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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES

MEDICAL ACADEMY, FACULTY OF MEDICINE DEPARTMENT OF GASTROENTEROLOGY

Matanel Cohen

The problem of liver steatosis and steatohepatitis in the modern

world

MEDICAL INTEGRATED MASTER'S STUDY PROGRAMME

Thesis Supervisor

Dr. Sigita Gelman

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TABLE OF CONTENTS

1.ABBREVIATIONS……….…,.…3 2. SUMMARY ... 4 3. ACKNOWLEGMENT... 5 4. CONFLICT OF INTEREST ... 6

5. CLEARANCE ISSUED BY THE ETHICS COMMITTEE... 7

6. TERMS ... 8

7. INTRODUCTION ... 9

8. AIM AND OBJECTIVES OF THE THESIS... 10

9. RESEARCH METHODOLOGY AND METHODS ... 11

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1. ABBREVIATIONS

ALD - Alcoholic liver disease

ANTI HCV - Antibodies to hepatitis

BMI - body mass index

CT - computed tomography

DIHS - drug-induced hepatic steatosis

HBV - Hepatitis B Virus

HCC - hepatocellular carcinoma

HCV - hepatitis C virus

HOMA - homeostatic model assessment

MetS - Metabolic Syndrome

MRI - magnetic resonance imaging

MRS - magnetic resonance spectroscopy

NAFLD - nonalcoholic fatty liver disease

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2. SUMMARY

Master thesis by- Matanel Cohen

Title – The problem of liver steatosis and steatohepatitis in the modern world

Introduction – Liver steatosis is characterized by the ectopic storage of triglycerides in hepatocytes and is

mainly related to the components of the hMetS, featuring metabolic dysfunction‐associated fatty liver disease. MAFLD is determined by an unbalance between the rate of hepatic triglycerides synthesis and catabolism because of an altered whole‐body energetic homeostasis resulting from caloric intake exceeding caloric expenditure. Nowadays, as there is a worldwide increase in many metabolic conditions, such as obesity, diabetes, and metabolic risk abnormalities, MAFLD is the most rapidly growing cause of chronic liver disease. An ultrasound typically makes the final diagnosis, and the treatment has many factors and includes lifestyle change and medication which primarily affect insulin resistance.

The aim of the theses- Review the burden, current diagnostics, and treatment approach of liver steatosis

and steatohepatitis in Europe, North and South America

Objectives of the study-

1. To perform an analysis of the literature about risk factors of liver steatosis and steatohepatitis.

2. To perform an analysis of the literature about the method of diagnosing liver steatosis and steatohepatitis.

3. To perform an analysis of the literature about the risk factors of progression from steatosis to steatohepatitis.

4. To perform an analysis of the literature about the treatment of liver steatosis and steatohepatitis.

Methodology - systematic review that analyzes different research works and publications in the last 10

years in the English language using PubMed Medline research engine.

Main findings- this condition is a significant burden on the health systems worldwide, the leading cause of

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3. ACKNOWLEDGMENT

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4. CONFLICT OF INTEREST

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5. CLEARANCE ISSUED BY THE ETHICS COMMITTEE

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6. TERMS

Hepatic steatosis - a condition characterized by the accumulation of triacylglycerol (TAG)-rich macro

vesicular and/or micro vesicular lipid droplets within the hepatocytes in the absence of inflammation or liver injury.1 Hepatic steatosis also known as fattly liver disease maybe classified into types .There are two

main types of fatty liver disease: alcohol-related fatty liver disease and non-alcoholic fatty liver disease (NAFLD). 2

Nonalcoholic Hepatic steatosis in the absence of secondary causes such as excess alcohol intake, viral

infection, or drug treatments and at least five percent liver eight or five percent of hepatocyte vacuole nonalcoholic hepatic steatosis diagnosis is met. Liver steatosis severity depend on hepatocyte fat lobules percentage.

While healthy liver defined as less than 5 percent 5 to 33 percent classified as first grade 33 to 66 percent defined as second grade and above 66 percent defined as third grade, and its severe.

