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© Borgis - Postępy Nauk Medycznych 5b/2013
*Andrzej Habior
Nonalcoholic fatty liver disease and obesity
Niealkoholowa stłuszczeniowa choroba wątroby a otyłość
Department of Gastroenterology and Hepatology, Medical Centre for Postgraduate Education, Warsaw
Head of Department: prof. Jarosław Reguła, MD, PhD
Streszczenie
Niealkoholowa stłuszczeniowa choroba wątroby (NAFLD) polega na nadmiernym nagromadzeniu ciał tłuszczowych (głównie triglicerydów) w hepatocytach. Ten stan nazywany stłuszczeniem wątroby jest łatwo rozpoznawany w badaniach obrazowych (USG) lub w badaniu histopatologicznym. Termin „NAFLD” jest zarezerwowany dla choroby polegającej na stłuszczeniu wątroby w związku z istniejącym u pacjenta zespołem metabolicznym i otyłością. W kontekście tej definicji, aby rozpoznać NAFLD, konieczne jest wykluczenie innych przyczyn stłuszczenia wątroby, do których między innymi należą leki, zakażenie wirusem hepatitis C, toksyny, niektóre choroby metaboliczne i co najważniejsze – nadmierne spożywanie alkoholu. Do niedawna powszechnie przyjmowano, że NAFLD jest spektrum różnie nasilonych zmian w wątrobie, od najłagodniejszej formy, jaką jest proste stłuszczenie, nazywane niealkoholowym stłuszczeniem wątroby (NAFL) do bardziej zaawansowanej formy – niealkoholowego stłuszczeniowego zapalenia wątroby (NASH). Według tej hipotezy nazywanej „teorią dwu uderzeń” (ang. „two hits”) choroba w wyniku pierwszego „uderzenia” („first hit”), jakim jest insulinooporność i zespół metaboliczny manifestuje się jako NAFL. Po drugim „uderzeniu” („second hit”) wywołanym na przykład endotoksynami napływającymi żyłą wrotną z jelit do wątroby, zmiany w wątrobie nasilają się, przybierają formę NASH i często postępują dalej, do zwłóknienia, marskości, a nawet raka wątrobowokomórkowego. Ostatnio pojawiło się inne wytłumaczenie patogenezy NAFLD. Według tej teorii NAFL i NASH są różnymi chorobami. W NAFL triglicerydy nagromadzone w hepatocytach pełnią rolę ochronną i choroba nie postępuje do NASH. Natomiast u innych osób, w wyniku równoczesnego działania wielu czynników (teoria „multi hit”) powstają zmiany zapalne a następnie włóknienie. Czynnikami usposabiającymi do NASH są między innymi mikroflora jelitowa, cytokiny produkowane w wisceralnej tkance tłuszczowej, stres metaboliczny w strukturach siateczki gładkiej endoplazmatycznej hepatocytów i dysbioza indukowana przez inflammasomy. NAFLD i NASH są jednymi z najczęstszych chorób wątroby w skali światowej. W wysoko rozwiniętych krajach europejskich NAFLD występuje do 44% populacji i koreluje z „epidemią” cukrzycy i otyłości. Ostatnie badania wykazały, że mikroflora jelitowa, która jest jednym z głównych czynników powstawania NASH odgrywa również rolę w powstawaniu otyłości, która z kolei także usposabia do NAFLD i NASH. W ostatniej części przeglądu omówiono rolę rosnącego spożycia fruktozy (szczególnie pod postacią stężonego syropu) w powstawaniu otyłości, insulinooporności, a także rolę tego powszechnie stosowanego w przemyśle spożywczym środka słodzącego w inicjowaniu zmian zapalnych w wątrobie prowadzących do NASH.
Summary
Nonalcoholic fatty liver disease (NAFLD) is defined as the accumulation of fat (mainly triglycerides) in the liver cells. This condition termed as hepatic steatosis is easily visualised on ultrasound or on liver histology. The term NAFLD is reserved for the liver disease that is predominantly associated with metabolic syndrome and obesity. In the context of this definition the exclusion of secondary causes of liver steatosis (medications, virus hepatitis C, toxins, some metabolic diseases and other medical conditions and, what is most important, excessive alcohol consumption) is mandatory for NAFLD diagnosis. NAFLD is categorised into simple steatosis, termed nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). According to the first “two hit” model of pathogenesis, NAFLD presents the wide spectrum of liver changes. Insulin resistance and metabolic syndrome, acting as a “firs hit” result in NAFL. After a “second hit” (e.g. gut-derived endotoxins), NAFL progress to NASH, the more advanced form of NAFLD. Furthermore, NASH frequently progress to fibrosis, cirrhosis and even to hepatocellular carcinoma. Recently, a new model of pathogenesis of NAFLD has been proposed. According to this model, NAFL and NASH are the distinct conditions. In NAFL the intrahepatic triglycerides exert rather protective effect and the disease does not progress to NASH. In other patients, many factors (“multi hit” theory) acting in parallel, result in liver inflammation (NASH). Gut microbiota and adipose tissue derived cytokines, endoplasmic reticulum stress, inflammasome mediated dysbiosis and other, actually less known factors, may play a central role in NASH developing. NAFLD and NASH are common causes of chronic liver diseases worldwide. In Western countries NAFLD is the most common liver disease (up to 44% in the general European population) closely associated with the epidemic of diabetes and obesity and is increasingly relevant public health issue. Recently published studies shown, that gut microbiota, which may be in important risk factor of NASH, may also predispose the host to obesity. In the last part of this review the role of growing consumption of fructose (especially in form of high fructose corn syrup) in development of obesity and insulin resistance and also in triggering of hepatic inflammation (NASH) is discussed.
INTRODUCTION AND HISTORICAL OVERVIEW
This article is published in a volume of „Postępy Nauk Medycznych” fully dedicated to simple obesity. The author recognized as purposeful to present the subject of NAFLD/NASH in broader perspective, because it is related to the problem of obesity.
Fatty liver, which refers to the build-up of lipids, mainly triglycerides (TG), in hepatocytes, is a pathological condition, well known for a long time, and it refers to an imbalance between the amounts of lipids inflowing to the liver or produced in the liver, and the amount being secreted in the form of very low density lipoproteins (VLDL). An excessive amount of TGs in the liver parenchymal cells is the most common type of nonspecific response of the organ to various harmful factors and usually it is reversible after the causal factor stops acting. One of the most common causes of fatty liver is ethyl alcohol, and this pathology is a classical example of the reversibility of hepatic lesions following the discontinuing intake of a substance causing fatty liver. There are many known factors and conditions which may lead to fatty liver (1). They include improper nutrition and lifestyle, congenital or acquired diseases, as well as numerous exogenous factors, such as drugs and other chemicals (tab. 1 and 2).

