microbiome.*

*DOI: http://dx.doi.org/10.5772/intechopen.97568*

*3.5.2.1 Diet*

NAFLD subjects [4, 25].

*3.5.2.2 Antibiotics*

*3.5.2.3 Prebiotics*

AST [35].

*3.5.2.4 Probiotics*

**Figure 9.**

(e.g., yogurt, cheese, and milk) (**Figure 10**).

strated a significant decrease of hepatic steatosis [38].

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome… DOI: http://dx.doi.org/10.5772/intechopen.97568*

#### *3.5.2.1 Diet*

*Advances in Hepatology*

subjects [79].

diet alone.

body weight)

**Table 3.**

(risk of aggravation of liver failure).

*3.5.2 Gut microbiome modulation*

*Lifestyle intervention for the treatment of NAFLD.*

Diet for weight loss (in case of excess

These subjects may also benefit from diet and weight loss.

morning versus the evening and avoid skipping meals [29].

**Lifestyle Intervention Description**

diets with different caloric content and different composition of macronutrients, fiber, minerals, and vitamins. They include hypocaloric diet, low-carbohydrate diet, low-fat, high-protein diet, high-fiber diet, and Mediterranean diet (nonexhaustive list) [8, 29, 30, 92]. In NAFLD subjects, hypocaloric diet is usually a deficit of 500–1,000 kcal/day. For macronutrient composition and according to most recommendations, carbohydrate intake should be between 40 and 50% (with exclusion of fructose from foods and beverages), fat intake no more than 30% (with saturated fat below 10%), and protein intake between 15 and 20% [28]. Even without significant weight loss, anti-inflammatory diets like Mediterranean diet (a mainly plant-based low-carbohydrate and high-unsaturated fat diet) have beneficial properties both in the prevention and treatment of NAFLD [8, 10, 25, 27–29, 93]. The omega-3 polyunsaturated fatty acids present in the Mediterranean diet may reduce hepatic steatosis. A diet containing sirtuin 1 activators (e.g., magnesium and zinc) can be beneficial in NAFLD

The objective in NAFLD subjects with excess body weight is a weight loss of 7–10%. To achieve weight loss, in addition to lifestyle intervention, other tools including drugs, medical devices, and bariatric surgery can also be used when needed and indicated [2, 28, 94–97]. Rapid sudden weight loss should be avoided

Lean NAFLD subjects may have visceral obesity that is not detected by BMI.

In addition to the type of diet, the timing and the frequency of the meals may also influence NAFLD. It is recommended to consume more daily calories in the

Regular exercise including moderate intensity aerobic activities (3–5 weekly sessions with approximately 40 minutes per session) and resistance training can reduce hepatic steatosis even without significant weight loss [1, 8, 28, 29]. Combination of exercise and diet has greater benefit than exercise or

Healthy diet Low-carbohydrate diet, Low-fat diet, High-fiber diet,

Exercise Aerobic activities, Resistance training

Mediterranean diet, etc.

Hypocaloric diet

The prevention and management of NAFLD may benefit from modulation and correction of gut microbiome [4, 17, 18, 20–22, 24, 25, 35–40]. Gut microbiome can be modulated through diet, antibiotics, prebiotics, probiotics, synbiotics, and fecal microbiota transplantation [4, 17, 18, 20–22, 24, 25, 33–40, 58–65]. To optimize the efficacy of these therapies, focus should be on the altered gut microbiome (e.g., taxa responsible for high alcohol and LPS

**148**

production) [17].

Diet is an important tool for the modulation of gut microbiome. The amount of daily caloric intake and the content of food significantly affect gut microbiome. A diet that is low in calories (when weight loss is needed), low in fat, and high in fiber has a favorable effect on weight control and gut microbiome (increase in richness, decrease in Firmicutes-to-Bacteroidetes phyla ratio) [58–64].

The diet, through the modulation of gut microbiome, could be beneficial in NAFLD subjects [4, 25].

#### *3.5.2.2 Antibiotics*

Antibiotics are medications used to fight local or systemic infection [98].

Antibiotics affect gut microbiome [4, 24, 59, 65]. They can deplete or alter gut microbiome (e.g., increase in Firmicutes phylum) and reduce liver disease development. However, their clinical use is limited since they may eliminate important beneficial bacterial species and cause antibiotic resistance.

#### *3.5.2.3 Prebiotics*

Prebiotics are chemicals (nondigestible food ingredients) inducing growth and/or activity of intestinal bacteria (e.g., inulin, lactulose, and resistant starch) [31, 69]. Some dietary fibers are prebiotics [25]. Prebiotics can be found in many foods (e.g., leek, asparagus, onion, soybean, apple, and banana) (**Figure 9**).

Prebiotics can positively modulate gut microbiome and improve NAFLD [4, 21, 24, 25, 35]. They lower the production of LPS. Treatment with oligofructose (16 g/day for 8 weeks) in subjects with NASH showed a significant decrease of AST [35].

**Figure 9.** *Prebiotics can be beneficial in the treatment of NAFLD by modulating gut microbiome.*

#### *3.5.2.4 Probiotics*

Probiotics are nonpathogenic living microorganisms with direct or indirect effect on gut microbiome [31, 32, 68]. Probiotics can be found in several foods (e.g., yogurt, cheese, and milk) (**Figure 10**).

Probiotics can positively impact gut microbiome and improve NAFLD [4, 21, 24, 36–39]. They reduce the production of LPS. Administration of *Lactobacillus rhamnosus* strain GG (12 billion CFU/day) for 8 weeks in children with NAFLD showed a significant decrease of ALT [36]. Treatment with VSL#3 (a mixture of 8 probiotic strains) for 4 months in children with NAFLD demonstrated a significant decrease of hepatic steatosis [38].

**Figure 10.** *Probiotics can be beneficial in the treatment of NAFLD by modulating gut microbiome.*

#### *3.5.2.5 Synbiotics*

Synbiotics are combination of prebiotics and probiotics. They have the potential to induce more effects than prebiotics or probiotics used alone.

There are few studies assessing the effects of synbiotics on NAFLD subjects. They showed several beneficial effects including reduction of inflammation and hepatic steatosis [4, 24, 40]. Administration of *Bifidobacterium longum* with fructo-oligosaccharides for 24 weeks in subjects with NASH showed a significant decrease of AST, serum endotoxin, hepatic steatosis, and NASH activity index [40].

#### *3.5.2.6 Fecal microbiota transplantation*

Fecal microbiota transplantation consists of transfer of feces from a healthy donor to a recipient. The addition of healthy stool can be done through colonoscopy, orogastric tube, esophagogastroduodenoscopy, or oral capsule (**Figure 11**) [99].

Fecal microbiota transplantation is an exciting therapy with important potential indications. It was first approved by the United States Food and Drug Administration for the treatment of *Clostridium difficile* infection. Fecal microbiota transplantation can modify gut microbiome for the purpose of obesity and metabolic disorders management [33, 34]. Clinical studies using fecal microbiota transplantation in NAFLD subjects are currently ongoing.

**151**

**Table 4.**

*3.5.5 Liver transplantation*

tion after hepatitis C [89].

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome…*

Restoring the intestinal epithelial barrier is an attractive therapeutic approach in NAFLD subjects. Currently, there is no approved drug for this indication. Intestinal permeability can be targeted and corrected directly (with diet) and/or through gut

A study using high-fiber diet for 6 months in subjects with NAFLD showed a decrease in intestinal permeability as demonstrated by a reduction of approximately 90% of serum zonulin, and a significant reduction of liver enzymes (e.g., AST, ALT,

There are no approved drugs for the treatment of NAFLD/NASH. Several investigational drugs are currently in various stages of clinical trials. They can impact at least four pathways related to NAFLD development and progression (hepatic fat accumulation, oxidative stress, gut microbiome, and hepatic fibrosis) [7, 8, 91]. Some of these investigational drugs have shown promising preliminary results (e.g., lanifibranor, cenicriviroc, and resmetirom) (non-exhaustive list)

Any drug that is currently used in the treatment of NAFLD/NASH (e.g., antidiabetic drugs, lipid-lowering drugs, and vitamin E) should be considered as an off-label treatment [1, 2, 6–9, 14–16, 28, 91, 100]. Among the antidiabetic drugs, pioglitazone has shown a strong efficacy and became the first-line therapy in subjects who have type 2 diabetes and NAFLD [1, 2, 6, 14,

The summary of different tools available in the United States of America (USA) or under investigation for the treatment of NAFLD/NASH is reported in **Table 4**.

Anti-obesity drug Xenical®, Qsymia®, Contrave®, Saxenda®

Intestinal permeability correction High-fiber diet, Gut microbiome modulation

Investigational drug Lanifibranor, Cenicriviroc, Resmetirom, etc.

Off-label drug Antidiabetic drugs, Vitamin E, etc.

Anti-obesity medical device Lap-Band®, AspireAssist®, Orbera® Intragastric Balloon

Plenity® Bariatric surgery Sleeve gastrectomy, Roux-en-Y gastric bypass

Gut microbiome modulation Diet, Antibiotics, Prebiotics, Probiotics, Synbiotics, Fecal

*Summary of different tools available in the USA or under investigation for the treatment of NAFLD/NASH.*

microbiota transplantation

System, TransPyloric Shuttle®, Obalon® Balloon System,

NASH is becoming one of the leading causes of liver transplantation. Currently, in the USA, NASH ranks as the second most common reason for liver transplanta-

*DOI: http://dx.doi.org/10.5772/intechopen.97568*

*3.5.3 Intestinal permeability correction*

microbiome modulation [17, 18, 43].

and GGT) and hepatic steatosis [43].

**Tool Description** Lifestyle intervention Diet, Exercise

*3.5.4 Drugs*

[6, 8, 91].

15, 28, 100].

**Figure 11.** *Fecal microbiota transplantation has the potential to treat NAFLD by modifying gut microbiome.*

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome… DOI: http://dx.doi.org/10.5772/intechopen.97568*

#### *3.5.3 Intestinal permeability correction*

Restoring the intestinal epithelial barrier is an attractive therapeutic approach in NAFLD subjects. Currently, there is no approved drug for this indication. Intestinal permeability can be targeted and corrected directly (with diet) and/or through gut microbiome modulation [17, 18, 43].

A study using high-fiber diet for 6 months in subjects with NAFLD showed a decrease in intestinal permeability as demonstrated by a reduction of approximately 90% of serum zonulin, and a significant reduction of liver enzymes (e.g., AST, ALT, and GGT) and hepatic steatosis [43].

#### *3.5.4 Drugs*

*Advances in Hepatology*

*3.5.2.5 Synbiotics*

**Figure 10.**

index [40].

*3.5.2.6 Fecal microbiota transplantation*

Synbiotics are combination of prebiotics and probiotics. They have the potential

There are few studies assessing the effects of synbiotics on NAFLD subjects. They showed several beneficial effects including reduction of inflammation and hepatic steatosis [4, 24, 40]. Administration of *Bifidobacterium longum* with fructo-oligosaccharides for 24 weeks in subjects with NASH showed a significant decrease of AST, serum endotoxin, hepatic steatosis, and NASH activity

Fecal microbiota transplantation consists of transfer of feces from a healthy donor to a recipient. The addition of healthy stool can be done through colonoscopy, orogastric tube, esophagogastroduodenoscopy, or oral capsule (**Figure 11**) [99]. Fecal microbiota transplantation is an exciting therapy with important potential indications. It was first approved by the United States Food and Drug Administration for the treatment of *Clostridium difficile* infection. Fecal microbiota transplantation can modify gut microbiome for the purpose of obesity and metabolic disorders management [33, 34]. Clinical studies using fecal microbiota

to induce more effects than prebiotics or probiotics used alone.

*Probiotics can be beneficial in the treatment of NAFLD by modulating gut microbiome.*

transplantation in NAFLD subjects are currently ongoing.

*Fecal microbiota transplantation has the potential to treat NAFLD by modifying gut microbiome.*

**150**

**Figure 11.**

There are no approved drugs for the treatment of NAFLD/NASH. Several investigational drugs are currently in various stages of clinical trials. They can impact at least four pathways related to NAFLD development and progression (hepatic fat accumulation, oxidative stress, gut microbiome, and hepatic fibrosis) [7, 8, 91]. Some of these investigational drugs have shown promising preliminary results (e.g., lanifibranor, cenicriviroc, and resmetirom) (non-exhaustive list) [6, 8, 91].

Any drug that is currently used in the treatment of NAFLD/NASH (e.g., antidiabetic drugs, lipid-lowering drugs, and vitamin E) should be considered as an off-label treatment [1, 2, 6–9, 14–16, 28, 91, 100]. Among the antidiabetic drugs, pioglitazone has shown a strong efficacy and became the first-line therapy in subjects who have type 2 diabetes and NAFLD [1, 2, 6, 14, 15, 28, 100].

The summary of different tools available in the United States of America (USA) or under investigation for the treatment of NAFLD/NASH is reported in **Table 4**.


#### **Table 4.**

*Summary of different tools available in the USA or under investigation for the treatment of NAFLD/NASH.*

#### *3.5.5 Liver transplantation*

NASH is becoming one of the leading causes of liver transplantation. Currently, in the USA, NASH ranks as the second most common reason for liver transplantation after hepatitis C [89].

### **4. Conclusions**

NAFLD is the most common chronic liver disease worldwide. It is a spectrum of liver disorders ranging from simple steatosis to NASH. NAFLD subjects have overweight/obesity in the majority of cases and the disease can be associated with disrupted gut microbiome and impaired intestinal barrier function.

In the absence of approved pharmacotherapy for the treatment of NAFLD/ NASH, in addition to lifestyle intervention with weight loss (in case of excess body weight), targeting gut microbiome and intestinal epithelial barrier with diet, prebiotics, probiotics, synbiotics, and fecal microbiota transplantation represents a promising novel therapeutic approach.

### **Conflict of interest**

The author declares no conflict of interest.

### **Author details**

Hassan M. Heshmati Endocrinology Metabolism Consulting, LLC, Anthem, AZ, USA

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

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

**153**

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome…*

disease: A focus on promising drugs for

Pharmacological Reports. 2020;**72**:1-12. DOI: 10.1007/s43440-019-00020-1

Pathophysiology, clinical outcomes, and future directions. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2019;**12**:1001-1012. DOI:

[10] Tilg H, Adolph TE, Moschen AR. Multiple parallel hits hypothesis in nonalcoholic fatty liver disease: Revisited after a decade. Hepatology.