Simple hepatic steatosis is a reversible condition that can be corrected by lifestyle modification such as physical activity and dietary intervention. 3

Steatohepatitis is a fatty liver disease characterized by liver inflammation with concurrent fat accumulation

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7. INTRODUCTION

Liver steatosis is characterized by the ectopic storage of triglycerides in hepatocytes. 4 It is mainly

related to the components of the MetS (a combination of abdominal obesity, impaired fasting glucose, atherogenic dyslipidemia, and elevated blood pressure) 5, featuring metabolic dysfunction‐associated fatty liver disease (MAFLD) 6 MAFLD is determined by an unbalance between the rate of hepatic triglycerides synthesis and catabolism because of an altered whole‐body energetic homeostasis resulting from caloric intake exceeding caloric expenditure. 7

Nowadays, as there is a worldwide increase in many metabolic conditions, such as obesity, diabetes, and metabolic risk abnormalities, MAFLD is the most rapidly growing cause of chronic liver disease8 9 and is strongly associated with the risk of liver fibrosis/cirrhosis, end‐stage liver disease and hepatocellular carcinoma (HCC), leading to increased liver‐related morbidity and mortality.10

Nonalcoholic steatohepatitis (NASH) is a fatty liver disease due to causes other than alcohol. Some studies suggest diet, exercise, and anti-glycemic drugs may alter the course of the disease. When dealing with this condition, it is recommended to improve metabolic risk factors and reducing alcohol intake.11 . NASH was first described in a group of Mayo Clinic patients in 1980. Its importance and widespread prevalence was recognized primarily in the 1990s. Some believe that NASH is a diagnosis of exclusion and that many cases are caused by other factors. be due to other causes.12

Alcoholic liver disease (ALD) refers to the liver manifestations of excessive alcohol consumption, such as fatty liver change, alcoholic hepatitis, and chronic hepatitis with cirrhosis or fibrosis. Now it is the primary cause of liver disease in Western countries. 13

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8. AIM AND OBJECTIVES OF THE THESIS

Aim: To estimate the problem of liver steatosis and steatohepatitis in the modern world. Objectives:

1. To perform an analysis of the literature about risk factors of liver steatosis and steatohepatitis.

2. To perform an analysis of the literature about the method of diagnosing liver steatosis and steatohepatitis.

3. To perform an analysis of the literature about the risk factors of progression from steatosis to steatohepatitis.

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9. RESEARCH METHODOLOGY AND METHODS

Data collection and search strategy:

This systematic review PRISMA 2009 statement and checklist were used as the primary resource for research methodology. The main search engine was MEDLINE PubMed that yielded about hepatosteatosis research works published from 2011 to- present day. Included Randomized clinical trials, retrospective studies, systematic and literature reviews.

Inclusion criteria:

- Randomized clinical trials, retrospective studies, systematic and literature reviews regarding the topic.

- Papers includes liver steatosis and steatohepatitis diagnosis and prevalence, treatment, and risk factors.

- Published in English.

- Published from 2011 to this day.

Exclusion criteria:

- Works have written not in English. - Not relevant title or abstract. - Published in 2010 or earlier.

Terms used:

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12 Sentences used:

prevalence of liver steatosis.

- Liver steatosis\ steatohepatitis prevalence. - Liver steatosis\ steatohepatitis prevention. - Liver steatosis\ steatohepatitis epidemiology. - Treatment diagnosis.

-

Information source:

MEDLINE PubMed online research engine

Identification

Screening

Eligibility

Inclusion

Abstracts identified after database search:

n= 12,463

Titles and abstracts screened after filter application

n=105

Studies included into qualitative analysis: n=54

Records excluded (n=51) - Abstracts only with no

external link(n=11)

- Irrelevance to subject after reading the abstract (n=30) - Lack of appropriate liver

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10. RESULTS

10.1 Pathogenesis

The liver is an essential organ with multiple life-supporting functions. The liver is in charge of bile production, which helps digestion. It produces proteins and stores iron. It converts nutrients into energy and creates substances that help blood clot formation.

The accumulation of triglycerides within the cytoplasm is referred to as fatty change. At first, the hepatocytes present small fat vacuoles called liposomes around the nucleus (microvesicular fatty change). At this stage, liver cells are filled with multiple fat droplets that do not displace the centrally located nucleus, the size of the vacuoles is increasing, moving the nucleus to the peripheral sides of the cells, characteristic sign ring appearance (macrovesicular fatty change). These vesicles are well-delineated and optically look vacate. During tissue processing, fats dissolve. Fatty cysts, which are irreversible lesions, can form when large vacuoles coalesce. The most common type of steatosis is macrovesicular steatosis, which is linked to alcohol, diabetes, obesity, and corticosteroids17.

Figure 1. Mechanism behind lipid accumulation in liver cells.

