Digestive and Liver Disease
Volume 42, Issue 4 , Pages 272-282, April 2010

Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease:

A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee

  • P. Loria

      Affiliations

    • Dipartimento di Medicina Interna, Endocrinologia, Metabolismo e Geriatria, Università di Modena e Reggio Emilia, Nuovo Ospedale Sant’Agostino Estense di Baggiovara, Via del Pozzo 71, 41100 Modena, MO, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39 059 3961801/422580; fax: +39 059 3961335.
    • ,
  • L.E. Adinolfi

      Affiliations

    • Dipartimento di Medicina Interna ed Epatologia, Seconda Università di Napoli, Naples, Italy
    • ,
  • S. Bellentani

      Affiliations

    • Centro studi Fegato, Gastroenterologia, Ospedale “Ramazzini” di Carpi, Modena, Italy
    • ,
  • E. Bugianesi

      Affiliations

    • Divisione di Gastro-Epatologia, Ospedale San Giovanni Battista, Università di Torino, Turin, Italy
    • ,
  • A. Grieco

      Affiliations

    • Istituto di Medicina Interna, Policlinico Universitario “A. Gemelli”, Università Cattolica del Sacro Cuore, Rome, Italy
    • ,
  • S. Fargion

      Affiliations

    • Dipartimento di Medicina Interna, Fondazione Policlinico, Mangiagalli e Regina Elena, IRCCS, Università di Milano, Milan, Italy
    • ,
  • A. Gasbarrini

      Affiliations

    • Dipartimento di Medicina Interna, Policlinico Universitario “A. Gemelli”, Università Cattolica del Sacro Cuore, Rome, Italy
    • ,
  • C. Loguercio

      Affiliations

    • Centro Interuniversitario per Ricerche su Alimenti, Nutrizione e Apparato Digerente, Naples, Italy
    • ,
  • A. Lonardo

      Affiliations

    • Dipartimento di Medicina Interna, Endocrinologia, Metabolismo e Geriatria, Università di Modena e Reggio Emilia, Nuovo Ospedale Sant’Agostino Estense di Baggiovara, Via del Pozzo 71, 41100 Modena, MO, Italy
    • ,
  • G. Marchesini

      Affiliations

    • Dietetica Clinica, Alma Mater Studiorum Università di Bologna, Ospedale S. Orsola-Malpighi, Bologna, Italy
    • ,
  • F. Marra

      Affiliations

    • Dipartimento di Medicina Interna, Azienda Ospedaliera Universitaria Careggi, Università di Firenze, Florence, Italy
    • ,
  • M. Persico

      Affiliations

    • Unità di Medicina Interna ed Epatologia, Seconda Università di Napoli, Naples, Italy
    • ,
  • D. Prati

      Affiliations

    • Dipartimento di Medicina Trasfusionale e di Ematologia dell’Ospedale “Alessandro Manzoni, Lecco, Italy
    • Centro di Medicina Trasfusionale, Terapia Cellulare e Criobiologia, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
    • ,
  • G. Svegliati- Baroni

      Affiliations

    • Dipartimento di Gastroenterologia, Università della Marche – Politecnico, Ancona, Italy
    • ,
  • The NAFLD Expert Committee of the Associazione Italiana per lo studio del Fegato (AISF)

Accepted 28 January 2010. published online 22 February 2010.

Article Outline

Abstract 

We report the evidence-based Italian Association for the Study of Liver guidelines for the appropriate diagnosis and management of patients with nonalcoholic fatty liver disease in clinical practice and its related research agenda.

The prevalence of nonalcoholic fatty liver disease varies according to age, gender and ethnicity. In the general population, the prevalence of nonalcoholic fatty liver disease is about 25% and the incidence is of two new cases/100 people/year. 2–3% of individuals in the general population will suffer from nonalcoholic steatohepatitis. Uncomplicated steatosis will usually follow a benign course. Individuals with nonalcoholic steatohepatitis, however, have a reduced life expectancy, mainly owing to vascular diseases and liver-related causes. Moreover, steatosis has deleterious effects on the natural history of HCV infection.