[11] Alisi A, Carpino G, Oliveira FL, Panera N, Nobili V, Gaudio E. The role of tissue macrophage-mediated inflammation on NAFLD pathogenesis and its clinical implications. Mediators

[12] Vesa CM, Behl T, Nemeth S, et al. Prediction of NAFLD occurrence in prediabetes patients. Experimental and Therapeutic Medicine. 2020;**20**:190.

[13] Radaelli MG, Martucci F, Perra S, et al. NAFLD/NASH in patients with type 2 diabetes and related treatment options. Journal of Endocrinological Investigation. 2018;**41**:509-521. DOI:

[14] Tacelli M, Celsa C, Magro B, et al. Antidiabetic drugs in NAFLD: The accomplishment of two goals at once. Pharmaceuticals. 2018;**11**:121. DOI:

[15] Kim KS, Lee BW. Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease. Clinical and

DOI: 10.3892/etm.2020.9320

10.1007/s40618-017-0799-3

10.3390/ph11040121

nonalcoholic steatohepatitis.

[9] Gharaibeh NE, Rahhal MN, Rahimi L, Ismail-Beigi F. SGLT-2 inhibitors as promising therapeutics for non-alcoholic fatty liver disease:

10.2147/DMSO.S212715

DOI: 10.1002/hep.31518

of Inflammation. DOI: 10.1155/2017/8162421

*DOI: http://dx.doi.org/10.5772/intechopen.97568*

[1] Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L. Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis. World Journal of Gastroenterology.

2018;**24**:3361-3373. DOI: 10.3748/wjg.

[2] Mundi MS, Velapati S, Patel J, Kellogg TA, Abu Dayyeh BK, Hurt RT.

Evolution of NAFLD and its management. Nutrition in Clinical Practice. 2020;**35**:72-84. DOI: 10.1002/

[3] Younossi ZB, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease – Metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;**64**:73-84. DOI: 10.1002/hep.28431

and Molecular Life Sciences. 2019;**76**:1541-1558. DOI: 10.1007/

10.1007/s00125-016-3944-1

[6] Drescher HK, Weiskirchen S,

Weiskirchen R. Current status in testing for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Cells.

2019;**8**:845. DOI: 10.3390/cells8080845

[7] Oseini AM, Sanyal AJ. Therapies in non-alcoholic steatohepatitis (NASH). Liver International. 2017;**37** (Suppl 1):

97-103. DOI: 10.1111/liv.13302

[8] Pydyn N, Miękus K, Jura J, Kotlinowski J. New therapeutic strategies in nonalcoholic fatty liver

[5] Yki-Järvinen. Diagnosis of nonalcoholic fatty liver disease (NAFLD). Diabetologia. 2016;**59**:1104-1111. DOI:

s00018-019-03011-w

[4] Safari Z, Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cellular

v24.i30.3361

**References**

ncp.10449

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome… DOI: http://dx.doi.org/10.5772/intechopen.97568*

#### **References**

*Advances in Hepatology*

**4. Conclusions**

**Conflict of interest**

promising novel therapeutic approach.

The author declares no conflict of interest.

**152**

**Author details**

Hassan M. Heshmati

Endocrinology Metabolism Consulting, LLC, Anthem, AZ, USA

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

NAFLD is the most common chronic liver disease worldwide. It is a spectrum of liver disorders ranging from simple steatosis to NASH. NAFLD subjects have overweight/obesity in the majority of cases and the disease can be associated with

In the absence of approved pharmacotherapy for the treatment of NAFLD/ NASH, in addition to lifestyle intervention with weight loss (in case of excess body weight), targeting gut microbiome and intestinal epithelial barrier with diet, prebiotics, probiotics, synbiotics, and fecal microbiota transplantation represents a

disrupted gut microbiome and impaired intestinal barrier function.

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

provided the original work is properly cited.

[1] Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L. Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis. World Journal of Gastroenterology. 2018;**24**:3361-3373. DOI: 10.3748/wjg. v24.i30.3361

[2] Mundi MS, Velapati S, Patel J, Kellogg TA, Abu Dayyeh BK, Hurt RT. Evolution of NAFLD and its management. Nutrition in Clinical Practice. 2020;**35**:72-84. DOI: 10.1002/ ncp.10449

[3] Younossi ZB, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease – Metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;**64**:73-84. DOI: 10.1002/hep.28431

[4] Safari Z, Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cellular and Molecular Life Sciences. 2019;**76**:1541-1558. DOI: 10.1007/ s00018-019-03011-w

[5] Yki-Järvinen. Diagnosis of nonalcoholic fatty liver disease (NAFLD). Diabetologia. 2016;**59**:1104-1111. DOI: 10.1007/s00125-016-3944-1

[6] Drescher HK, Weiskirchen S, Weiskirchen R. Current status in testing for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Cells. 2019;**8**:845. DOI: 10.3390/cells8080845

[7] Oseini AM, Sanyal AJ. Therapies in non-alcoholic steatohepatitis (NASH). Liver International. 2017;**37** (Suppl 1): 97-103. DOI: 10.1111/liv.13302

[8] Pydyn N, Miękus K, Jura J, Kotlinowski J. New therapeutic strategies in nonalcoholic fatty liver disease: A focus on promising drugs for nonalcoholic steatohepatitis. Pharmacological Reports. 2020;**72**:1-12. DOI: 10.1007/s43440-019-00020-1

[9] Gharaibeh NE, Rahhal MN, Rahimi L, Ismail-Beigi F. SGLT-2 inhibitors as promising therapeutics for non-alcoholic fatty liver disease: Pathophysiology, clinical outcomes, and future directions. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2019;**12**:1001-1012. DOI: 10.2147/DMSO.S212715

[10] Tilg H, Adolph TE, Moschen AR. Multiple parallel hits hypothesis in nonalcoholic fatty liver disease: Revisited after a decade. Hepatology. DOI: 10.1002/hep.31518

[11] Alisi A, Carpino G, Oliveira FL, Panera N, Nobili V, Gaudio E. The role of tissue macrophage-mediated inflammation on NAFLD pathogenesis and its clinical implications. Mediators of Inflammation. DOI: 10.1155/2017/8162421

[12] Vesa CM, Behl T, Nemeth S, et al. Prediction of NAFLD occurrence in prediabetes patients. Experimental and Therapeutic Medicine. 2020;**20**:190. DOI: 10.3892/etm.2020.9320

[13] Radaelli MG, Martucci F, Perra S, et al. NAFLD/NASH in patients with type 2 diabetes and related treatment options. Journal of Endocrinological Investigation. 2018;**41**:509-521. DOI: 10.1007/s40618-017-0799-3

[14] Tacelli M, Celsa C, Magro B, et al. Antidiabetic drugs in NAFLD: The accomplishment of two goals at once. Pharmaceuticals. 2018;**11**:121. DOI: 10.3390/ph11040121

[15] Kim KS, Lee BW. Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease. Clinical and

Molecular Hepatology. 2020;**26**:430- 443. DOI: 10.3350/cmh.2020.0137

[16] Iqbal U, Perumpail BJ, John N, et al. Judicious use of lipid lowering agents in the management of NAFLD. Diseases. 2018;**6**:87. DOI: 10.3390/ diseases6040087

[17] Zhu L, Baker RD, Baker SS. Gut microbiome and nonalcoholic fatty liver diseases. Pediatric Research. 2015;**77**:245-251. DOI: 10.1038/ pr.2014.157

[18] Vespasiani-Gentilucci U, Gallo P, Picardi A. The role of intestinal microbiota in the pathogenesis of NAFLD: Starting points for intervention. Archives of Medical Science. 2018;**14**:701-706. DOI: 10.5114/ aoms.2016.58831

[19] Grabherr F, Grander C, Effenberger M, Adolph TE, Tilg H. Gut dysfunction and non-alcoholic fatty liver disease. Frontiers in Endocrinology. 2019;**10**:611. DOI: 10.3389/fendo.2019.00611

[20] Kolodziejczyk AA, Zheng D, Shibolet O, Elinav E. The role of the microbiome in NAFLD and NASH. EMBO Molecular Medicine. 2019;**11**:e9302. DOI: 10.15252/ emmm.201809302

[21] Durate SMB, Stefano JT, Oliveira CP. Microbiota and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH). Annals of Hepatology. 2019;**18**:416-421. DOI: 10.1016/j. aohep.2019.04006

[22] Liu Q, Liu S, Chen L, et al. Role and effective therapeutic target of gut microbiota in NAFLD/NASH (review). Experimental and Therapeutic Medicine. 2019;**18**:1935-1944. DOI: 10.3892/etm.2019.7781

[23] Jadhav K, Cohen TS. Can you trust your gut? Implicating a disrupted

intestinal microbiome in the progression of NAFLD/NASH. Frontiers in Endocrinology. 2020;**11**:592157. DOI: 10.3389/fendo.2020.592157

[24] Hu H, Lin A, Kong M, et al. Intestinal microbiome and NAFLD: Molecular insights and therapeutic perspectives. Journal of Gastroenterology. 2020;**55**:142-158. DOI: 10.1007/s00535-019-01649-8

[25] Pérez-Montes de Oca A, Julián MT, Ramos A, Puig-Domingo M, Alonso N. Microbiota, fiber, and NAFLD: Is there any connection? Nutrients. 2020;**12**:3100. DOI: 10.3390/nu12103100

[26] Luther J, Garber JJ, Khalili H, et al. Hepatic injury in nonalcoholic steatohepatitis contributes to altered intestinal permeability. Cellular and Molecular Gastroenterology and Hepatology. 2015;**1**:222-232. DOI: 10.1016/j.jcmgh.2015.01.001

[27] Biolato M, Manca F, Marrone G, et al. Intestinal permeability after Mediterranean diet and low-fat diet in non-alcoholic fatty liver disease. World Journal of Gastroenterology. 2019;**25**:509-520. DOI: 10.3748/wjg. v25.i4.509

[28] Hossain N, Kanwar P, Mohanty SR. A comprehensive updated review of pharmaceutical and nonpharmaceutical treatment for NAFLD. Gastroenterology Research and Practice. DOI: 10.1155/2016/7109270

[29] El-Agroudy NN, Kurzbach A, Rodionov RN, et al. Are lifestyle therapies effective for NAFLD treatment? Trends in Endocrinology & Metabolism. 2019;**30**:701-709. DOI: 10.1016/j.tem.2019.07.013

[30] Plaz Torres MC, Aghemo A, Lleo A, et al. Mediterranean diet and NAFLD: What we know and questions that still need to be answered. Nutrients. 2019;**11**:2971. DOI: 10.3390/nu11122971

**155**

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome…*

[38] Alisi A, Bedogni G, Baviera G, et al. Randomized clinical trial: The beneficial effects of VSL#3 in obese children with

Therapeutics. 2014;**39**:1276-1285. DOI:

[39] Lavekar AS, Raje DV, Manohar T, Lavekar AA. Role of probiotics in the treatment of nonalcoholic fatty liver disease: A meta-analysis. Euroasian Journal of Hepato-Gastroenterology.

[40] Malaguarnera M, Vacante M, Antic T, et al. *Bifidobacterium longum* with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Digestive Diseases and Sciences. 2012;**57**:545-553. DOI: 10.1007/

non-alcoholic steatohepatitis. Alimentary Pharmacology and

10.1111/apt.12758

2017;**7**:130-137

s10620-011-1887-4

nrgastro.2016.169

10.3390/nu10111793

2017;**4**:13-24

[41] Bischoff SC, Barbara G, Buurman W, et al. Intestinal

prevention and therapy. BMC Gastroenterology. 2014;**14**:189. DOI:

[42] Odenwald MA, Turner JR. The intestinal epithelial barrier: A therapeutic target? Nature Reviews. Gastroenterology & Hepatology. 2017;**14**:9-21. DOI: 10.1038/

[43] Krawczyk M, Maciejewska D, Ryterska K, et al. Gut permeability might be improved by dietary fiber in individuals with nonalcoholic fatty liver disease (NAFLD) undergoing weight reduction. Nutrients. 2018;**10**:1793. DOI:

[44] Ozougwu JC. Physiology of the liver. International Journal of Research

[45] The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human

in Pharmacy and Biosciences.

10.1186/s12876-014-0189-7

permeability – A new target for disease

*DOI: http://dx.doi.org/10.5772/intechopen.97568*

[32] Kobyliak N, Conte C, Cammarota G, et al. Probiotics in prevention and treatment of obesity: A critical view. Nutrition and Metabolism. 2016;**13**:14. DOI: 10.1186/s12986-016-0067-0

[33] Jayasinghe TN, Chiavaroli V, Holland DJ, Cutfield WS, O'Sullivan JM. The new era of treatment for obesity and metabolic disorders: Evidence and expectations for gut microbiome transplantation. Frontiers in Cellular and Infection Microbiology. 2016;**6**:15. DOI: 10.3389/

[34] Marotz CA, Zarrinpar A. Treating obesity and metabolic syndrome with fecal microbiota transplantation. Yale Journal of Biology and Medicine.

nonalcoholic steatohepatitis: Results of a pilot study. European Journal of Clinical Nutrition. 2005;**59**:723-726. DOI:

[36] Vajro P, Mandato C, Licenziati MR, et al. Effects of *Lactobacillus rhamnosus* strain GG in pediatric obesity-related liver disease. Journal of Pediatric Gastroenterology and Nutrition. 2011;**52**:740-743. DOI: 10.1097/ MPG.0b013e31821f9b85

[37] Ma YY, Li L, Yu CH, Shen Z, Chen LH, Li YM. Effects of probiotics on nonalcoholic fatty liver disease: A meta-analysis. World Journal of Gastroenterology. 2013;**19**:6911-6918.

DOI: 10.3748/wjg.v19.i40.6911

[35] Daubioul CA, Horsmans Y, Lambert P, Danse E, Delzenne NM. Effects of oligofructose on glucose and lipid metabolism in patients with

10.1038/sj.ejcn.1602127

[31] Dahiya DK, Renuka, Puniya M, et al. Gut microbiota modulation and its relationship with obesity using prebiotics fibers and probiotics: A review. Frontiers in Microbiology.