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Insulin resistance is likely to be caused by a combination of genetic polymorphisms that affect insulin secretion and action and environmental factors that promote obesity and immobility. Hyperinsulinemia raises serum levels of free fatty acids absorbed by the liver and cause triglyceride production and steatosis, Chronic hyperinsulinemia also promotes de novo hepatic lipogenesis by upregulating lipogenic transcription factors and activating profibrotic cytokines like connective tissue growth factor.18

Typically, Healthy liver contains a small amount of fat. It becomes an issue. When the amount of fat reaches 5% to 10% of the liver's weight. mostly fatty liver disease does not cause any severe problems or prevent the normal function of the liver. Some 7% to 30% of people with fatty liver disease conditions may worsen over time. It progresses through three stages:

1. Inflammation (swollen), which damages its tissue by forming accumulation of inflammatory cells which destroy hepatocyte and prevent them from function normally. This stage is called steatohepatitis.

2. Fibrosis -is the formation of Scar tissue that forms where the liver is damaged in a fibrosis process. When liver damage occurs, stellate cell in a liver is activated causing changes such as degradation of the normal liver parenchyma, deposition of scar molecules, vascular and organ contraction, and release of cytokines which cause liver cell dysfunction.

3. Extensive scar tissue replaces healthy tissue, which can cause liver cirrhosis.

Cirrhosis of the liver is a result of severe damage to the liver. The hard scar tissue that replaces healthy liver tissue slows down the liver's functioning. Eventually, it can block liver function entirely. Cirrhosis may lead to liver failure and liver cancer.

There are two main forms of fatty liver disease:

- Alcoholic liver disease- Alcoholic fatty liver accumulates fat in the liver due to heavy drinking. - Nonalcoholic fatty liver disease- Nonalcoholic fatty liver disease occurs because of fat accumulation

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15 10.2 Etiology

 Metabolic Causes- These factors are primarily relevant to NAFLD and are divided into 2 main categories:

inborn errors of metabolism and acquired metabolic disorders. Inborn errors of metabolism include abetalipoproteinemia, galactosemia, glycogen storage disease, hereditary fructose intolerance, homocystinuria, systemic carnitine deficiency, tyrosinemia, Refsum syndrome, Shwachman syndrome, Weber-Christian syndrome, and Wilson disease. Acquired metabolic disorders are inflammatory bowel disease, jejunoileal bypass, Kwashiorkor and marasmus, starvation and cachexia, and total parenteral nutrition.19

 Viral Causes- HCV, especially genotype, is associated with hepatic steatosis. The prevalence of hepatic steatosis in chronic HCV infection ranges from 40%-80%.The possible mechanisms of hepatic steatosis in HCV infection are direct steatogenic or insulin-resistance effects of HCV viral proteins. The direct steatogenic effect explains hepatic steatosis even in the absence of obesity in patients infected with genotype 3a HCV. Moreover, several viral proteins interfere with insulin signaling, which results in insulin resistance and hepatic steatosis. Hepatic steatosis observed in patients infected with hepatitis B virus is thought to be associated with metabolic factors rather than hepatitis B virus infection.20

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Pediatric Hepatic Steatosis- Different factors can be identified in the pathogenesis of hepatic

steatosis in children. However, with increasing prevalence, NAFLD is the leading cause of hepatic steatosis in pediatric patients.

Less common factors of hepatic steatosis are nutritional causes (starvation and malnutrition),

intoxications (carbon tetrachloride, organic phosphates, organic solvents, and alcohol), drugs (glucocorticoids, estrogens, tetracyclines, and methotrexate), metabolic disorders, hepatitis C infection, and total parenteral nutrition. 22 NAFLD in the pediatric population is a progressive disease, and 6% of the subjects develop cirrhosis and end-stage liver disease. Therefore, these patients should be closely monitored. 23

Main etiologies of liver steatosis:

Etiology Explanation Reference

Metabolic causes inborn errors of metabolism and acquired metabolic disorders.

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Viral Causes HCV, especially genotype, the possible mechanisms is a direct steatogenic or insulin-resistance effects of HCV viral proteins.

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Drug-Induced Hepatic Steatosis

adverse reaction to some medications such as tetracycline, valproic acid, dexamethasone, amiodarone, methotrexate, tamoxifen, and acetylsalicylic acid.

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17 Symptoms of fatty liver disease:

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18 10.3 Prevalence

Nonalcoholic Fatty Liver Disease (NAFLD) is the most common form of hepatic steatosis and affects 30%-40% of men and 15%-20% of women in the general population. According to C.D Bryne et al It is accepted as a hepatic manifestation of metabolic syndrome and has is strongly linked to insulin resistance, atherosclerosis, obesity, dyslipidemia, and hypertension. Nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, is caused by the accumulation of lipids in hepatocytes, which causes oxidative stress and inflammatory response. By 2030, NAFLD is expected to be the most common reason for a liver transplant.24