Nonalcoholic fatty liver disease is usually diagnosed in asymptomatic patients prompted by the occasional discovery of increased liver enzymes and/or of ultrasonographic steatosis. Medical history, complete physical examination, etiologic screening of liver injury, liver biochemistry tests, serum lipids and insulin sensitivity tests should be performed in every patient. Occult alcohol abuse should be ruled out.

Ultrasonography is the first-line imaging technique. Liver biopsy, the gold standard in diagnosis and prognosis of nonalcoholic fatty liver disease, is an invasive procedure and its results will not influence treatment in most cases but will provide prognostic information. Assessment of fibrosis by composite scores, specific laboratory parameters and transient elastography might reduce the number of nonalcoholic fatty liver disease patients requiring liver biopsy.

Dieting and physical training reinforced by behavioural therapy are associated with improved nonalcoholic fatty liver disease.

Diabetes and the metabolic syndrome should be ruled out at timed intervals in nonalcoholic fatty liver disease. Nonalcoholic steatohepatitis patients should undergo periodic evaluation of cardiovascular risk and of advancement of their liver disease; those with nonalcoholic steatohepatitis-cirrhosis should be evaluated for early diagnosis of hepatocellular carcinoma.

Keywords: Diagnosis and management, Fibrosis, Metabolic syndrome

 

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1. Introduction 

Nonalcoholic fatty liver disease (NAFLD), which includes the whole spectrum from non-evolutive simple steatosis to progressive nonalcoholic steatohepatitis (NASH) with/without cirrhosis and hepatocellular carcinoma (HCC) [1] is a relevant issue in public health owing to its epidemiologic burden. It represents the most common chronic liver disease in the general population and is expected to increase in the future as a result of an ageing population, the improving control of other major causes of chronic liver disease and the epidemics of obesity and diabetes [1], [2]. From a health resources perspective, subjects with NAFLD have 26% higher overall health care costs at 5-year follow-up owing to direct and indirect expenditure [3]. From a clinical point of view, NAFLD is relevant due to the risk of its evolution into cirrhosis, liver failure and, in an as yet poorly defined proportion of cases, HCC [4].

There are three published Review studies/Scientific Society Guidelines [5], [6], [7] but none of them is evidence-based. Recently, the Chinese Society of Hepatology published the guidelines for the diagnosis and treatment of NAFLD [8]. The Italian Association for the Study of the Liver (AISF) asked a committee of experts to summarise the present knowledge of issues clinically relevant to the diagnosis and management of NAFLD. This position paper, intended for use by practicing physicians, offers evidence-based general suggestions, which may be modulated in individual cases. The pathogenesis of the disease, for which excellent reviews are available [9], [10], [11], [12] is beyond the scope of the present manuscript.

The present guidelines consist of 10 issues (“decalogue”) including: (1) Introduction and methodology; (2) Prevalence, incidence and natural history; (3) NALFD, HCV and the metabolic syndrome; (4) Diagnosis; (5) Differential diagnosis with alcoholic liver disease; (6) Treatment; (7) Follow-up; (8) Prevention; (9) NAFLD and orthotopic liver transplantation (OLT); (10) Research agenda.

1.1. Methodology 

This document represents the synthesis, in English, of a much larger review of the literature, which is available, in Italian, on the AISF web site (http://www.webaisf.org). The AISF appointed an Expert Committee of Italian researchers with the task of drawing up diagnostic and therapeutic guidelines on NAFLD. To this end, the pertinent literature was first reviewed, with particular attention to evidence-based classifications. Members of the Committee then took care of specific chapters, which were revised and received final approval by all members of the Committee. Therefore, the present guidelines represent the official AISF position paper on NAFLD. Based on the national plan for guidelines [13], the levels of evidence range from I to VI and the strength of recommendations ranges from A to E (Table 1) [13]. Where no clear evidence exists, guidance is based on the consensus amongst the members of the Committee.