2017;**8**:563. DOI: 10.3389/

fmicb.2017.00563

fcimb.2016.00015

2016;**89**:383-388

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome… DOI: http://dx.doi.org/10.5772/intechopen.97568*

[31] Dahiya DK, Renuka, Puniya M, et al. Gut microbiota modulation and its relationship with obesity using prebiotics fibers and probiotics: A review. Frontiers in Microbiology. 2017;**8**:563. DOI: 10.3389/ fmicb.2017.00563

*Advances in Hepatology*

2018;**6**:87. DOI: 10.3390/

diseases6040087

pr.2014.157

aoms.2016.58831

[19] Grabherr F, Grander C,

liver disease. Frontiers in

10.3389/fendo.2019.00611

emmm.201809302

aohep.2019.04006

Molecular Hepatology. 2020;**26**:430- 443. DOI: 10.3350/cmh.2020.0137

[17] Zhu L, Baker RD, Baker SS. Gut microbiome and nonalcoholic fatty liver

[18] Vespasiani-Gentilucci U, Gallo P, Picardi A. The role of intestinal microbiota in the pathogenesis of NAFLD: Starting points for intervention. Archives of Medical Science. 2018;**14**:701-706. DOI: 10.5114/

Effenberger M, Adolph TE, Tilg H. Gut dysfunction and non-alcoholic fatty

Endocrinology. 2019;**10**:611. DOI:

[20] Kolodziejczyk AA, Zheng D, Shibolet O, Elinav E. The role of the microbiome in NAFLD and NASH. EMBO Molecular Medicine. 2019;**11**:e9302. DOI: 10.15252/

[21] Durate SMB, Stefano JT, Oliveira CP. Microbiota and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH). Annals of Hepatology.

[22] Liu Q, Liu S, Chen L, et al. Role and effective therapeutic target of gut microbiota in NAFLD/NASH (review).

[23] Jadhav K, Cohen TS. Can you trust your gut? Implicating a disrupted

2019;**18**:416-421. DOI: 10.1016/j.

Experimental and Therapeutic Medicine. 2019;**18**:1935-1944. DOI:

10.3892/etm.2019.7781

diseases. Pediatric Research. 2015;**77**:245-251. DOI: 10.1038/

[16] Iqbal U, Perumpail BJ, John N, et al. Judicious use of lipid lowering agents in the management of NAFLD. Diseases.

intestinal microbiome in the progression

Gastroenterology. 2020;**55**:142-158. DOI:

[25] Pérez-Montes de Oca A, Julián MT, Ramos A, Puig-Domingo M, Alonso N. Microbiota, fiber, and NAFLD: Is there

2020;**12**:3100. DOI: 10.3390/nu12103100

[26] Luther J, Garber JJ, Khalili H, et al.

[27] Biolato M, Manca F, Marrone G, et al. Intestinal permeability after Mediterranean diet and low-fat diet in non-alcoholic fatty liver disease. World

[28] Hossain N, Kanwar P, Mohanty SR. A comprehensive updated review of pharmaceutical and nonpharmaceutical treatment for NAFLD. Gastroenterology

of NAFLD/NASH. Frontiers in Endocrinology. 2020;**11**:592157. DOI:

[24] Hu H, Lin A, Kong M, et al. Intestinal microbiome and NAFLD: Molecular insights and therapeutic

10.3389/fendo.2020.592157

perspectives. Journal of

10.1007/s00535-019-01649-8

any connection? Nutrients.

Hepatic injury in nonalcoholic steatohepatitis contributes to altered intestinal permeability. Cellular and Molecular Gastroenterology and Hepatology. 2015;**1**:222-232. DOI: 10.1016/j.jcmgh.2015.01.001

Journal of Gastroenterology. 2019;**25**:509-520. DOI: 10.3748/wjg.

Research and Practice. DOI: 10.1155/2016/7109270

10.1016/j.tem.2019.07.013

[29] El-Agroudy NN, Kurzbach A, Rodionov RN, et al. Are lifestyle therapies effective for NAFLD

treatment? Trends in Endocrinology & Metabolism. 2019;**30**:701-709. DOI:

[30] Plaz Torres MC, Aghemo A, Lleo A, et al. Mediterranean diet and NAFLD: What we know and questions that still need to be answered. Nutrients. 2019;**11**:2971. DOI: 10.3390/nu11122971

v25.i4.509

**154**

[32] Kobyliak N, Conte C, Cammarota G, et al. Probiotics in prevention and treatment of obesity: A critical view. Nutrition and Metabolism. 2016;**13**:14. DOI: 10.1186/s12986-016-0067-0

[33] Jayasinghe TN, Chiavaroli V, Holland DJ, Cutfield WS, O'Sullivan JM. The new era of treatment for obesity and metabolic disorders: Evidence and expectations for gut microbiome transplantation. Frontiers in Cellular and Infection Microbiology. 2016;**6**:15. DOI: 10.3389/ fcimb.2016.00015

[34] Marotz CA, Zarrinpar A. Treating obesity and metabolic syndrome with fecal microbiota transplantation. Yale Journal of Biology and Medicine. 2016;**89**:383-388

[35] Daubioul CA, Horsmans Y, Lambert P, Danse E, Delzenne NM. Effects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: Results of a pilot study. European Journal of Clinical Nutrition. 2005;**59**:723-726. DOI: 10.1038/sj.ejcn.1602127

[36] Vajro P, Mandato C, Licenziati MR, et al. Effects of *Lactobacillus rhamnosus* strain GG in pediatric obesity-related liver disease. Journal of Pediatric Gastroenterology and Nutrition. 2011;**52**:740-743. DOI: 10.1097/ MPG.0b013e31821f9b85

[37] Ma YY, Li L, Yu CH, Shen Z, Chen LH, Li YM. Effects of probiotics on nonalcoholic fatty liver disease: A meta-analysis. World Journal of Gastroenterology. 2013;**19**:6911-6918. DOI: 10.3748/wjg.v19.i40.6911

[38] Alisi A, Bedogni G, Baviera G, et al. Randomized clinical trial: The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Alimentary Pharmacology and Therapeutics. 2014;**39**:1276-1285. DOI: 10.1111/apt.12758

[39] Lavekar AS, Raje DV, Manohar T, Lavekar AA. Role of probiotics in the treatment of nonalcoholic fatty liver disease: A meta-analysis. Euroasian Journal of Hepato-Gastroenterology. 2017;**7**:130-137

[40] Malaguarnera M, Vacante M, Antic T, et al. *Bifidobacterium longum* with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Digestive Diseases and Sciences. 2012;**57**:545-553. DOI: 10.1007/ s10620-011-1887-4

[41] Bischoff SC, Barbara G, Buurman W, et al. Intestinal permeability – A new target for disease prevention and therapy. BMC Gastroenterology. 2014;**14**:189. DOI: 10.1186/s12876-014-0189-7

[42] Odenwald MA, Turner JR. The intestinal epithelial barrier: A therapeutic target? Nature Reviews. Gastroenterology & Hepatology. 2017;**14**:9-21. DOI: 10.1038/ nrgastro.2016.169

[43] Krawczyk M, Maciejewska D, Ryterska K, et al. Gut permeability might be improved by dietary fiber in individuals with nonalcoholic fatty liver disease (NAFLD) undergoing weight reduction. Nutrients. 2018;**10**:1793. DOI: 10.3390/nu10111793

[44] Ozougwu JC. Physiology of the liver. International Journal of Research in Pharmacy and Biosciences. 2017;**4**:13-24

[45] The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human

microbiome. Nature. 2012;**486**:207-214. DOI: 10.1038/nature11234

[46] Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;**489**:220-230. DOI: 10.1038/ nature11550

[47] Kundu P, Blacher E, Elinav E, Pettersson S. Our gut microbiome: The evolving inner self. Cell. 2017;**171**:1481- 1493. DOI: 10.1016/j.cell.2017.11.024

[48] Barko PC, McMichael MA, Swanson KS, Williams DA. The gastrointestinal microbiome: A review. Journal of Veterinary Internal Medicine. 2018;**32**:9-25. DOI: 10.1111/jvim.14875

[49] Schmidt TSB, Raes J, Bork P. The human gut microbiome: From association to modulation. Cell. 2018;**172**:1198-1215. DOI: 10.1016/j. cell.2018.02.044

[50] Heshmati HM. Gut microbiome in obesity management. In: Himmerich H, editor. Weight Management. London: IntechOpen; 2020. p. 255-268. DOI: 10.5772/intechopen.91974

[51] Conrad R, Vlassov AV. The human microbiota: Composition, functions, and therapeutic potential. Medical Science Review. 2015;**2**:92-103. DOI: 10.12659/MSRev.895154

[52] Ramakrishna BS. Role of the gut microbiota in human nutrition and metabolism. Journal of Gastroenterology and Hepatology. 2013;**28**(Suppl 4):9-17. DOI: 10.1111/ jgh.12294

[53] Kovatcheva-Datchary P, Nilsson A, Akrami R, et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of *Prevotella*. Cell Metabolism. 2015;**22**:971-982. DOI: 10.1016/j. cmet.2015.10.001

[54] Gerard C, Vidal H. Impact of gut microbiota on host glycemic control. Frontiers in Endocrinology. 2019;**10**:29. DOI: 10.3389/fendo.2019.00029

[55] Covasa M, Stephens RW, Toderean R, Cobuz C. Intestinal sensing by gut microbiota: Targeting gut peptides. Frontiers in Endocrinology. 2019;**10**:82. DOI: 10.3389/ fendo.2019.00082

[56] Fu J, Bonder MJ, Cenit MC. The gut microbiome contributes to a substantial proportion of the variation in blood lipids. Circulation Research. 2015;**117**:817-824. DOI: 10.1161/ CIRCRESAHA.115.306807

[57] Chen YC, Greenbaum J, Shen H, Deng HW. Association between gut microbiota and bone health: Potential mechanisms and prospective. The Journal of Clinical Endocrinology & Metabolism. 2017;**102**:3635-3646. DOI: 10.1210/jc.2017-00513

[58] Moschen AR, Wieser V, Tilg H. Dietary factors: Major regulators of the gut's microbiota. Gut and Liver. 2012;**6**:411-416. DOI: 10.5009/ gnl.20126.4.411

[59] Voreades N, Kozil A, Weir TL. Diet and the development of the human intestinal microbiome. Frontiers in Microbiology. 2014;**5**:494. DOI: 10.3389/ fmicb.2014.00494

[60] Graf D, Di Cagno R, Fåk F, et al. Contribution of diet to the composition of the human gut microbiota. Microbial Ecology in Health and Disease. 2015;**26**:26164. DOI: 10.3402/mehd. v26.26164

[61] Bibbò S, Ianiro G, Giorgio V, et al. The role of diet on gut microbiota composition. European Review for Medical and Pharmacological Sciences. 2016;**20**:4742-4749

[62] Singh RK, Chang HW, Yan D, et al. Influence of diet on the gut microbiome

**157**

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome…*

contribute to inflammatory and autoimmune diseases. Science. 2018;**359**:1097-1098. DOI: 10.1126/

[71] Dai X, Wang B. Role of gut barrier function in the pathogenesis of nonalcoholic fatty liver disease.

Gastroenterology Research and Practice.

Long MT, Valenti L. MAFLD vs NAFLD:

International. 2020;**40**:2079-2081. DOI:

[73] Ballestri S, Nascimbeni F, Baldelli E, Marrazzo A, Romagnoli D, Lonardo A. NAFLD as a sexual dimorphic disease: Role of gender and reproductive status in the development and progression of nonalcoholic fatty liver disease and inherent cardiovascular risk. Advances in Therapy. 2017;**34**:1291-1326. DOI:

DOI: 10.1155/2015/287348

Let the contest begin. Liver

10.1007/s12325-017-0556-1

[74] Wang L, Guo J, Lu J. Risk factor compositions of nonalcoholic fatty liver disease change with body mass index in

[75] Lonardo A, Mantovani A, Lugari S, Targher G. NAFLD in some common endocrine diseases: Prevalence, pathophysiology, and principles of diagnosis and management. International Journal of Molecular Sciences. 2019;**20**:2841. DOI: 10.3390/

[76] Lee IH. Mechanisms and disease implications of sirtuin-mediated autophagic regulation. Experimental & Molecular Medicine. 2019;**51**:102. DOI:

[77] Nassir F, Ibdah JA. Sirtuins and nonalcoholic fatty liver disease. World

2016;**22**:10084-10092. DOI: 10.3748/wjg.

10.1038/s12276-019-0302-7

Journal of Gastroenterology.

males and females. Oncotarget.

2016;**7**:35632-35642

ijms20112841

v22.i46.10084

10.1111/liv.14620

[72] Bianco C, Romeo S, Petta S,

science.aat0835

*DOI: http://dx.doi.org/10.5772/intechopen.97568*

and implications for human health. Journal of Translational Medicine.

Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;**505**:559-563.

[64] Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;**334**:105-108. DOI: 10.1126/

Déraspe M, et al. The initial state of the human gut microbiome determines its reshaping by antibiotics. The ISME Journal. 2016;**10**:707-720. DOI: 10.1038/

2017;**15**:73. DOI: 10.1186/ s12967-017-1175-y

[63] David LA, Maurice CF,

DOI: 10.1038/nature12820

[65] Raymond F, Ouameur AA,

[66] Le Bastard Q, Al-Ghalith GA, Grégoire M, et al. Systematic review: Human gut dysbiosis induced by

Alimentary Pharmacology &

non-antibiotic prescription medications.

[67] Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;**555**:623-628. DOI: 10.1038/

[68] Hill C, Guarner F, Reid G, et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews. Gastroenterology & Hepatology. 2014;**11**:506-514. DOI:

[69] Carnahan S, Balzer A, Panchal SK,

[70] Citi S. Intestinal barriers protect against disease. Leaky cell-cell junctions

Therapeutics. 2018;**47**:332-345. DOI:

science.1208344

ismej.2015.148

10.1111/apt.14451

nature25979

10.1038/nrgastro.2014.66

Brown L. Prebiotics in obesity. Panminerva Medica. 2014;**56**:165-175 *Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome… DOI: http://dx.doi.org/10.5772/intechopen.97568*

and implications for human health. Journal of Translational Medicine. 2017;**15**:73. DOI: 10.1186/ s12967-017-1175-y

*Advances in Hepatology*

nature11550

cell.2018.02.044

10.5772/intechopen.91974

10.12659/MSRev.895154

metabolism. Journal of

*Prevotella*. Cell Metabolism. 2015;**22**:971-982. DOI: 10.1016/j.

cmet.2015.10.001

jgh.12294

DOI: 10.1038/nature11234

microbiome. Nature. 2012;**486**:207-214.

[54] Gerard C, Vidal H. Impact of gut microbiota on host glycemic control. Frontiers in Endocrinology. 2019;**10**:29.