NAFLD ranges from liver steatosis to nonalcoholic steatohepatitis (NASH). The latter may progress to liver cirrhosis with its complications, namely portal hypertension and hepatocellular carcinoma. Many researchers have estimated that the global prevalence of NAFLD is 25.24%, with 40.76% progression to fibrosis and 0.09% mean annual rate of progression in NASH25

Alcoholic Fatty Liver Disease is a chronic alcohol intake that is another cause of hepatic steatosis, and up to 90% of alcoholic patients have AFLD. Patients with pure AFLD have a 10% risk of progressing to cirrhosis. Consumption of 30 g ethanol/day was shown to increase the risk of chronic liver damage and cirrhosis in alcoholic patients. Furthermore, female sex, cigarette smoking, obesity, and accompanying hepatic disorders predispose factors for liver damage in AFLD. 26

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19 America

As seen from this meta-analysis, most studies of NAFLD have focused on specific groups rather than the general population. Therefore, there are few studies on the overall prevalence of NAFLD in some specific countries or regions. As a result, the precise incidence and prevalence across the continent are unknown. The prevalence of NAFLD is expected to increase in Given the socioeconomic and demographic transitions over the past 20 years, as well as the associated unhealthy dietary habits, acquisition of an industrial urban lifestyle, and changes in the epidemiological profile of disease prevalence, particularly in South America according to Aballay et al.27 Because of increases in longevity and decreases in the prevalence of infectious diseases, the prevalence of chronic noncommunicable diseases, primarily cardiovascular disease and cancer, has increased.28

A significant meta-analysis study conducted by younossi et al, in 2016 can shed light on the prevalence in the USA. It states that imaging or other indirect methods were used to determine NAFLD prevalence in the general population. In this context, the prevalence of NAFLD as detected by ultrasonography in the United States was estimated to be 24.13% (95% CI 19.73–29.15%). However, the prevalence of NAFLD as determined by other noninvasive methods (such as the Fatty Liver Index, ICD 9 or ICD 10 coding) was reported to be 21.09 percent (95 percent CI 15.0–28.8%), implying that diagnosing NAFLD solely based on blood testing or ICD coding may lead to under-reporting of its true prevalence. 29

According to Browning et al, the prevalence of NAFLD varies by ethnicity in the United States. In this context, Hispanic Americans have the highest prevalence of NAFLD, followed by European Americans, and finally, African Americans. 30 Several factors, including genetic factors, environmental factors, access to health care, and the presence of chronic diseases such as metabolic syndrome, could explain the reported ethnic disparities in the prevalence of NAFLD in the United States. Due to the higher prevalence of obesity and hypertension in African American patients, the lower prevalence of NAFLD among African Americans than among Hispanic Americans is especially surprising. 31

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Despite some conflicting evidence on the interaction of NAFLD and components of the metabolic syndrome in African Americans, this study suggests that ethnicity may play a role in the metabolic syndrome's association with NAFLD.32

In another study that use data from the Nonalcoholic Steatohepatitis Clinical Research, investigators compared Latino patients with NASH with non-Latino white patients with NASH. The study discovered that Latino NASH patients were younger, did less physical activity, and consumed more carbohydrates than non-Latino white patients. They also discovered that ethnicity influenced the effect of insulin resistance, as measured by the homeostatic model assessment (HOMA), on the risk of NASH. 33

South America

The prevalence of NAFLD in South America, according to Kallwitz et al, is higher than in the United States. NAFLD prevalence in South America was estimated to be 30.45 percent (95 percent CI 22.74–39.4 percent) using ultrasonography.34. Nonetheless, in one study from Chile, the prevalence of NAFLD (as diagnosed by ultrasonography) was estimated to be 23%. Another Columbia study found a prevalence of 26.6 percent in men using ultrasonography. Peru, Argentina, Ecuador, Paraguay, and Uruguay could have rates ranging from 13 percent (Peru) to 24 percent (Uruguay)35. Although there are estimates for the prevalence of NAFLD in South America, the data regarding the prevalence of NASH is even more scarce. Nonetheless, NASH was found in 61 percent of morbidly obese patients with NAFLD in South America in one study, suggesting that the prevalence of NASH could be 6–18 percent. Once more, these rates can be influenced by genetic predisposition, as will be described later.36

Europe

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Although prevalence is different from place to place, according to the method used to detect NAFLD, about a quarter of the European population is affected by the disease. According to a meta-analysis published in 2016, the average prevalence in Europe is 23.71 percent, ranging from 5 percent to 44 percent in different countries37.

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22 10.4 Diagnosis

The diagnosis of hepatic steatosis is complicated. The severity of the condition and the escalation that differs from one individual to another makes tracking the patients very difficult, especially when most of them are asymptomatic for an extended period.