Table 1. Exogenous factors, diseases and other pathological conditions, which may be accompanied by fatty liver (1).
Drugs (see table 2)
Toxins
Ethyl alcohol
Hydrocarbons, solvents
Some metals (e.g. inorganic phosphorus compounds)
Insulin resistance
Obesity
Type 2 diabetes mellitus
Hypertriglyceridemia
Hypertension
Improper nutrition
Excessive carbohydrate intake (diet, parenteral alimentation)
Protein deficiency in diet
Sudden weight loss (slimming)
Vitamin B12 deficiency
Anatomical lesions in the small intestine
Surgically created blind loop (e.g. in obesity treatment)
Diverticulosis of the small intestine
Short Bowel Syndrome
Metabolic diseases
Hypobetalipoproteinemia and abetalipoproteinemia
Wilson’s disease
Lipodystrophies
Weber-Christian syndrome
Infections
Hepatitis C virus (in particular genotype 3)
HIV
Recently diagnosed coexistence
Polycystic ovary syndrome
Hypothyroidism
Sleep Apnoea Syndrome
Hypopituitarism
Hypogonadism
Table 2. Some well known and generally used drugs, which may lead to fatty liver (6).
AmiodaroneMethotrexateSynthetic estrogens
CorticosteroidsTamoxifenAspirin
Valproic acidThioridazineCalcium channel blockers
TetracyclinesChloroquineZidovudine
DidanosineFialuridineGriseofulvin
In 1980, Ludwig et al. pointed out for the first time that after ruling out alcohol during interviews with subjects as a cause of their fatty liver, there are some cases with a morphological picture, which is “richer” than simple fatty liver. These cases revealed signs of hepatitis and fibrosis of various intensities (2). There were the first descriptions of a new disease called nonalcoholic steatohepatits (NASH), which has been interesting for clinicians and representatives of basic sciences involved in hepatology for three decades. During the initial period of studies, a definition was established for the liver pathology including steatosis, as well as expressions (see further in document), which are binding till now with some modifications. Aforementioned pathologies include: nonalcoholic fatty liver disease (NAFLD), which comprises two types of pathologies – nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatits (NASH).
In 1998, Day and James presented a concept of NASH pathogenesis (3). According to this hypothesis, NASH is being developed in two “hits”. The first “hit” is simple steatosis, which is facilitated by insulin resistance, and the second “hit” includes developing inflammation, apoptosis and necrosis in hepatocytes, which results from oxidative stress induced by many factors – mainly by proinflammatory cytokines, environmental and genetic factors. This pathogenesis of NASH was generally accepted till the end of the first decade of this century, when new concepts occurred (see further).
The increasing interest in liver diseases belonging to NAFLD group and a need to improve the quality of diagnoses and accuracy in communication, not only among scientists, but also in everyday clinical practice, forced the conduction of works on classification of morphological lesions in the liver. The first histopathological classification of NASH, which has been used till now, was developed in 1999 by Brunt et al. (4). Since 2005, more precise, but more time-consuming score classification has been available, which considers a significantly larger number of parameters than the classification by Brunt et al. However, due to its complexity, score classification of NASH is almost exclusively used in scientific publications (5).
In the 1980’s, before distinguishing NAFLD as a new disease, steatosis was treated as a histopathologic abnormality included in the picture of a specific disease or syndrome. Then, the term “NAFLD” referred to various pathological conditions with steatosis in the course of a disease, while most frequently it meant the toxic action of drugs and no association with any specific disease (e.g. Wilson’s disease), provided that alcohol etiology was ruled out. Not until 2002, the criteria of diagnosing NAFLD were narrowed and it was adopted that this expression referred only to fatty lesions in the liver observed in persons with insulin resistance and clinical, extrahepatic symptom of this abnormality, which is metabolic syndrome, or its individually occurring components – overweight or obesity, type 2 diabetes mellitus, hypertension and dyslipidemia (shadowed area in tab. 1). All other causes of fatty liver listed in tables 1 and 2 are currently recognized as falling out of the diagnosis of NAFLD and they are referred to as secondary fatty liver (6).