Toderean R, Cobuz C. Intestinal sensing

[56] Fu J, Bonder MJ, Cenit MC. The gut microbiome contributes to a substantial proportion of the variation in blood

[57] Chen YC, Greenbaum J, Shen H, Deng HW. Association between gut microbiota and bone health: Potential mechanisms and prospective. The Journal of Clinical Endocrinology & Metabolism. 2017;**102**:3635-3646. DOI:

[58] Moschen AR, Wieser V, Tilg H. Dietary factors: Major regulators of the

[59] Voreades N, Kozil A, Weir TL. Diet and the development of the human intestinal microbiome. Frontiers in Microbiology. 2014;**5**:494. DOI: 10.3389/

[60] Graf D, Di Cagno R, Fåk F, et al. Contribution of diet to the composition of the human gut microbiota. Microbial

[61] Bibbò S, Ianiro G, Giorgio V, et al. The role of diet on gut microbiota composition. European Review for Medical and Pharmacological Sciences.

[62] Singh RK, Chang HW, Yan D, et al. Influence of diet on the gut microbiome

Ecology in Health and Disease. 2015;**26**:26164. DOI: 10.3402/mehd.

gut's microbiota. Gut and Liver. 2012;**6**:411-416. DOI: 10.5009/

DOI: 10.3389/fendo.2019.00029

by gut microbiota: Targeting gut peptides. Frontiers in Endocrinology.

[55] Covasa M, Stephens RW,

2019;**10**:82. DOI: 10.3389/

lipids. Circulation Research. 2015;**117**:817-824. DOI: 10.1161/ CIRCRESAHA.115.306807

10.1210/jc.2017-00513

gnl.20126.4.411

fmicb.2014.00494

2016;**20**:4742-4749

v26.26164

fendo.2019.00082

[46] Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the

human gut microbiota. Nature. 2012;**489**:220-230. DOI: 10.1038/

[47] Kundu P, Blacher E, Elinav E, Pettersson S. Our gut microbiome: The evolving inner self. Cell. 2017;**171**:1481- 1493. DOI: 10.1016/j.cell.2017.11.024

[48] Barko PC, McMichael MA, Swanson KS, Williams DA. The

gastrointestinal microbiome: A review. Journal of Veterinary Internal Medicine. 2018;**32**:9-25. DOI: 10.1111/jvim.14875

[49] Schmidt TSB, Raes J, Bork P. The human gut microbiome: From association to modulation. Cell. 2018;**172**:1198-1215. DOI: 10.1016/j.

[50] Heshmati HM. Gut microbiome in obesity management. In: Himmerich H, editor. Weight Management. London: IntechOpen; 2020. p. 255-268. DOI:

[51] Conrad R, Vlassov AV. The human microbiota: Composition, functions, and therapeutic potential. Medical Science Review. 2015;**2**:92-103. DOI:

[52] Ramakrishna BS. Role of the gut microbiota in human nutrition and

Gastroenterology and Hepatology. 2013;**28**(Suppl 4):9-17. DOI: 10.1111/

[53] Kovatcheva-Datchary P, Nilsson A, Akrami R, et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of

**156**

[63] David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;**505**:559-563. DOI: 10.1038/nature12820

[64] Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;**334**:105-108. DOI: 10.1126/ science.1208344

[65] Raymond F, Ouameur AA, Déraspe M, et al. The initial state of the human gut microbiome determines its reshaping by antibiotics. The ISME Journal. 2016;**10**:707-720. DOI: 10.1038/ ismej.2015.148

[66] Le Bastard Q, Al-Ghalith GA, Grégoire M, et al. Systematic review: Human gut dysbiosis induced by non-antibiotic prescription medications. Alimentary Pharmacology & Therapeutics. 2018;**47**:332-345. DOI: 10.1111/apt.14451

[67] Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;**555**:623-628. DOI: 10.1038/ nature25979

[68] Hill C, Guarner F, Reid G, et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews. Gastroenterology & Hepatology. 2014;**11**:506-514. DOI: 10.1038/nrgastro.2014.66

[69] Carnahan S, Balzer A, Panchal SK, Brown L. Prebiotics in obesity. Panminerva Medica. 2014;**56**:165-175

[70] Citi S. Intestinal barriers protect against disease. Leaky cell-cell junctions contribute to inflammatory and autoimmune diseases. Science. 2018;**359**:1097-1098. DOI: 10.1126/ science.aat0835

[71] Dai X, Wang B. Role of gut barrier function in the pathogenesis of nonalcoholic fatty liver disease. Gastroenterology Research and Practice. DOI: 10.1155/2015/287348

[72] Bianco C, Romeo S, Petta S, Long MT, Valenti L. MAFLD vs NAFLD: Let the contest begin. Liver International. 2020;**40**:2079-2081. DOI: 10.1111/liv.14620

[73] Ballestri S, Nascimbeni F, Baldelli E, Marrazzo A, Romagnoli D, Lonardo A. NAFLD as a sexual dimorphic disease: Role of gender and reproductive status in the development and progression of nonalcoholic fatty liver disease and inherent cardiovascular risk. Advances in Therapy. 2017;**34**:1291-1326. DOI: 10.1007/s12325-017-0556-1

[74] Wang L, Guo J, Lu J. Risk factor compositions of nonalcoholic fatty liver disease change with body mass index in males and females. Oncotarget. 2016;**7**:35632-35642

[75] Lonardo A, Mantovani A, Lugari S, Targher G. NAFLD in some common endocrine diseases: Prevalence, pathophysiology, and principles of diagnosis and management. International Journal of Molecular Sciences. 2019;**20**:2841. DOI: 10.3390/ ijms20112841

[76] Lee IH. Mechanisms and disease implications of sirtuin-mediated autophagic regulation. Experimental & Molecular Medicine. 2019;**51**:102. DOI: 10.1038/s12276-019-0302-7

[77] Nassir F, Ibdah JA. Sirtuins and nonalcoholic fatty liver disease. World Journal of Gastroenterology. 2016;**22**:10084-10092. DOI: 10.3748/wjg. v22.i46.10084

[78] Martins I. The future of genomic medicine involves the maintenance of sirtuin I in global populations. International Journal of Molecular Biology. 2017;**2**:42-45. DOI: 10.15406/ ijmboa.2017.02.00013

[79] Martins IJ. Nutrition therapy regulates caffeine metabolism with relevance to NAFLD and induction of type 3 diabetes. Journal of Diabetes and Metabolic Disorders. 2017;**4**:019. DOI: 10.24966/DMD-201X/100019

[80] Ye J. Mechanisms of insulin resistance in obesity. Frontiers of Medicine. 2013;**7**:14-24. DOI: 10.1007/ s11684-013-0262-6

[81] Niriella MA, Kasturiratne A, Pathmeswaran A, et al. Lean nonalcoholic fatty liver disease (lean NAFLD): Characteristics, metabolic outcomes and risk factors from a 7-year prospective, community cohort study from Sri Lanka. Hepatology International. 2019;**13**:314-322. DOI: 10.1007/s12072-018-9916-4

[82] Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: A systematic review and meta-analysis. Lancet Gastroenterology & Hepatology. 2020;**5**:739-752. DOI: 10.1016/S2468-1253(20)30077-7

[83] Holmes E, Li JV, Athanasiou T, Ashrafian H, Nicholson JK. Understanding the role of gut microbiome-host metabolic signal disruption in health and disease. Trends in Microbiolgy. 2011;**19**:349-359. DOI: 10.1016/j.tim.2011.05.006

[84] Cleveland E, Bandy A, VanWagner LB. Diagnostic challenges of nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis. Clinical Liver Disease. 2018;**11**:98-104

[85] Zhou JH, Cai JJ, She ZG, Li HL. Noninvasive evaluation of nonalcoholic fatty liver disease: Current evidence and practice. World Journal of Gastroenterology. 2019;**25**:1307-1326. DOI: 10.3748/wjg.v25.i11.1307

[86] Lee DH. Noninvasive evaluation of nonalcoholic fatty liver disease. Endocrinology and Metabolism. 2020;**35**:243-259. DOI: 10.3803/ EnM.2020.35.2.243

[87] Fu CP, Ali H, Rachakonda VP, Oczypok EA, DeLany JP, Kershaw EE. The ZJU index is a powerful surrogate marker for NAFLD in severely obese North American women. Plos One. 2019;**14**:e0224942. DOI: 10.1371/journal. pone.0224942

[88] Kaswala DH, Lai M, Afdhal NH. Fibrosis assessment in nonalcoholic fatty liver disease (NAFLD) in 2016. Digestive Diseases and Sciences. 2016;**61**:1356-1364. DOI: 10.1007/ s10620-016-4079-4

[89] Paul S, Davis AM. Diagnosis and management of nonalcoholic fatty liver disease. Journal of the American Medical Association. 2018;**320**:2474-2475

[90] Bedossa P. Histological assessment of NAFLD. Digestive Diseases and Sciences. 2016;**61**:1348-1355. DOI: 10.1007/s10620-016-4062-0

[91] Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. Journal of Gastroenterology. 2018;**53**:362-376. DOI: 10.1007/s00535-017-1415-1

[92] Freedman MR, King J, Kennedy E. Popular diets: A scientific review. Obesity Research. 2001;**9**(Suppl 1): 1S–40S

[93] Tyrovolas S, Panagiotakos DB, Georgousopoulou EN, et al. The antiinflammatory potential of diet and nonalcoholic fatty liver disease: The ATTICA study. Therapeutic Advances in

**159**

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome…*

*DOI: http://dx.doi.org/10.5772/intechopen.97568*

Gastroenterology. 2019;**12**:1-11. DOI:

Berthoud HR, Heymsfield SB. Obesity. Pathophysiology and management. Journal of the American College of Cardiology. 2018;**71**:69-84. DOI:

[96] Heshmati HM. Anti-obesity medical devices. In: Himmerich H, editor. Weight Management. London: IntechOpen; 2020. p. 239-253. DOI:

[97] Radvinsky D, Iskandar M, Ferzli G. Bariatric surgery today: The good, the

Laparoscopic and Endoscopic Surgery.

[98] Coates ARM, Halls G, Hu Y. Novel classes of antibiotics or more of the same? British Journal of Pharmacology.

10.1177/1756284819858039

[94] Gadde KM, Martin CK,

10.1016/j.jacc.2017.11.011

oby.22581

[95] Saxon DR, Iwamoto SJ, Mettenbrink CJ, et al. Antiobesity medication use in 2.2 million adults across eight large health care organizations: 2009-2015. Obesity. 2019;**27**:1975-1981. DOI: 10.1002/

10.5772/intechopen.91697

bad, and the ugly. Annals of

2017;**2**:52. DOI: 10.21037/

2011;**163**:184-194. DOI:

jfma.2018.08.011

10.1111/j.1476-5381.2011.01250.x

[99] Wang JW, Kuo CH, Kuo FC, et al. Fecal microbiota transplantation: Review and update. Journal of the Formosan Medical Association. 2019;**118**:S23-S31. DOI: 10.1016/j.

[100] Sawangjit R, Chongmelaxme B, Phisalprapa P, et al. Comparative efficacy of interventions on nonalcoholic fatty liver disease (NAFLD). A PRISMA-compliant systematic review and network meta-analysis. Medicine.

2016;**95**:32(e4529). DOI: 10.1097/

MD.0000000000004529

ales.2017.02.26

*Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome… DOI: http://dx.doi.org/10.5772/intechopen.97568*

Gastroenterology. 2019;**12**:1-11. DOI: 10.1177/1756284819858039

*Advances in Hepatology*

ijmboa.2017.02.00013

s11684-013-0262-6

[78] Martins I. The future of genomic medicine involves the maintenance of sirtuin I in global populations. International Journal of Molecular Biology. 2017;**2**:42-45. DOI: 10.15406/

fatty liver disease: Current evidence and

Gastroenterology. 2019;**25**:1307-1326.

[86] Lee DH. Noninvasive evaluation of

practice. World Journal of

DOI: 10.3748/wjg.v25.i11.1307

nonalcoholic fatty liver disease. Endocrinology and Metabolism. 2020;**35**:243-259. DOI: 10.3803/

[87] Fu CP, Ali H, Rachakonda VP, Oczypok EA, DeLany JP, Kershaw EE. The ZJU index is a powerful surrogate marker for NAFLD in severely obese North American women. Plos One. 2019;**14**:e0224942. DOI: 10.1371/journal.

[88] Kaswala DH, Lai M, Afdhal NH. Fibrosis assessment in nonalcoholic fatty liver disease (NAFLD) in 2016. Digestive Diseases and Sciences. 2016;**61**:1356-1364. DOI: 10.1007/

[89] Paul S, Davis AM. Diagnosis and management of nonalcoholic fatty liver disease. Journal of the American

[90] Bedossa P. Histological assessment of NAFLD. Digestive Diseases and Sciences. 2016;**61**:1348-1355. DOI: 10.1007/s10620-016-4062-0

[91] Sumida Y, Yoneda M. Current and future pharmacological therapies for

Gastroenterology. 2018;**53**:362-376. DOI:

[92] Freedman MR, King J, Kennedy E. Popular diets: A scientific review. Obesity Research. 2001;**9**(Suppl 1):

[93] Tyrovolas S, Panagiotakos DB, Georgousopoulou EN, et al. The antiinflammatory potential of diet and nonalcoholic fatty liver disease: The ATTICA study. Therapeutic Advances in

NAFLD/NASH. Journal of

10.1007/s00535-017-1415-1

1S–40S

EnM.2020.35.2.243

pone.0224942

s10620-016-4079-4

Medical Association. 2018;**320**:2474-2475

[79] Martins IJ. Nutrition therapy regulates caffeine metabolism with relevance to NAFLD and induction of type 3 diabetes. Journal of Diabetes and Metabolic Disorders. 2017;**4**:019. DOI:

10.24966/DMD-201X/100019

[80] Ye J. Mechanisms of insulin resistance in obesity. Frontiers of Medicine. 2013;**7**:14-24. DOI: 10.1007/

[81] Niriella MA, Kasturiratne A, Pathmeswaran A, et al. Lean nonalcoholic fatty liver disease (lean NAFLD): Characteristics, metabolic outcomes and risk factors from a 7-year prospective, community cohort study

from Sri Lanka. Hepatology

10.1007/s12072-018-9916-4

International. 2019;**13**:314-322. DOI:

[82] Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: A systematic review and meta-analysis. Lancet Gastroenterology & Hepatology. 2020;**5**:739-752. DOI: 10.1016/S2468-1253(20)30077-7

[83] Holmes E, Li JV, Athanasiou T, Ashrafian H, Nicholson JK. Understanding the role of gut microbiome-host metabolic signal disruption in health and disease. Trends in Microbiolgy. 2011;**19**:349-359. DOI:

10.1016/j.tim.2011.05.006

[84] Cleveland E, Bandy A,

Liver Disease. 2018;**11**:98-104

[85] Zhou JH, Cai JJ, She ZG, Li HL. Noninvasive evaluation of nonalcoholic

VanWagner LB. Diagnostic challenges of nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis. Clinical

**158**

[94] Gadde KM, Martin CK, Berthoud HR, Heymsfield SB. Obesity. Pathophysiology and management. Journal of the American College of Cardiology. 2018;**71**:69-84. DOI: 10.1016/j.jacc.2017.11.011

[95] Saxon DR, Iwamoto SJ, Mettenbrink CJ, et al. Antiobesity medication use in 2.2 million adults across eight large health care organizations: 2009-2015. Obesity. 2019;**27**:1975-1981. DOI: 10.1002/ oby.22581

[96] Heshmati HM. Anti-obesity medical devices. In: Himmerich H, editor. Weight Management. London: IntechOpen; 2020. p. 239-253. DOI: 10.5772/intechopen.91697

[97] Radvinsky D, Iskandar M, Ferzli G. Bariatric surgery today: The good, the bad, and the ugly. Annals of Laparoscopic and Endoscopic Surgery. 2017;**2**:52. DOI: 10.21037/ ales.2017.02.26

[98] Coates ARM, Halls G, Hu Y. Novel classes of antibiotics or more of the same? British Journal of Pharmacology. 2011;**163**:184-194. DOI: 10.1111/j.1476-5381.2011.01250.x

[99] Wang JW, Kuo CH, Kuo FC, et al. Fecal microbiota transplantation: Review and update. Journal of the Formosan Medical Association. 2019;**118**:S23-S31. DOI: 10.1016/j. jfma.2018.08.011

[100] Sawangjit R, Chongmelaxme B, Phisalprapa P, et al. Comparative efficacy of interventions on nonalcoholic fatty liver disease (NAFLD). A PRISMA-compliant systematic review and network meta-analysis. Medicine. 2016;**95**:32(e4529). DOI: 10.1097/ MD.0000000000004529

**161**

**Chapter 10**

**Abstract**

Fatty Liver

post-liver transplant patients.