Although many people have both alcoholic and nonalcoholic fatty liver disease, nonalcoholic fatty liver disease requires a daily alcohol intake of less than 20 grams for women and less than 30 grams for men per day to be diagnosed.This is the equivalent of two standard alcoholic drinks for men and 1.5 standard alcoholic drinks for women per day.41

Figure 3. Flow chart of fatty liver diagnosis

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The diagnosis of nonalcoholic fatty liver disease (NAFLD) requires all of the following42:

- Demonstration of hepatic steatosis by imaging or biopsy - Exclusion of significant alcohol consumption

- Exclusion of other causes of hepatic steatosis - Absence of coexisting chronic liver disease

In those undergoing a radiologic evaluation, radiologic findings are often sufficient to diagnose if other causes of hepatic steatosis have been excludedWhile a liver biopsy is not indicated for the majority of patients, it may be necessary if the diagnosis is unclear or to determine the severity of hepatic injury. Furthermore, liver biopsy is the only way to differentiate between nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis at the moment (NASH).

Laboratory tests

Laboratory tests, such as the serum aminotransferase, are often abnormal in NAFLD. These abnormalities, however, are neither necessary nor sufficient for making the diagnosis, as laboratory tests in patients with NAFLD can be normal while also being abnormal in patients with a variety of other conditions. However, laboratory testing is required to evaluate for other conditions in the differential diagnosis of hepatic steatosis.

According to Drecher et al, the prediction of NASH severity by a noninvasive fibrosis marker, score, a diagnostic test, or an algorithm incorporating a panel of biomarkers is not necessarily capable of making a comprehensive statement of the disease outcome. Confounding factors, comorbidities, or simple blood parameters can significantly impact the progression or overall outcome of NASH.

Today there is no specific serum marker to assess hepatic steatosis available. However, several reproducible blood biomarker panels and scores were developed to help diagnose NAFLD.

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Panel Parameters Included

NAFLD ridge score ALT, HDL, cholesterol, triglycerides, HbA1c, leukocyte count, hypertension

NAFLD Liver Fat Score (NLFS) Liver fat content, metabolic syndrome, type 2 diabetes, AST, AST:ALT, fasting

insulin level

Hepatic Steatosis Index (HIS) AST:ALT, BMI, diabetes, sex

Fatty liver index (FLI) BMI, waist circumference, triglycerides, γ-GT

Lipid accumulation product (LAP)

index sex, triglycerides, weight circumference

Fatty Liver Inhibition of Progression

(FLIP) algorithm histological steatosis, disease activity, fibrosis score

CHeK score age, HbA1c, γ-GT, adiponectin, M30

NAFLD Fibrosis Score (NFS) AST:ALT, albumin, platelet count, age, BMI, hyperglycemia (impaired fasting

glucose)

Fibrosis-4 Score (FIB-4) AST, ALT, platelet count, age

AST to Platelet Ratio Index (APRI) AST:platelet count

BARD Score BMI, AST:ALT, diabetes

Enhanced Liver Fibrosis panel (ELF) Age, TIMP-1, PIIINP, HA

Hepascore bilirubin, γ-GT, HA, α2M, age, gender

FibroTest-FibroSURE/ActiTest α2M, haptoglobin, γ-GT, total bilirubin, apolipoprotein A1, ALT, age, gender

FibroMeter NAFLD index

(FibroMeterVCTE)

platelet count, prothrombin index, ferritin, AST, ALT, body weight, age, liver stiffness determined by vibration controlled transient elastography (VCTE)

Radiographic examinations (CT and MRI)

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who have not yet undergone imaging. However, hepatic steatosis can also be detected using computed tomography (CT) and magnetic resonance imaging (MRI).

It is considered a radiologic diagnosis to be sufficient for diagnosing NAFLD if all of the following conditions are met: first, radiographic imaging is consistent with fatty infiltration. Secondly, cirrhosis symptoms and signs are not present in the patient, and finally, the patient is not at high risk for cirrhosis or advanced fibrosis. 44

Ultrasound

The reason why some NAFLD patients develop NASH, even if they have a small amount of fat in their liver, is unknown. The degree of liver steatosis is well known to be linked to metabolic syndrome and cardiovascular risk. Significant steatosis, on the other hand, has recently been linked to fibrosis progression in NAFLD patients. As a result, in the diagnostic work-up of patients with liver steatosis, an accurate estimate of the amount of fat in the liver is of great interest. The review by Ferraeoeli et al is focused on assessing liver steatosis using ultrasound (US) techniques. 45