Despite a significant number of scientific studies and clinical observations, problems of fatty liver disease are not well known and many questions and doubts regarding pathogenesis, diagnosis and treatment, and especially regarding prognosis in NAFLD remain unanswered. The latter mainly refers to NASH because of the increasing evidence for the progressive nature of this disease, which in a substantial percentage of cases leads to advanced fibrosis (37-41%), cirrhosis (over 5%) and even to liver cancer, and in general evaluation, it leads to a significantly higher mortality rate than it is in the general population (7-9). In order to summarize current knowledge about NAFLD, to determine direction for the studies and to provide clinicians with management based on the highest quality evidence, prestigious liver associations – European (European Association for the Study of Liver, EASL) in 2010 (10) and American (American Association for the Study of Liver Diseases, AASLD) together with two American gastroenterological associations: American College of Gastroenterology (ACG) and American Gastroenterological Association (AGA) in 2012 (11) published a formal position (10) and guidelines (11) for management of NAFLD.

The purpose of this publication is to familiarize Polish readers of „Postępy Nauk Medycznych” with the most important, and above all, practical information regarding NASH based on the aforementioned guidelines and more recent publications as well as to discuss some aspects connecting NAFLD/NASH with the “obesity epidemic”, which has been recently observed all over the world.
DEFINITIONS, EPIDEMIOLOGY, DIAGNOSIS OF NAFLD, NAFL AND NASH
It is assumed that the expression “nonalcoholic fatty liver disease” (NAFLD) refers to the liver pathology related to systemic metabolic abnormalities, including insulin resistance and metabolic syndrome developing on its basis. NAFLD does not include alcoholic damage (steatosis) and previously listed (tab. 1 and 2) secondary fatty liver (fig. 1). NAFLD includes two forms – less advanced, i.e. nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). In the microscopic picture, NAFL reveals simple steatosis (with no signs of hepatocyte damage), but NASH, in addition to hepatocyte steatosis, reveals the following signs, which are observed in various intensities and in various combinations (4, 5): lobular hepatitis, hepatocyte necrosis, Mallory’s hyaline, glycogen degeneration of liver cell nuclei, fibrosis/cirrhosis.
Fig. 1. Classification of fatty liver diseases.
Global epidemiological data regarding the incidence of NAFLD and two forms of this syndrome – NAFL and NASH, are highly diverse, depending on the region, the studied population as well as the criteria and investigation methods. The incidence of NAFLD diagnosed based on an ultrasound evaluation ranges from 17% to 46% depending on the world region. Percentages in Europe are higher than they are in Asia (20-30% vs. 15%, respectively). These percentages stand in contrast with the results obtained in living liver donors – histologically documented NAFLD was established in 12-18% of potential donors in European centres, 27-38% – in the U.S. and in as much as 51% of healthy subjects donating part of the liver in Korea (10, 11). The most recent review of European epidemiological data demonstrates that the incidence of NAFLD in the population of our continent (including children and obesity) ranges from 2% to 44%, and among subjects with type 2 diabetes mellitus, it amounts to 42.6-69.5% (12). The incidence of NASH is estimated at the level of 3-5% in the general population of developed countries. Recent American studies show that among subjects with NAFLD diagnosed based on ultrasound evaluation, histologically confirmed NASH was diagnosed in 12.2% (13). Large epidemiological studies regarding fatty liver disease have not been conducted in Poland. Results of autopsies recently conducted in children, who died in accidents, may contribute to clarifying the incidence of this pathology. In nearly 350 subjects, 5.3% were diagnosed with fatty liver and 0.3% with NASH. It has to be emphasized that 54.4% of children with fatty liver were overweight (14).

In order to diagnose NAFLD, it is necessary to meet 2 conditions (10, 11):
1. Confirming fatty liver (with imaging tests or histopathological evaluation).
2. Ruling out alcohol as a potential etiological factor of the disease and ruling out other causes of steatosis (so-called secondary fatty liver).

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Piśmiennictwo
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otrzymano: 2013-02-19
zaakceptowano do druku: 2013-02-27

Adres do korespondencji:
*Andrzej Habior
Department of Gastroenterology and Hepatology Medical Centre for Postgraduate Education
ul. W. K. Roentgena 5, 02-781 Warszawa
tel.: +48 (22) 546-23-28, fax: +48 (22) 546-30-35
e-mail: ahab@coi.waw.pl

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