**1. Introduction**

*Anja Geerts and Sander Lefere*

The Role of Bariatric Surgery in

Non-alcoholic fatty liver disease (NAFLD) is a crucial health problem with a prevalence that is increasing concurrently with the obesity epidemic on a global scale. Steatosis, nonalcoholic steatohepatitis (NASH), hepatocellular carcinoma (HCC), cirrhosis, and advanced fibrosis constitute the disease spectrum covered by NAFLD. NASH-related cirrhosis and HCC is currently the second most common indication for liver transplantation. Although lifestyle modifications, especially weight loss, effectively reduces the liver injury in NASH, adherence in the clinical setting is low. Potential treatments for NASH are still under investigation in phase 2–3 studies. Bariatric surgery can improve metabolic components and cause great weight loss. Therefore, bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients. However, complications such as liver failure after bariatric surgery can occur. This chapter will give an overview of the benefits and pitfalls of bariatric surgery in patients with NAFLD, liver transplant candidates and

**Keywords:** bariatric surgery, NAFLD, NASH, liver transplant, liver failure

the United States were obese (BMI (body mass index) > 30 kg/m2

and consititute the major cause of deaths in patients with NAFLD.

Over the last decades, there has been a drastic increase in obesity prevalence. Health statistics reports of 2018 showed that 40% of the total adult population of

The obesity epidemic has led to a dramatic rise in the obesity-related liver disease non-alcoholic fatty liver disease (NAFLD). NAFLD currentlyaffects one quarter of the global population [1]. Steatosis or fatty liver, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) make up the spectrum of conditions that NAFLD represents. The frequency of liver transplantation undertaken in patients with cirrhosis and HCC due to NASH has been increasing worldwide [2]. NAFLD has also been found to be associated with several health conditions like cardiovascular diseases which affect organs outside the liver

Lifestyle modification is the cornerstone of NAFLD therapy. As a matter of fact, reduced intake of calories combined with increased activity can make this achievable. The main driver of NAFLD improvement is the amount of actual weight loss, while the type of diet seems to be less important. Rrespective of how one achieves weight loss, the highest rates of steatohepatitis resolution (90%) as well as improvement of fibrosis (45%) can only be induced by >10% weight loss. A weight loss of >5% improves steatosis in about 64% and weight loss of >7% can resolve

).

**Chapter 10**

## The Role of Bariatric Surgery in Fatty Liver

*Anja Geerts and Sander Lefere*

#### **Abstract**

Non-alcoholic fatty liver disease (NAFLD) is a crucial health problem with a prevalence that is increasing concurrently with the obesity epidemic on a global scale. Steatosis, nonalcoholic steatohepatitis (NASH), hepatocellular carcinoma (HCC), cirrhosis, and advanced fibrosis constitute the disease spectrum covered by NAFLD. NASH-related cirrhosis and HCC is currently the second most common indication for liver transplantation. Although lifestyle modifications, especially weight loss, effectively reduces the liver injury in NASH, adherence in the clinical setting is low. Potential treatments for NASH are still under investigation in phase 2–3 studies. Bariatric surgery can improve metabolic components and cause great weight loss. Therefore, bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients. However, complications such as liver failure after bariatric surgery can occur. This chapter will give an overview of the benefits and pitfalls of bariatric surgery in patients with NAFLD, liver transplant candidates and post-liver transplant patients.

**Keywords:** bariatric surgery, NAFLD, NASH, liver transplant, liver failure

#### **1. Introduction**

Over the last decades, there has been a drastic increase in obesity prevalence. Health statistics reports of 2018 showed that 40% of the total adult population of the United States were obese (BMI (body mass index) > 30 kg/m2 ).

The obesity epidemic has led to a dramatic rise in the obesity-related liver disease non-alcoholic fatty liver disease (NAFLD). NAFLD currentlyaffects one quarter of the global population [1]. Steatosis or fatty liver, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) make up the spectrum of conditions that NAFLD represents. The frequency of liver transplantation undertaken in patients with cirrhosis and HCC due to NASH has been increasing worldwide [2]. NAFLD has also been found to be associated with several health conditions like cardiovascular diseases which affect organs outside the liver and consititute the major cause of deaths in patients with NAFLD.

Lifestyle modification is the cornerstone of NAFLD therapy. As a matter of fact, reduced intake of calories combined with increased activity can make this achievable. The main driver of NAFLD improvement is the amount of actual weight loss, while the type of diet seems to be less important. Rrespective of how one achieves weight loss, the highest rates of steatohepatitis resolution (90%) as well as improvement of fibrosis (45%) can only be induced by >10% weight loss. A weight loss of >5% improves steatosis in about 64% and weight loss of >7% can resolve

steatohepatitis in 72% [3]. Regrettably, the necessary weight loss goal of >7% to 10% is achieved only by a minority of the patients.

Currently, a vast array of drugs are being tested for NASH, and some of them are already in the third phase, but until now, there is no pharmacological therapy for NASH [4]. In our current understanding, any pharmacological treatment that is indicative for NASH should be prescribed only to patients with NASH and advanced liver fibrosis. The recommendations above result from data which show that fibrosis is the strongest prognostic predictor, with a decline in survival from fibrosis stage 2 onwards [5].

The use of bariatric surgery as a therapy for obesity is increasingly common, and evidence that also supports its therapeutic use for metabolic disturbances (so called "metabolic surgery") is increasing [6]. In addition, bariatric surgery is a promising therapeutic alternative for NAFLD as risk factors such as diabetes, inflammation, insulin resistance, and dyslipidemia that contribute to NAFLD pathogenesis can be reversed by it, and it is also effective for achieving long-term weight loss in patients [7].

According to current reimbursement guidelines, it is only administered to obese patients who are 18 years or over with a BMI > 40 kg/m2 or BMI > 35 kg/m<sup>2</sup> with related co-morbidities such as diabetes mellitus, uncontrolled arterial high blood pressure and OSAS despite triple therapy. Consequently, NASH is not one of the co-morbidities regarded as an indication for bariatric surgery.

In this chapter, we will first elucidate the benefit of bariatric surgery in the field of NAFLD. Secondly, the possible role of bariatric surgery will be discussedin patients who are candidates for liver transplantation. Special considerationwill also be given to patients who develop recurrent or de novo NASH after liver transplantation. Finally, we outline the possible pitfalls with the risk of liver failure after bariatric surgery.

#### **2. Types of bariatric surgery**

A variety of procedures for bariatric surgery have been developed over the last decades**.** The 2 most frequently performed types of bariatric surgery are Roux-en-Y gastric bypass (RYGB) and Sleeve gastrectomy (SG). There has been a progressive decline in the use of the adjustable gastric banding procedure after sleeve gastrectomy was developed. Biliopancreatic diversion with duodenal switch (BPD–DS) is the procedure of choice for severe morbidly obese patients. Very low mortality and morbidity rates are associated with almost all bariatric operations performed laparoscopically [8]. In the USA and countries around the world, the currently most performed bariatric procedure is sleeve gastrectomy. The increase in popularity of the SG could be due to its relative technical simplicity, as there are no concerns for late complications such as internal herniation, ulcerations on anastomosis and no malabsorption of iron, calcium and vitamins. Malabsorptive surgery as jejunoileal bypass, biliopancreatic diversion (BDP), biliopancreatic diversion with duodenal switch (BDP-DS), and distal gastric bypass (D-GBP) can lead to large weight loss, yet can cause severe long-term complications.

**Figure 1** shows the different types of surgery. The RYGB procedure consists of two components. First, a small gastric pouch of ∼30 cm3 in volume is constructed, secondly the small intestine is divided ∼30–50 cm distal to the ligament of Treitz. The distal end of the small intestine that has been divided also known as the Roux limb is connected to the gastric pouch that was newly fabricated. The Roux limb ranges from 75–150 cm in length. SG is formed from a tubular gastric pouch (sleeve) that remains after ∼80% of the lateral part of the stomach has

**163**

**Figure 1.**

*The Role of Bariatric Surgery in Fatty Liver DOI: http://dx.doi.org/10.5772/intechopen.96975*

been removed. The BPD–DS is a procedure where first a vertical gastrectomy is performed, similar to the SG. Next, a large portion (∼50%) of the small intestine is bypassed, which creates malabsorption. The duodenum is divided immediately after the pylorus. At 250 cm proximal to the ileocecal valve, a portion of the distal ileum is divided and anastomosed to the duodenum in a Roux-en-Y configuration after bringing it up. Another anastomosis of the ileoileostomy is performed at

*Bariatric surgery procedures.(A) sleeve gastrectomy, (B) roux-en-Y gastric bypass, (C) biliopancreatic* 

*diversion with duodenal switch (reproduced with permission from www.uzgent.be).*

Already in 2008, Mathurin et al. published data showing animprovement of steatosis, ballooning and NAS score 5 years after bariatric surgery in NAFLD patients. However they reporteda worsening of fibrosis in 19.8% of patients. This initial finding made the use of bariatric surgery questionable in the area of NASH. However, the worsening of fibrosis at 5 years was slight, 95% of the patients had a fibrosis score less than 1 and a lot of patients had no biopsy-proven NASH [10]. The same

100 cm proximal to the ileocaecal valve to complete the operation [9].

**3. Benefits of bariatric surgery in NAFLD patients**

*The Role of Bariatric Surgery in Fatty Liver DOI: http://dx.doi.org/10.5772/intechopen.96975*

*Advances in Hepatology*

onwards [5].

patients [7].

bariatric surgery.

**2. Types of bariatric surgery**

yet can cause severe long-term complications.

of two components. First, a small gastric pouch of ∼30 cm3

steatohepatitis in 72% [3]. Regrettably, the necessary weight loss goal of >7% to

Currently, a vast array of drugs are being tested for NASH, and some of them are already in the third phase, but until now, there is no pharmacological therapy for NASH [4]. In our current understanding, any pharmacological treatment that is indicative for NASH should be prescribed only to patients with NASH and advanced liver fibrosis. The recommendations above result from data which show that fibrosis is the strongest prognostic predictor, with a decline in survival from fibrosis stage 2

The use of bariatric surgery as a therapy for obesity is increasingly common, and evidence that also supports its therapeutic use for metabolic disturbances (so called "metabolic surgery") is increasing [6]. In addition, bariatric surgery is a promising therapeutic alternative for NAFLD as risk factors such as diabetes, inflammation, insulin resistance, and dyslipidemia that contribute to NAFLD pathogenesis can be reversed by it, and it is also effective for achieving long-term weight loss in

According to current reimbursement guidelines, it is only administered to obese

related co-morbidities such as diabetes mellitus, uncontrolled arterial high blood pressure and OSAS despite triple therapy. Consequently, NASH is not one of the

In this chapter, we will first elucidate the benefit of bariatric surgery in the field of NAFLD. Secondly, the possible role of bariatric surgery will be discussedin patients who are candidates for liver transplantation. Special considerationwill also be given to patients who develop recurrent or de novo NASH after liver transplantation. Finally, we outline the possible pitfalls with the risk of liver failure after

A variety of procedures for bariatric surgery have been developed over the last decades**.** The 2 most frequently performed types of bariatric surgery are Roux-en-Y gastric bypass (RYGB) and Sleeve gastrectomy (SG). There has been a progressive decline in the use of the adjustable gastric banding procedure after sleeve gastrectomy was developed. Biliopancreatic diversion with duodenal switch (BPD–DS) is the procedure of choice for severe morbidly obese patients. Very low mortality and morbidity rates are associated with almost all bariatric operations performed laparoscopically [8]. In the USA and countries around the world, the currently most performed bariatric procedure is sleeve gastrectomy. The increase in popularity of the SG could be due to its relative technical simplicity, as there are no concerns for late complications such as internal herniation, ulcerations on anastomosis and no malabsorption of iron, calcium and vitamins. Malabsorptive surgery as jejunoileal bypass, biliopancreatic diversion (BDP), biliopancreatic diversion with duodenal switch (BDP-DS), and distal gastric bypass (D-GBP) can lead to large weight loss,

**Figure 1** shows the different types of surgery. The RYGB procedure consists

structed, secondly the small intestine is divided ∼30–50 cm distal to the ligament of Treitz. The distal end of the small intestine that has been divided also known as the Roux limb is connected to the gastric pouch that was newly fabricated. The Roux limb ranges from 75–150 cm in length. SG is formed from a tubular gastric pouch (sleeve) that remains after ∼80% of the lateral part of the stomach has

or BMI > 35 kg/m<sup>2</sup>

in volume is con-

with

10% is achieved only by a minority of the patients.

patients who are 18 years or over with a BMI > 40 kg/m2

co-morbidities regarded as an indication for bariatric surgery.