US B-mode imaging allows to subjectively estimate the degree of fatty infiltration in the liver. The brightness of the liver, the contrast between the liver and the kidney, the US appearance of the intrahepatic vessels, liver parenchyma, and the diaphragm are all used to grade liver steatosis. Steatosis is graded as follows46:

 Absent (score 0) when the echotexture of the liver is normal;

 mild (score 1), when there is a slight and diffuse increase of liver echogenicity with normal visualization of the diaphragm and the portal vein wall.

 moderate (score 2), in case of a moderate increase of liver echogenicity with the slightly impaired appearance of the portal vein wall and the diaphragm;

 severe (score 3), in case of the marked increase of liver echogenicity with poor or no visualization of the portal vein wall, diaphragm, and posterior part of the right liver lobe

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26 Vibration controlled transient elastography

Vibration controlled transient elastography, which is regularly used to grade fibrosis based on liver stiffness, is also being developed to grade hepatic steatosis. However, more data are necessary to show how transient elastography measurements are reproducible, valid, and associated with clinical outcomes. The optimal cutoff value for steatosis grade >S0 was 248 dB/m (95 percent CI 237-261) in a meta-analysis of 19 biopsy-controlled studies involving over 2700 patients, and for steatosis grade >S1 was 268 dB/m (95 percent CI 257-284).48

CT, MRI, and magnetic resonance spectroscopy

CT and MRI can both detect steatosis, but they aren't sensitive enough to detect inflammation or fibrosis. The advantage of magnetic resonance spectroscopy (MRS) is that it is quantitative rather than qualitative or semiquantitative, but it is not widely available. One of the challenges in determining the sensitivity and specificity of CT and MRI for hepatic steatosis diagnosis is that not every patient undergoes liver biopsy confirmation.49

In a study that used histology as the gold standard, the sensitivity of CT scan for detecting hepatic steatosis was quite low, while MRI had low specificity. It included 131 patients with a non-contrast CT, contrast-enhanced CT, or MRI before undergoing a partial hepatectomy, which was usually for malignancy. Noncontract CT, contrast-enhanced CT, and MRI had a sensitivity of 33, 50, and 88 percent, respectively, for detecting hepatic steatosis. The specificities were 100%, 83%, and 63%, correspondingly.

Furthermore, the accuracy of non-contrast CT decreases as body index mass increases. However, in a study of 33 patients with diabetes at risk for NAFLD, the sensitivity and specificity of in-phase and out-of-phase MRI for hepatic steatosis were 95 and 98 percent, respectively. 50

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Table 252. Clinical evidence profile (SENSITIVITY and SPECIFICITY): Diagnostic tests for steatosis

≥30%

Index Test (Threshold) Inconsistency Imprecision

Sensitivity % (median/ range/ 95% CI)

Specificity % (median/ range/

95% CI) Quality

CAP at 200–249 threshold No serious inconsistency Serious 87 (78, 94) 83 (63, 95) 74 (70, 78) 78 (66, 87) LOW CAP at 250–299 threshold

Pooled meta-analysis data

Very seriousb Serious 82 (68, 92) 83 (71, 91) VERY LOW

CAP at 300+ threshold No serious inconsistency

Serious 58 (39, 75) 94 (86, 98) LOW

FLI at 93.9 threshold FLI at 82 threshold

Very seriousb Very seriousd 27 (13, 46) 59 (52, 66) 96 (89, 99) 69 (61, 77) VERY LOW

MRI-DE at 6.5 threshold No serious inconsistency

Very serious 91 (59, 100) 94 (89, 97) VERY LOW

MRI PDFF at 11.08 threshold MRI PDFF at 22.1 threshold

Seriousb Very serious 88 (47, 100) 64 (48, 78)

88 (78, 95)

96 (85, 99)

VERY LOW

MRI %RSID at 19.22 threshold No serious inconsistency

Very serious 78 (40, 97) 100 (87, 100) VERY LOW

MRS at 2.7 threshold MRS at 7.7 threshold MRS at 10.2 threshold

Serious Very serious 100 (74, 100)

73 (39, 94) 100 (66, 100) 87 (66, 97) 79 (72, 86) 92 (75, 99) VERY LOW

NAFLD LFS at 0.16 threshold No serious inconsistency

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Index Test (Threshold) Inconsistency Imprecision

Sensitivity % (median/ range/ 95% CI)

Specificity % (median/ range/

95% CI) Quality

SteatoTest at 0.94 threshold SteatoTest at 0.69 threshold

Very serious Serious 9 (2, 24) 42 (33, 50)

42 (33, 50)

79 (72, 85)

VERY LOW

Ultrasound with no specified threshold

Pooled meta-analysis data

Very serious Serious 79 (59, 91) 85 (77, 92) VERY LOW

Ultrasound (hepatorenal contrast) with 7 threshold

No serious inconsistency

Serious 86 (67, 96) 85 (78, 90) LOW

Table 3. Main diagnostic tools for liver steatosis

Method Explanation Reference

Laboratory tests serum aminotransferase and ferritin levels, are often abnormal in NAFLD. however, they are neither necessary nor sufficient for making the diagnosis.