**162**

#### **Figure 1.**

*Bariatric surgery procedures.(A) sleeve gastrectomy, (B) roux-en-Y gastric bypass, (C) biliopancreatic diversion with duodenal switch (reproduced with permission from www.uzgent.be).*

been removed. The BPD–DS is a procedure where first a vertical gastrectomy is performed, similar to the SG. Next, a large portion (∼50%) of the small intestine is bypassed, which creates malabsorption. The duodenum is divided immediately after the pylorus. At 250 cm proximal to the ileocecal valve, a portion of the distal ileum is divided and anastomosed to the duodenum in a Roux-en-Y configuration after bringing it up. Another anastomosis of the ileoileostomy is performed at 100 cm proximal to the ileocaecal valve to complete the operation [9].

#### **3. Benefits of bariatric surgery in NAFLD patients**

Already in 2008, Mathurin et al. published data showing animprovement of steatosis, ballooning and NAS score 5 years after bariatric surgery in NAFLD patients. However they reporteda worsening of fibrosis in 19.8% of patients. This initial finding made the use of bariatric surgery questionable in the area of NASH. However, the worsening of fibrosis at 5 years was slight, 95% of the patients had a fibrosis score less than 1 and a lot of patients had no biopsy-proven NASH [10]. The same

group reported recently data of a biopsy-proven cohort of NASH patients with liver samples 1 and 5 years after bariatric surgery [11, 12]. In this long-term prospective trial, NASH resolution was induced by bariatric surgery without fibrosis worsening in 84% of the patients at 5 years. Regression of fibrosis was seen in 70% of the patients, beginning to improve within 1 year and continued throughout 5 year follow-up. Also in patients with baseline fibrosis grade 3, there was an improvement seen in 68%.The non-responders (20%) to bariatric surgery were patients with low weight loss and less improvement in insulin resistance after their surgery. This large trial has demonstrated that there is an understandable benefit to consider bariatric surgery as a treatment option for patients with clinically significant NASH.

Lee et al. published in 2019 a systematic review with data of 32 cohort studies comprising 3093 biopsy-confirmed NAFLD patients and the effect of bariatric surgery [13]. The authors looked at complete resolution of the different features of NAFLD instead of improvement. The study results indicated that there was complete resolution of steatosis, inflammation, ballooning and fibrosis in 66%, 50%, 76% and 40%, respectively. A meta-analysis in 2008 of 15 cohort studies showed similar results [14]. By focusing on complete NAFLD resolution, these reviews provide further evidence that bariatric surgery is efficacious and that NAFLD as a comorbidity should prompt evaluation for bariatric surgery in patients with a BMI of 35 to 40 kg/m2.

Klebanoff et al. showed that bariatric surgery led to more QALY's for all obese patients and overweight patients regardless of fibrosis stage compared to lifestyle interventions. Their analysis also suggests that for patients in all obesity classes, bariatric surgery, as a therapy, is cost-effective and may even be considered costeffective therapy for overweight individuals with advanced fibrosis [15]. The majority of the patients in the reported cohorts underwent RYGB, only 5 to 10% underwent Sleeve gastrectomy. A few studies have examined the effect other bariatric surgeries have on NASH. Caiazzo et al. showed that RYGB was associated with significantly greater improvement in the amount of steatosis and NASH at 1 and 5 years after surgery compared to adjustable gastric banding [16].

The use of comparative randomized trials that study the impact of bariatric surgery compared with current medical therapies should be the focus of future clinical studies. Data on new endoscopic bariatric therapies and the effect on NASH are also urgently needed.

#### **4. Bariatric surgery related to liver transplantation**

Candidates for transplantation with a BMI > 40 kg/m<sup>2</sup> havea significantly higher mortality on the waiting list compared with candidates with a BMI > 30 kg/m<sup>2</sup> . The reason is a faster progression of liver detioration among obese patients versus nonobese [17]. The most frequently used BMI cutoffs in the literature as relative and absolute contra-indication for livertransplantation were 40 and 45, respectively. This is mainly based on the fact that studies reported a higher risk of perioperative complications, mostly wound-related infections, in obese patients. Morbid obesity cannot be considered as an absolute contra-indication for liver transplant despite the presence of associated complications in these patients. This observation leads us to the need to address obesity before and after liver transplantation.

#### **4.1 Bariatric surgery in pre-liver transplant candidates**

Treating obesity before transplantation can reduce the risk of decompensation and reduce co-morbiditities such infections and metabolic syndrome in the postoperative period [18, 19].

**165**

*The Role of Bariatric Surgery in Fatty Liver DOI: http://dx.doi.org/10.5772/intechopen.96975*

this study (median BMI of 52 kg/m<sup>2</sup>

RYGB [22].

liver disease.

cirrhosis patients [23, 24].

been reported [27, 28].

before promoting this approach.

**4.3 Bariatric surgery after liver transplantation**

abolic syndrome, especially those with a BMI > 30 kg/m<sup>2</sup>

The first issue to consider is whether bariatric surgery is safe in cirrotic patients.

tions or increased mortality were noted in this cohort. Jan et al. published a review with pooled data of nine similar studies with a total of 122 cirrhotic patients. The characteristics of the patients were mainly Child Pugh A patients, a few Child Pugh B and 7 patients with portal hypertension. The type of procedure was again predominantly RYGB. There was an overall complication rate of 22.5% with also a 6.5% liver decompensation rate and a late mortality rate of 2.45%. A lower complication rate in cirrhotic patientswas seen in the group who underwent SG or gastric banding when compared with malabsorptive bariatric procedures including

Bariatric surgery can be done in a carefully selected patient group with cirrhosis, especially Child Pugh A patients without significant portal hypertension. It is important to recognize and diagnose cirrhosis, estimate liver function and the presence or absence of portal hypertension pre-operatively. This can help in deciding the type of procedure and anticipatingcomplications. Most of the data currently available indicatethat sleeve gastrectomy can be done safely in compensated liver

The risk of 30-day mortality in decompensated cirrotic patients undergoing bariatric surgery was noted to be 16.7% versus 0.9% in compensated cirrhosis. So, bariatric surgery is absolutely contra-indicated in patients with a decompensated

For patients who are too sick before transplant, a simultaneous bariatric surgery and liver transplantation is another approach to manage obesity in this population. Small series of patients who underwent combined sleeve gastrectomy and liver transplantation has been published from the group of the Mayo Clinic [25]. Death, graft loss, operative complications were similar between the two groups, however post-liver transplantation metabolic outcomes were superior in the group who underwentthe combined SG and transplantation. Long-term outcomes were described recently with demonstrating efficacy and maintaining wieght loss and favorable metabolic profiles [26]. So far, there are only two other case reports of sleeve gastrectomy and liver transplantation combined that have

The main disadvantage of this approach can be the impact on the nutritional state in the immediate post-operative period. More data and experience in is needed

Long-term weight gain and development of metabolic syndrome are the main concerns post-liver transplantation. Up to 46% of the patients will develop themet-

plant BMI. Recently it has been shown that NASH liver transplant recipients have a 10 year graft survival of 61% which is significantly lower than primary sclerosing

or higherpre-liver trans-

**4.2 Bariatric surgery simultaneously with liver transplantation**

). No long-term cirrhosis-related complica-

Data are mostly coming from retrospective incidental findings at the time of bariatric surgery with a prevalence between 0.14% to 1.5% [20, 21]**.** Younus et al. described a cohort of 26 patients with incidental finding of cirrhosis (proven with biopsy) at the time of bariatric surgery [20]. The type of procedure was mainly RYGB (55%). A higher risk of immediate complications postoperative (38.5% versus 16.7% in non-cirrhotic group) was seen, probably also dueto a high BMI in

#### *The Role of Bariatric Surgery in Fatty Liver DOI: http://dx.doi.org/10.5772/intechopen.96975*

*Advances in Hepatology*

are also urgently needed.

operative period [18, 19].

group reported recently data of a biopsy-proven cohort of NASH patients with liver samples 1 and 5 years after bariatric surgery [11, 12]. In this long-term prospective trial, NASH resolution was induced by bariatric surgery without fibrosis worsening in 84% of the patients at 5 years. Regression of fibrosis was seen in 70% of the patients, beginning to improve within 1 year and continued throughout 5 year follow-up. Also in patients with baseline fibrosis grade 3, there was an improvement seen in 68%.The non-responders (20%) to bariatric surgery were patients with low weight loss and less improvement in insulin resistance after their surgery. This large trial has demonstrated that there is an understandable benefit to consider bariatric

surgery as a treatment option for patients with clinically significant NASH.

and 5 years after surgery compared to adjustable gastric banding [16].

**4. Bariatric surgery related to liver transplantation**

Candidates for transplantation with a BMI > 40 kg/m<sup>2</sup>

to the need to address obesity before and after liver transplantation.

**4.1 Bariatric surgery in pre-liver transplant candidates**

The use of comparative randomized trials that study the impact of bariatric surgery compared with current medical therapies should be the focus of future clinical studies. Data on new endoscopic bariatric therapies and the effect on NASH

mortality on the waiting list compared with candidates with a BMI > 30 kg/m<sup>2</sup>

The reason is a faster progression of liver detioration among obese patients versus nonobese [17]. The most frequently used BMI cutoffs in the literature as relative and absolute contra-indication for livertransplantation were 40 and 45, respectively. This is mainly based on the fact that studies reported a higher risk of perioperative complications, mostly wound-related infections, in obese patients. Morbid obesity cannot be considered as an absolute contra-indication for liver transplant despite the presence of associated complications in these patients. This observation leads us

Treating obesity before transplantation can reduce the risk of decompensation and reduce co-morbiditities such infections and metabolic syndrome in the post-

havea significantly higher

.

Lee et al. published in 2019 a systematic review with data of 32 cohort studies comprising 3093 biopsy-confirmed NAFLD patients and the effect of bariatric surgery [13]. The authors looked at complete resolution of the different features of NAFLD instead of improvement. The study results indicated that there was complete resolution of steatosis, inflammation, ballooning and fibrosis in 66%, 50%, 76% and 40%, respectively. A meta-analysis in 2008 of 15 cohort studies showed similar results [14]. By focusing on complete NAFLD resolution, these reviews provide further evidence that bariatric surgery is efficacious and that NAFLD as a comorbidity should prompt evaluation for bariatric surgery in patients with a BMI of 35 to 40 kg/m2. Klebanoff et al. showed that bariatric surgery led to more QALY's for all obese patients and overweight patients regardless of fibrosis stage compared to lifestyle interventions. Their analysis also suggests that for patients in all obesity classes, bariatric surgery, as a therapy, is cost-effective and may even be considered costeffective therapy for overweight individuals with advanced fibrosis [15]. The majority of the patients in the reported cohorts underwent RYGB, only 5 to 10% underwent Sleeve gastrectomy. A few studies have examined the effect other bariatric surgeries have on NASH. Caiazzo et al. showed that RYGB was associated with significantly greater improvement in the amount of steatosis and NASH at 1

**164**

The first issue to consider is whether bariatric surgery is safe in cirrotic patients. Data are mostly coming from retrospective incidental findings at the time of bariatric surgery with a prevalence between 0.14% to 1.5% [20, 21]**.** Younus et al. described a cohort of 26 patients with incidental finding of cirrhosis (proven with biopsy) at the time of bariatric surgery [20]. The type of procedure was mainly RYGB (55%). A higher risk of immediate complications postoperative (38.5% versus 16.7% in non-cirrhotic group) was seen, probably also dueto a high BMI in this study (median BMI of 52 kg/m<sup>2</sup> ). No long-term cirrhosis-related complications or increased mortality were noted in this cohort. Jan et al. published a review with pooled data of nine similar studies with a total of 122 cirrhotic patients. The characteristics of the patients were mainly Child Pugh A patients, a few Child Pugh B and 7 patients with portal hypertension. The type of procedure was again predominantly RYGB. There was an overall complication rate of 22.5% with also a 6.5% liver decompensation rate and a late mortality rate of 2.45%. A lower complication rate in cirrhotic patientswas seen in the group who underwent SG or gastric banding when compared with malabsorptive bariatric procedures including RYGB [22].

Bariatric surgery can be done in a carefully selected patient group with cirrhosis, especially Child Pugh A patients without significant portal hypertension. It is important to recognize and diagnose cirrhosis, estimate liver function and the presence or absence of portal hypertension pre-operatively. This can help in deciding the type of procedure and anticipatingcomplications. Most of the data currently available indicatethat sleeve gastrectomy can be done safely in compensated liver cirrhosis patients [23, 24].

The risk of 30-day mortality in decompensated cirrotic patients undergoing bariatric surgery was noted to be 16.7% versus 0.9% in compensated cirrhosis. So, bariatric surgery is absolutely contra-indicated in patients with a decompensated liver disease.

#### **4.2 Bariatric surgery simultaneously with liver transplantation**

For patients who are too sick before transplant, a simultaneous bariatric surgery and liver transplantation is another approach to manage obesity in this population. Small series of patients who underwent combined sleeve gastrectomy and liver transplantation has been published from the group of the Mayo Clinic [25]. Death, graft loss, operative complications were similar between the two groups, however post-liver transplantation metabolic outcomes were superior in the group who underwentthe combined SG and transplantation. Long-term outcomes were described recently with demonstrating efficacy and maintaining wieght loss and favorable metabolic profiles [26]. So far, there are only two other case reports of sleeve gastrectomy and liver transplantation combined that have been reported [27, 28].

The main disadvantage of this approach can be the impact on the nutritional state in the immediate post-operative period. More data and experience in is needed before promoting this approach.

#### **4.3 Bariatric surgery after liver transplantation**

Long-term weight gain and development of metabolic syndrome are the main concerns post-liver transplantation. Up to 46% of the patients will develop themetabolic syndrome, especially those with a BMI > 30 kg/m<sup>2</sup> or higherpre-liver transplant BMI. Recently it has been shown that NASH liver transplant recipients have a 10 year graft survival of 61% which is significantly lower than primary sclerosing

cholangitis, auto-immuun hepatitis and primary biliary cholangitisrecipients (respectively 74%, 71,7% and 71%) [29]. Probably the outcomes of NASH cirrhosis liver transplant recipients are not as good as previously thought and this is due to the development of metabolic risk factors. The bulk of weight gain appears to occur within the first year, with studies reporting a median weight gain of 5 to 10 kg at 12 months after liver transplantation. Recurrent NAFLD/NASH after transplantation is very common, ranging in cohorts from respectively 10 to 100% and 4 to 28%. Risk factors are older age, higher BMI at the time of liver transplantation, presence of diabetes mellitus type 2 pre-livertransplant and dislipidemia [30–32].