43

Radiographic examinations (CT and MRI)

It is considered a radiologic diagnosis to be sufficient for diagnosing NAFLD.

No imaging modality is routinely used to distinguish between the histologic subtypes of steatosis.

43

Ultrasound US B-mode imaging allows to subjectively estimate the degree of fatty infiltration in the liver.

44, 45

Vibration

controlled transient elastography

Method used to grade fibrosis based on liver stiffness, is also being developed to grade hepatic steatosis. However, more data necessary to prove effectiveness.

47

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11. TREATMENT GUILDLINES

General recommendations for patients include53:

- Avoiding alcohol - in particular, recommend avoiding heavy alcohol use (i.e., >14 drinks per week or >4 drinks on a day for men and >7 drinks per week or >3 drinks on a given day for women). - Immunizations - Vaccination for hepatitis A virus and hepatitis B virus should be given to patients

without serologic evidence of immunity. Additional vaccines for patients with chronic liver disease include pneumococcal vaccination and standard immunizations given to the general population. - Modification of risk factors for cardiovascular disease – Patients with NAFLD are at increased risk

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- Diabetes- Management of patients with NAFLD and diabetes includes optimization of blood glucose control.

- Weight loss – it is the primary therapy for most patients with NAFLD. The optimal BMI to reach is 25 or less. Pharmacologic therapy can promote weight loss in patients who fail to achieve their goals through diet and exercise. Bariatric surgery might be recommended to patients with severe obesity to help them lose weight faster.

New treatments were introduced in the past years that might bring a solution to this situation other than lifestyle change and co-existing disease management.

Current new treatments

 Antioxidant Carotenoids for the Treatment of NAFLD

One of the new treatments presented is Antioxidant Carotenoids for the Treatment of NAFLD.54 Despite the critical role of immune cell infiltration in obesity-related insulin resistance and metabolic diseases like NAFLD and NASH, there is no agreement on the most effective pharmacological agents for treating the conditions because their pathologies are not fully understood.Patients with chronic liver disease have low antioxidant levels in their serum and liver tissue and are associated with liver dysfunction. As a result, deficiency in micronutrient antioxidants may play a role in the development of obesity and comorbidities like insulin resistance and NASH. In two studies, it has been shown that carotenoids, including β-cryptoxanthin and astaxanthin, exhibit antioxidant and anti-inflammatory effects, in addition to regulating M1/M2 macrophage polarization in NASH.

 β-Cryptoxanthin

β-Cryptoxanthin is a xanthophyll carotenoid readily absorbed by the body and relatively abundant in human plasma. Consistent with its antioxidant activity, serum concentrations of β-cryptoxanthin are inversely related to oxidative DNA damage and lipid peroxidation indices. In non-diabetic people, high serum levels -cryptoxanthin have been linked to improved insulin resistance and alcoholic liver dysfunction in recent epidemiological studies. Furthermore, -cryptoxanthin has been shown to have anti-inflammatory effects in both in vivo and in vitro studies, primarily by modulating the innate immune response induced by macrophages.52

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The antioxidant effect of astaxanthin is well established; indeed, astaxanthin activity is more potent than that of vitamin E, and β-carotene astaxanthin inhibits carbon tetrachloride-induced lipid peroxidation in a rat's liver and is 100 to 500 times more effective than vitamin E at inhibiting lipid peroxidation. Astaxanthin also prevents the activation of hepatic stellate cells, thereby suppressing the up-regulation of fibrogenic genes by blocking transforming growth factor-β/Smad3 signaling. In addition, it interferes with diet-induced obesity and hepatic lipid accumulation in mice and ameliorates oxidative-stress-induced insulin resistance through the enhancement of insulin signaling and the inhibition of pro-inflammatory signaling.52

According to a recent study, the Mediterranean diet, which has long been considered a healthy diet, effectively reduces the risk of cardiovascular disease and cancer. A Mediterranean diet has also been an effective non-pharmaceutical treatment for type 2 diabetes and obesity. Another treatment option is the Silymarin treatment which is associated with reducing insulin resistance and an improvement in liver function. Therefore, a dietetic regimen should also be considered to prevent the progression to NASH and its associated metabolic diseases.52