The development of de novo NAFLD is also frequent after liver transplantation. There are reports that described 78% de novo NAFLD and 4% NASH in 2378 liver transplant recipients at 5 year follow-up [33]. A very important finding is the faster progression of fibrosis in patients with de novo NASH after liver transplantation [30–33].

Case reports and series of bariatric surgery in post transplant recipients showed no difference in mortality with the general population [34–36]. Sleeve gastrectomy is the most performed procedure with lack of malabsorption and no interference of immuunsuppressive drugs. Optimal timing of bariatric surgery post liver transplantation need to be defined, because delaying too long can cause fibrosis and reduce patient survival.

#### **5. Liver failure as a result of prior bariatric surgery**

Decompensated cirrhosis that results from an earlier bariatric surgery, is a clinical condition that is far more demanding. Complications including severely impaired hepatic function are mostly described after jejunoileal bypass (JIB) and biliopancreatic diversion (BPD) procedures. They occurred in up to 10% of the patients. The occurrence of these and other complications resulted in abandonment of JIB surgery. The frequency of hepatic complications after BPD is unclear, but hepatocellular failure has been reported in small series and case reports. In 1992, the first case of chronic end-stage liver disease after BPD was reported [37]. We published a multicenter Belgian Survey on liver transplantation for hepatocellular failure after bariatric surgery. 10 patients who underwent bariatric surgery and developed liver failure afterward were reported in the Belgian survey: 1 after JIB and 9 after BPD. Patients who underwent JIB or BPD subsequently became candidates for liver transplantation, even >20 years after bariatric surgery [38]. Probably, the real incidence of hepatic complications after BPD surgery is underreported in the current literature; so we are still unaware of the real incidence of Scopinaro procedure-induced liver failure. The pathogenesis of post-BPD steatohepatitis remains poorly understood. One important factor implicated in the pathogenesis of liver injury after JIB or BPD was intestinal bacterial overgrowth in the excluded small intestine segment. As we see no liver failure after equivalent intestinal resection, this may explain the role of excluded segment. Bacterial overgrowth leads to mucosal injury and increases gut permeability toespecially endotoxins. When these toxins are absorbed via the portal vein to the liver, they can induce hepatocellular damage. Another factor in the pathogenesis of liver failure postbypass surgery is protein and amino acid malnutrition, which can perpetuate or increase lipid accumulation in the liver.

Mahawar et al. confirmed that the lenght of the biliopancreatic limb (BPL) matters [39]. A long BPL (100–150 cm) results in better weight loss, intensifies the antidiabetic effect in RYGB compared with a shorter BPL of 50–75 cm. The increased risk of insufficiency of protein with successive malnutrition constitute

**167**

**Conflict of interest**

The authors declare no conflict of interest.

*The Role of Bariatric Surgery in Fatty Liver DOI: http://dx.doi.org/10.5772/intechopen.96975*

would suffer from liver failure.

monitoring of liver function tests.

liver failure.

**6. Conclusions**

the drawback of using a long BPL with a shorter alimentary limb lenght (TALL). Recent data suggests that at least 350–400 cm of TALL must remain [40, 41]. Although liver transplantation and intestinal anatomy restoration have been regarded as the standard therapy for liver failure that results from BDP or JIB surgery, the use of these measures has been reported to be unsuccessful in some cases [42, 43]. We reported a case of refractory subacute steatohepatitis after BPD [43]**.** There may be a significant improvement when surgery is used to achieve a gastric bypass-like anatomy, however, its feasibility is directly related to the severity of liver decompensation as well as effects of nutritional correction. Correction of vitamine depletion, malnutrition and aggressive nutrition is warranted and might already significantly improve the patient's condition. In case of incipient deteriora-

The exact magnitude of liver failure after RYGB, which is not associated with much malabsorption, has not yet been fully established. There are some case reports. Mahawar et al. found10 reports of liver failure after RYGB in the entire surgical literature [39]. In view of the fact that RYGB is the most common performed bariatric procedure worldwide, potentially millions have been carried out, this means that only a minuscule proportion of patients undergoing this operation

4 out of the 10 reports were seen in cirrhotic patients, 2 had extended limb RYGB, 1 distal RYGB, 2 had early or late complication. Extended limb or distal versions of RYGB can behave like biliopancreatic diversion with higher potential for malabsorption. These versions of RYGB may hence be more likely to predispose to

High risk groups of patients undergoing RYGB, such as patients with incidental finding of cirrhosis, extented limb or distal versions of RYGB, complications of surgery and alcohol abuse, should be follow up carefully withroutine lifelong

Bariatric surgery provides effective treatment for obesity and metabolic complications. Lifestyle modification with weight loss is currently the most important treatment in NAFLD patients, but this is hard to achieve in clinical practice. Recent reports showed that bariatric surgery could resolve NASH in 84%of the patients without worsening of fibrosis. These findings support the notionthat bariatric surgery is an effective treatment for NASH patients. Bariatric surgery, especially sleeve gastrectomy, also seems to be feasible in compensated cirrhotic patients. Special attention should be paid to recurrent and de novo NAFLD after liver transplantation. It is worthy of note that, on a case-by-case basis and prior to liver transplantation, the feasibility of bariatric surgery as well as interventions and how they are timed and sequenced should be discussed in a broad multidisciplinary discussion. Liver decompensation or failure hardly occurs in patients undergoing RYGB without pre-existing cirrhosis. Potentially fatal liver complications are described with severe malabsorptive bariatric procedures such as biliopancreatic diversion or distal versions of RYGB. Closely monitoring of liver function is recommended in

this high risk group and early referral for surgical conversion is necessary.

tion, early referral to a liver transplant center is necessary.

#### *The Role of Bariatric Surgery in Fatty Liver DOI: http://dx.doi.org/10.5772/intechopen.96975*

*Advances in Hepatology*

[30–33].

patient survival.

cholangitis, auto-immuun hepatitis and primary biliary cholangitisrecipients (respectively 74%, 71,7% and 71%) [29]. Probably the outcomes of NASH cirrhosis liver transplant recipients are not as good as previously thought and this is due to the development of metabolic risk factors. The bulk of weight gain appears to occur within the first year, with studies reporting a median weight gain of 5 to 10 kg at 12 months after liver transplantation. Recurrent NAFLD/NASH after transplantation is very common, ranging in cohorts from respectively 10 to 100% and 4 to 28%. Risk factors are older age, higher BMI at the time of liver transplantation, presence

of diabetes mellitus type 2 pre-livertransplant and dislipidemia [30–32].

**5. Liver failure as a result of prior bariatric surgery**

The development of de novo NAFLD is also frequent after liver transplantation. There are reports that described 78% de novo NAFLD and 4% NASH in 2378 liver transplant recipients at 5 year follow-up [33]. A very important finding is the faster progression of fibrosis in patients with de novo NASH after liver transplantation

Case reports and series of bariatric surgery in post transplant recipients showed no difference in mortality with the general population [34–36]. Sleeve gastrectomy is the most performed procedure with lack of malabsorption and no interference of immuunsuppressive drugs. Optimal timing of bariatric surgery post liver transplantation need to be defined, because delaying too long can cause fibrosis and reduce

Decompensated cirrhosis that results from an earlier bariatric surgery, is a clinical condition that is far more demanding. Complications including severely impaired hepatic function are mostly described after jejunoileal bypass (JIB) and biliopancreatic diversion (BPD) procedures. They occurred in up to 10% of the patients. The occurrence of these and other complications resulted in abandonment of JIB surgery. The frequency of hepatic complications after BPD is unclear, but hepatocellular failure has been reported in small series and case reports. In 1992, the first case of chronic end-stage liver disease after BPD was reported [37]. We published a multicenter Belgian Survey on liver transplantation for hepatocellular failure after bariatric surgery. 10 patients who underwent bariatric surgery and developed liver failure afterward were reported in the Belgian survey: 1 after JIB and 9 after BPD. Patients who underwent JIB or BPD subsequently became candidates for liver transplantation, even >20 years after bariatric surgery [38]. Probably, the real incidence of hepatic complications after BPD surgery is underreported in the current literature; so we are still unaware of the real incidence of Scopinaro procedure-induced liver failure. The pathogenesis of post-BPD steatohepatitis remains poorly understood. One important factor implicated in the pathogenesis of liver injury after JIB or BPD was intestinal bacterial overgrowth in the excluded small intestine segment. As we see no liver failure after equivalent intestinal resection, this may explain the role of excluded segment. Bacterial overgrowth leads to mucosal injury and increases gut permeability toespecially endotoxins. When these toxins are absorbed via the portal vein to the liver, they can induce hepatocellular damage. Another factor in the pathogenesis of liver failure postbypass surgery is protein and amino acid malnutrition, which can perpetuate or increase lipid

Mahawar et al. confirmed that the lenght of the biliopancreatic limb (BPL) matters [39]. A long BPL (100–150 cm) results in better weight loss, intensifies the antidiabetic effect in RYGB compared with a shorter BPL of 50–75 cm. The increased risk of insufficiency of protein with successive malnutrition constitute

**166**

accumulation in the liver.

the drawback of using a long BPL with a shorter alimentary limb lenght (TALL). Recent data suggests that at least 350–400 cm of TALL must remain [40, 41].

Although liver transplantation and intestinal anatomy restoration have been regarded as the standard therapy for liver failure that results from BDP or JIB surgery, the use of these measures has been reported to be unsuccessful in some cases [42, 43]. We reported a case of refractory subacute steatohepatitis after BPD [43]**.** There may be a significant improvement when surgery is used to achieve a gastric bypass-like anatomy, however, its feasibility is directly related to the severity of liver decompensation as well as effects of nutritional correction. Correction of vitamine depletion, malnutrition and aggressive nutrition is warranted and might already significantly improve the patient's condition. In case of incipient deterioration, early referral to a liver transplant center is necessary.

The exact magnitude of liver failure after RYGB, which is not associated with much malabsorption, has not yet been fully established. There are some case reports. Mahawar et al. found10 reports of liver failure after RYGB in the entire surgical literature [39]. In view of the fact that RYGB is the most common performed bariatric procedure worldwide, potentially millions have been carried out, this means that only a minuscule proportion of patients undergoing this operation would suffer from liver failure.

4 out of the 10 reports were seen in cirrhotic patients, 2 had extended limb RYGB, 1 distal RYGB, 2 had early or late complication. Extended limb or distal versions of RYGB can behave like biliopancreatic diversion with higher potential for malabsorption. These versions of RYGB may hence be more likely to predispose to liver failure.

High risk groups of patients undergoing RYGB, such as patients with incidental finding of cirrhosis, extented limb or distal versions of RYGB, complications of surgery and alcohol abuse, should be follow up carefully withroutine lifelong monitoring of liver function tests.

#### **6. Conclusions**

Bariatric surgery provides effective treatment for obesity and metabolic complications. Lifestyle modification with weight loss is currently the most important treatment in NAFLD patients, but this is hard to achieve in clinical practice. Recent reports showed that bariatric surgery could resolve NASH in 84%of the patients without worsening of fibrosis. These findings support the notionthat bariatric surgery is an effective treatment for NASH patients. Bariatric surgery, especially sleeve gastrectomy, also seems to be feasible in compensated cirrhotic patients. Special attention should be paid to recurrent and de novo NAFLD after liver transplantation. It is worthy of note that, on a case-by-case basis and prior to liver transplantation, the feasibility of bariatric surgery as well as interventions and how they are timed and sequenced should be discussed in a broad multidisciplinary discussion.

Liver decompensation or failure hardly occurs in patients undergoing RYGB without pre-existing cirrhosis. Potentially fatal liver complications are described with severe malabsorptive bariatric procedures such as biliopancreatic diversion or distal versions of RYGB. Closely monitoring of liver function is recommended in this high risk group and early referral for surgical conversion is necessary.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Advances in Hepatology*

#### **Author details**

Anja Geerts\* and Sander Lefere Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium

\*Address all correspondence to: anja.geerts@uzgent.be

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

**169**

*The Role of Bariatric Surgery in Fatty Liver DOI: http://dx.doi.org/10.5772/intechopen.96975*

[1] Younossi Z, Anstee Q, Marietti M, Hardy T, Henry L et al. Global burden of NAFLD and NASH; trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15:11-20.

[9] Nguyen N, Varela J. Bariatric surgery for obesity and metabolic disorders: state of the art. Nat Rev Gastroenterol

Hepatol 2017;14:160-169.

2009;137:532-540.

2015;149:379-388.

2020;159:1290-1301.

2019;17:1040-1060

[10] Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E et al. Prosepctive study of the longterm effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology

[11] Lassailly G, Caiazzo R, Buob D,

Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly

[12] Lassailly G, Caiazzo R, Ntandja-Wandji LC, Gnemmi V, Baud G et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology

[13] Lee Y, Doumouras AG, Yu J,

Hong D. Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis. Clinical gastroenterology and Hepatology

[14] Mummadi R, Kasturi K, Chennareddygari S, Sood G. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meat-analysis. Clin Gastroenterol

Hepatol 2008;12:1396-402.

[15] Klebanoff MJ, Corey KE, Chhatwal J, Kaplan LM, Chung RT et al.Bariatric surgery for nonalcoholic

steatohepatitis in morbidly obese patients. Gastroenterology

2015;149:379-388.

Brar K, Banfield L, Gmora S, Anvari M,

obese patients. Gastroenterology

Pigeyre M, Verkindt H et al.

[2] Younossi ZM. Non-alcoholic fatty liver disease – a global health perspective. J Hepatol 2019; 70:531-544.

[3] Villar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzales A, Gra-Oramas B et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology

[4] Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebocontrolled phase 3 trial. Lancet

**References**

2017;149:367-378.

2019;394:2184-2196.

2017;65:1557-1565.

2012;307:56-65

2004;351:2683-93.

[5] Dulai PS, Singhi S, Patel J, Soni M, Prokop LJ et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease:systematic review and meta-analysis. Hepatology

[6] Sjostrom L, Peltonen M, Jacobson P et al. Bariatric surgery and longterm cardiovascular events. JAMA

[8] Cardoso L, Rodrigues D, Gomes L, Carrilho F. Short-and long-term mortality after bariatric surgery: a systematic review and meta-analysis. Diabetes Obes Metab 2017;19:1223-1232.

[7] Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med *The Role of Bariatric Surgery in Fatty Liver DOI: http://dx.doi.org/10.5772/intechopen.96975*

#### **References**

*Advances in Hepatology*

**168**

**Author details**

Anja Geerts\* and Sander Lefere

Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver

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

Research Center Ghent, Ghent University, Ghent, Belgium

\*Address all correspondence to: anja.geerts@uzgent.be

provided the original work is properly cited.

[1] Younossi Z, Anstee Q, Marietti M, Hardy T, Henry L et al. Global burden of NAFLD and NASH; trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15:11-20.

[2] Younossi ZM. Non-alcoholic fatty liver disease – a global health perspective. J Hepatol 2019; 70:531-544.

[3] Villar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzales A, Gra-Oramas B et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2017;149:367-378.

[4] Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebocontrolled phase 3 trial. Lancet 2019;394:2184-2196.

[5] Dulai PS, Singhi S, Patel J, Soni M, Prokop LJ et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease:systematic review and meta-analysis. Hepatology 2017;65:1557-1565.

[6] Sjostrom L, Peltonen M, Jacobson P et al. Bariatric surgery and longterm cardiovascular events. JAMA 2012;307:56-65

[7] Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683-93.

[8] Cardoso L, Rodrigues D, Gomes L, Carrilho F. Short-and long-term mortality after bariatric surgery: a systematic review and meta-analysis. Diabetes Obes Metab 2017;19:1223-1232. [9] Nguyen N, Varela J. Bariatric surgery for obesity and metabolic disorders: state of the art. Nat Rev Gastroenterol Hepatol 2017;14:160-169.

[10] Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E et al. Prosepctive study of the longterm effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 2009;137:532-540.

[11] Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015;149:379-388.

[12] Lassailly G, Caiazzo R, Ntandja-Wandji LC, Gnemmi V, Baud G et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology 2020;159:1290-1301.

[13] Lee Y, Doumouras AG, Yu J, Brar K, Banfield L, Gmora S, Anvari M, Hong D. Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis. Clinical gastroenterology and Hepatology 2019;17:1040-1060

[14] Mummadi R, Kasturi K, Chennareddygari S, Sood G. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meat-analysis. Clin Gastroenterol Hepatol 2008;12:1396-402.

[15] Klebanoff MJ, Corey KE, Chhatwal J, Kaplan LM, Chung RT et al.Bariatric surgery for nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015;149:379-388.

[16] Caiazzo R, Lassailly G, Leteurtre E, Baud G, Verkindt H et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5 year controlled longitudinal study. Ann Surg 2014;260:893-8

[17] Berzigotti A, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK et al. Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis. Hepatology 2011;54:555-61.

[18] Takata MC, Campos G, Ciovia R, Rabl C, Rogers S et al. Laparoscopic bariatric surgery improves candidacy in morbidly obese patients awaiting transplantation. Surg Obes Relat Dis 2008;4:159-164

[19] Lin MY, Tavakol MM, Sarin A, Amirkiai S, Rogers S et al. Laparscopic sleeve gastrectomy is safe and efficacious for pretransplant candidates. Surg Obes Relat Dis 2013;9:653-8

[20] Younus H, Sharma A, Miquel R, Uaglia A, Kanchustambam S et al. Bariatric surgery in cirrhotic patients: is it safe? Obes Surg 2020;30:1241-1248

[21] Spengler E, O'Leary J, Te H, Rogal S, Pillai A et al. Liver transplantation in the obese cirrhotic patient. Transplantation 2017;101:2288-2296.

[22] Jan A, Narwaria M, Mahawar K. A systematic review of bariatric surgery in patients with liver cirrhosis. Obes Surg 2015;25:1518-26

[23] Garcia-Sesma A, Calvo J, Manrique A, Cambra F, Justo I et al. Morbidly obese patients awaiting liver transplantation-sleeve gastrectomy: safety and efficacy from a liver transplant unit experience. Transplantation Proceddings 2019:51; 33-37

[24] Ayloo S, Guss C, Pentakota SR, Hanna J, Molinan M. Minimally

invasive sleeve gastrectomy as a surgical treatment for nonalcoholic fatty liver disease in liver transplant recipients. Transplantation proceedings 2020;52:276-283

[25] Heimbach J, Watt K, Poterucha J, Francisco-Ziller N, Cecco S et al. Combined liver transplantation and gastric sleeve resection for patients with medically complicated obesity and end-stage liver disease. Am J Transplant 2013;13:363-8.

[26] Zamora-Valdes D, Watt K, Kellogg T, Poterucha J, Di Cecco S et al. Long-term outcomes of patients undergoing simultaneous liver transplantation and sleeve gastrectomy. Hepatology 2018;68: 485-495.

[27] Nesher E, Mor E, Shlomai A, Naftaly-Cohen M, Yemini R et al. Simultaneous liver transplantation and sleeve gastrectomy: prohibitive combination or a necessity? Obes Surg 2017;27:1387-1390.

[28] Tariciotti L, D'Ugo S, Manzia T, Tognoni V, Sica G et al. Combined liver transplantation and sleeve gastrectomy for end-stage liver disease in a bariatric patient; First European case-report. Int J Surg Case Rep 2016;28:38-41.

[29] Cotter T, Charlton M. Nonalcoholic steatohepatitis after liver transplantation. Liver Transplantation 2020;26:141-159.

[30] Dumortier J, Giostra E, Belbouab S, Morard I, Guillaud O et al. Nonalcoholic fatty liver disease in liver transplant recipients: another story of "seed and soil". Am J Gastroenterol 2010;105:613-20.

[31] Narayanan P, Mara K, Izzy M, Dierkhising R, Heimbach J et al. Recurrent or de novo allograft steatosis and long-term outcomes after liver transplantation. Transplantation 2019;103:e14-e21.

**171**

*The Role of Bariatric Surgery in Fatty Liver DOI: http://dx.doi.org/10.5772/intechopen.96975*

> [40] Shah K, Nergard BJ, Fagerland MW, Gislason H. Limb lenght in gastric bypass in super-obese patients

importance of lenght of total almentary small bowel tract. Obes surg 2019

[41] Kraljevic M, Kostler T, Susstrunk J, Lazaridis I, Taheri A et al. Revisional surgery for insufficient loss or regain of weight after Roux-en-Y gastric bypass:biliopancreatic limb lenght matters. Obes Surg 2020; 30:804-811.

[42] D'Albuquerque MA, Gonzalez AM,

Wahle RC, de Oliveira Souza E, Mancero JM et al.Liver transplantation for subacute hepatocellular failure due to massive steatohepatitis after bariatri surgery. Liver Transpl 2008;14:881-885.

[43] Lefere S, Hoorens A, Raevens S, Troisi R, Verhelst X,et al. Refractory subacute steatohepatitis after

biliopancreatic diversion. Hepatology

2017;66:289-291.

Jul:29(7):2012-21.

[33] Galvin Z, Rajakumar R, Chen E, Adeyi O, Selzner M et al. Predictors of de novo nonalcoholic fatty liver disease after liver transplantation and associated fibrosis. Liver transplantation

[34] Morris M, Jung A, Kim Y, Lee T, Kaiser T et al. Delayed sleeve gastrectomy following liver transplantation: a 5 year experience. Liver Transpl 2019;25:1673-1681.

[35] Elli EF, Gonzalez-Heredia R, Sanchez-Johnsen L, Patel N, Garcia-Roca R et al. Sleeve gastrectomy surgery in obese patients post-organ transplantation. Surg Obes Relat Dis

[36] Khoraki J, Katz MG, Funk LM, Greenberg JA, Fernandez LA et al. Feasibility and outcomes of laparoscopic sleeve gastrectomy after solid organ transplantation. Surg Obes Relat Dis

[37] Grimm IS, Schindler W, Haluszka O. Steatohepatitis and fatal hepatic failure after biliopancreatic diversion. Am J

[38] Geerts A, Darius T, Chapelle T, Roeyen G, Francque S et al. The multicenter belgian survey on liver transplantation for hepatocellular failure after bariatric surgery. Transplant Proc 2010, 42:4395-4398.

[39] Mahawar K, Parmar C, Graham Y, De Alwis N, Carr W et al. Monitoring of liver function tests after Rouxen-Y gastric bypass: an examination

of evidence base. Obes Surg

2016;26:2516-2522.

Gastroenterol 1992; 87:775.

[32] Saeed N, Glass L, Sharma P, Shannon C, Sonnenday C, Tincopa M. Incidence and risks for nonalcoholic fatty liver disease and steatohepatitis post-liver transplant: systematic review and meta-analysis. Transplantation

2019;103

2019;25:56-67.

2016;12:528-534.

2016;12:75-83.

*The Role of Bariatric Surgery in Fatty Liver DOI: http://dx.doi.org/10.5772/intechopen.96975*

*Advances in Hepatology*

2014;260:893-8

2008;4:159-164

2017;101:2288-2296.

2015;25:1518-26

2019:51; 33-37

[16] Caiazzo R, Lassailly G, Leteurtre E, Baud G, Verkindt H et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5 year controlled longitudinal study. Ann Surg

invasive sleeve gastrectomy as a surgical treatment for nonalcoholic fatty liver disease in liver transplant recipients. Transplantation proceedings

[25] Heimbach J, Watt K, Poterucha J, Francisco-Ziller N, Cecco S et al. Combined liver transplantation and gastric sleeve resection for patients with medically complicated obesity and end-stage liver disease. Am J Transplant

[26] Zamora-Valdes D, Watt K, Kellogg T, Poterucha J, Di Cecco S et al. Long-term outcomes of patients undergoing simultaneous liver

Hepatology 2018;68: 485-495.

2017;27:1387-1390.

[27] Nesher E, Mor E, Shlomai A, Naftaly-Cohen M, Yemini R et al. Simultaneous liver transplantation and sleeve gastrectomy: prohibitive combination or a necessity? Obes Surg

[28] Tariciotti L, D'Ugo S, Manzia T, Tognoni V, Sica G et al. Combined liver transplantation and sleeve gastrectomy for end-stage liver disease in a bariatric patient; First European case-report. Int

Nonalcoholic steatohepatitis after liver transplantation. Liver Transplantation

[30] Dumortier J, Giostra E, Belbouab S,

Morard I, Guillaud O et al. Nonalcoholic fatty liver disease in liver transplant recipients: another story of "seed and soil". Am J Gastroenterol

[31] Narayanan P, Mara K, Izzy M, Dierkhising R, Heimbach J et al. Recurrent or de novo allograft steatosis and long-term outcomes after liver transplantation. Transplantation

J Surg Case Rep 2016;28:38-41.

[29] Cotter T, Charlton M.

2020;26:141-159.

2010;105:613-20.

2019;103:e14-e21.

transplantation and sleeve gastrectomy.

2020;52:276-283

2013;13:363-8.

[17] Berzigotti A, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK et al. Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis. Hepatology 2011;54:555-61.

[18] Takata MC, Campos G, Ciovia R, Rabl C, Rogers S et al. Laparoscopic bariatric surgery improves candidacy in morbidly obese patients awaiting transplantation. Surg Obes Relat Dis

[19] Lin MY, Tavakol MM, Sarin A, Amirkiai S, Rogers S et al. Laparscopic

efficacious for pretransplant candidates.

[21] Spengler E, O'Leary J, Te H, Rogal S, Pillai A et al. Liver transplantation in the obese cirrhotic patient. Transplantation

[22] Jan A, Narwaria M, Mahawar K. A systematic review of bariatric surgery in patients with liver cirrhosis. Obes Surg

[23] Garcia-Sesma A, Calvo J, Manrique A, Cambra F, Justo I et al. Morbidly obese patients awaiting liver transplantation-sleeve gastrectomy: safety and efficacy from a liver transplant unit experience. Transplantation Proceddings

[24] Ayloo S, Guss C, Pentakota SR, Hanna J, Molinan M. Minimally

sleeve gastrectomy is safe and

Surg Obes Relat Dis 2013;9:653-8

[20] Younus H, Sharma A, Miquel R, Uaglia A, Kanchustambam S et al. Bariatric surgery in cirrhotic patients: is it safe? Obes Surg 2020;30:1241-1248

**170**

[32] Saeed N, Glass L, Sharma P, Shannon C, Sonnenday C, Tincopa M. Incidence and risks for nonalcoholic fatty liver disease and steatohepatitis post-liver transplant: systematic review and meta-analysis. Transplantation 2019;103

[33] Galvin Z, Rajakumar R, Chen E, Adeyi O, Selzner M et al. Predictors of de novo nonalcoholic fatty liver disease after liver transplantation and associated fibrosis. Liver transplantation 2019;25:56-67.

[34] Morris M, Jung A, Kim Y, Lee T, Kaiser T et al. Delayed sleeve gastrectomy following liver transplantation: a 5 year experience. Liver Transpl 2019;25:1673-1681.

[35] Elli EF, Gonzalez-Heredia R, Sanchez-Johnsen L, Patel N, Garcia-Roca R et al. Sleeve gastrectomy surgery in obese patients post-organ transplantation. Surg Obes Relat Dis 2016;12:528-534.

[36] Khoraki J, Katz MG, Funk LM, Greenberg JA, Fernandez LA et al. Feasibility and outcomes of laparoscopic sleeve gastrectomy after solid organ transplantation. Surg Obes Relat Dis 2016;12:75-83.

[37] Grimm IS, Schindler W, Haluszka O. Steatohepatitis and fatal hepatic failure after biliopancreatic diversion. Am J Gastroenterol 1992; 87:775.

[38] Geerts A, Darius T, Chapelle T, Roeyen G, Francque S et al. The multicenter belgian survey on liver transplantation for hepatocellular failure after bariatric surgery. Transplant Proc 2010, 42:4395-4398.

[39] Mahawar K, Parmar C, Graham Y, De Alwis N, Carr W et al. Monitoring of liver function tests after Rouxen-Y gastric bypass: an examination of evidence base. Obes Surg 2016;26:2516-2522.

[40] Shah K, Nergard BJ, Fagerland MW, Gislason H. Limb lenght in gastric bypass in super-obese patients importance of lenght of total almentary small bowel tract. Obes surg 2019 Jul:29(7):2012-21.

[41] Kraljevic M, Kostler T, Susstrunk J, Lazaridis I, Taheri A et al. Revisional surgery for insufficient loss or regain of weight after Roux-en-Y gastric bypass:biliopancreatic limb lenght matters. Obes Surg 2020; 30:804-811.

[42] D'Albuquerque MA, Gonzalez AM, Wahle RC, de Oliveira Souza E, Mancero JM et al.Liver transplantation for subacute hepatocellular failure due to massive steatohepatitis after bariatri surgery. Liver Transpl 2008;14:881-885.

[43] Lefere S, Hoorens A, Raevens S, Troisi R, Verhelst X,et al. Refractory subacute steatohepatitis after biliopancreatic diversion. Hepatology 2017;66:289-291.

**173**

Section 8

Liver Cirrhosis

and Complications

Section 8