The research has shown that by regulating M1/M2 macrophage/Kupffer cell polarization, dietary administration of -cryptoxanthin or astaxanthin prevents and reverses NASH progression in mice. However, there is no evidence that these carotenoids have a beneficial effect on NAFLD patients. Furthermore, there are no validated noninvasive biomarkers for the therapeutic effects of β-cryptoxanthin or astaxanthin. A Biopsy is currently the only clinical tool available for diagnosing pathological changes in the liver. Future research is needed to understand better the pathogenesis of NAFLD and the potential role of carotenoids in the prevention and treatment of this increasingly common disease.52

NLRP3 inflammasome inhibitor CY-09 as reducing hepatic steatosis in experimental NAFLD mice55

According to Xiafnei et at, it has been suggested that CY-09 has remarkable therapeutic effects on a mouse model of type 2 diabetes, clot retraction impairment in human platelets, and attenuates liver injury in hyperglycemic mice. They demonstrated that the inhibitor of the NLRP3 inflammasome CY-09 can effectively improve insulin resistance and alleviate hepatic steatosis induced by HFD in mice.

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NLRP3–NLRP3, NLRP3–ASC, or NEK7–NLRP3 interaction, suggesting that it might target an unknown upstream signaling event of theNLRP3 inflammasome. CY-09 may affect the occurrence and development of NAFLD by directly and explicitly targeting NLRP3 itself.

CY-09 can reduce the TC content in the blood and increase the TG content at 27 weeks, suggesting that CY-09 can alleviate the increase of blood lipids caused by HFD. The increase of TG may result from the excretion of TG formed in the liver, and this result echoes the decrease in epididymal fat.

They also found, after 8 weeks of injection of CY-09, the fasting blood glucose and OGTT of NAFLD mice can be significantly reduced, suggesting that insulin resistance can be effectively alleviated. Insulin resistance is an essential inducer of NAFLD, related to ectopic lipid deposition in the liver. Their results show that CY-09 not only decreases the number and size of liver lipid droplets but also improves the insulin resistance.53

CY-09 significantly decreases the NAS, alleviating hepatic inflammation and steatosis. CY-09 reduces blood TC and epididymal fat and significantly reduces liver lipid deposition on pathology. Therefore, it is suggested that CY-09 may be a promising therapeutic drug and can be applied to treat NAFLD/NASH in the furture.53

In summary of this chapter, the unique characteristics of this illness require a variety of solutions for our patients. Although there is no easy solution for this situation, the patient, as well as the treating physicians, must carry in mind the importance of conventional treatments as well as lifestyle changes.

Table 4. Summary of treatments

Parameter Explanation

Diabetes Disease control

Avoiding alcohol recommend avoiding heavy alcohol use (i.e., >14 drinks per week or >4 drinks on a day for men and >7 drinks per week or >3 drinks on a given day for women).

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33 Modification of risk

factors for

cardiovascular disease

Routine checkups, medications

Weight loss Pharmacologic, Bariatric surgery

Table 5. Summary of current tested treatments

Trial Mechanism Agents References

Antioxidant Carotenoids

NASH decreases antioxidant levels in the serum and liver tissue and are associated with liver dysfunction. It may play a role in the development of obesity and comorbidities like insulin resistance and NASH.

β-cryptoxanthin and astaxanthin, exhibit antioxidant and anti-inflammatory effects, in addition to regulating M1/M2 macrophage polarization in NASH.

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34 Astaxanthin Astaxanthin is potent at inhibiting lipid

peroxidation as well as prevents the activation of hepatic stellate cells, thereby suppressing the up-regulation of fibrogenic genes by blocking

transforming growth factor-β/Smad3 signaling.

53

NLRP3

inflammasome inhibitor CY-09

has therapeutic effects on a mouse model of type 2 diabetes, clot retraction impairment in human platelets, and attenuates liver injury in hyperglycemic mice.

CY-09

(experiment in mice)

54

12. CONCNLUSIONS

This study aimed to describe the global problem of liver steatosis and steatohepatitis. It reviewed the pathology, etiology, and epidemiology of the conditions. The main conclusions that were made from the paper are as follows:

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2. The diagnosis of the condition is complicated, and the average patient goes through several tests that include: US, CT, MRI, Biopsy and blood tests as well as detailed questioners.

3. In most cases, fatty liver disease doesn't cause any serious problems or prevent the liver from functioning normally. However, for 7% to 30% of people with the condition, the fatty liver disease worsens over time.

4. Risk factors of progressing from steatosis to steatohepatitis include several metabolic risk factors during follow-up: body mass index, triglyceride levels, arterial hypertension and the HOMA index.

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Li,

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