Table 1. Levels of evidence and strength of recommendations [13].
Levels of evidence
IEvidence from multiple RCTs and or systematic reviews of randomised studies
IIEvidence from a single well designed controlled trial
IIIEvidence from non-randomised cohort studies with concurrent or historical controls or their metanalytic review
IVEvidence from retrospective studies or their metanalytic review
VEvidence from case series without a control group
VIEvidence from Expert opinion or Expert Committees as indicated in guidelines or Consensus Conferences or based on the opinions of individual members of Expert Committees responsible for writing guidelines

Strength of recommendations
AProcedure/diagnostic test strongly recommended, supported by good quality scientific evidence, even if not necessarily type I or II
BProcedure/diagnostic test not invariably recommended but to be carefully considered
CProcedure/diagnostic test surrounded by substantial uncertainty
DProcedure not recommended
EProcedure strongly advised against

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2. Prevalence, incidence and natural history 

2.1. Prevalence of primary NAFLD/NASH 

The prevalence of NAFLD in general population in Western countries, including Italy, is about 25% [2], [14], [15]. The prevalence varies as a function of age, gender and ethnicity [2], [16], [17].

Level of evidence: I

According to the best available evidence the prevalence of NASH in USA lean subjects is 2.7% [18], a figure in the same order magnitude reported for hepatitis C (Table 2) [19].

Table 2. Prevalence of various etiologies of liver diseases in the general population, USA [19].
AetiologyPrevalence
NAFLDApproximately 25%
HCV2%
Alcoholic liver disease1%
HBV0.3–0.4%
HFE-linked hereditary haemochromatosis1:200–1:400
Autoimmune liver diseaseUp to 17/100,000
Alpha1-AT deficiency1/1500–1/7600
Wilson's disease1/30,000

Level of evidence: II–III

Elevated ALT levels do not discriminate NAFLD either from normal liver or from alcoholic fatty liver disease (AFLD) since liver enzymes are normal in almost half of NAFLD cases [20]. Studies have also shown that normal ALT values do not rule out NASH and fibrosis [21], [22].

Level of evidence: I

2.2. Incidence of NAFLD/NASH 

The incidence of “fatty liver” in the general Italian population was estimated by the Dyonisos study at two new cases/100 people/year [23]. A Japanese study in a selected population reported 10 new NAFLD cases/100 people/year [24].

Level of evidence: II

2.3. Natural history 

Whilst pure steatosis is not associated with excess mortality in long-term follow-up studies [25], [26], individuals with NASH have a reduced life expectancy [4], [26], [27]. Recent evidence suggests that, further to liver-related death (due to end-stage liver failure, complications of portal hypertension and HCC), patients are exposed to increased frequency of cardiovascular diseases [28] leading to excess mortality [26]. Middle-aged adults may be at particularly high risk [29]. Patients with either uncomplicated fatty liver or NASH appear to be at risk of developing the full-blown metabolic syndrome or its individual components, particularly type 2 diabetes and impaired fasting glucose [30], [31].

Fig. 1, modified from de Alwis and Day [32], depicts the natural history of NAFLD as can be derived from relevant studies [4], [23], [25], [26], [31], [33], [34], [35], [36], [37], [38], [39], [40], [41].

Level of evidence: II

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3. NALFD, HCV and the metabolic syndrome 

Steatosis is present, on average, in 55% of cases of chronic HCV infection [42].

The prevalence and the extent of steatosis vary as a function of viral (genotype) and host factors [43].

Genotype 3 is directly steatogenic [43], [44], [45]. In genotype 1, steatosis is associated with the features of the metabolic syndrome such as insulin resistance, increased BMI and visceral obesity [43], and ethnicity [46]. Additional host's genetic features may increase the risk of developing steatosis in those infected with HCV [47], [48].

Level of evidence: I–III

Although insulin resistance is present both in NAFLD and in HCV-associated steatosis in a high proportion of cases (>70%), in comparative studies the metabolic syndrome is more prevalent amongst NAFLD patients (41–52%) than amongst those with HCV-associated steatosis (4.4–25%) [49], [50], [51], [52].

Level of evidence: III

Irrespective of genotype, HCV-associated steatosis is a risk factor for fibrosis progression in cross-sectional [53], [54] and prospective studies [55], [56], [57]. Moreover, steatosis is a risk factor for the development of HCC in patients with chronic HCV infection, with or without cirrhosis [58], [59], [60], [61].

Level of evidence: III

HCV-associated steatosis is linked with a lower sustained response rate to treatment with Peg-interferon (Peg-IFN) and ribavirin (RBV) in genotype 1-infected patients [45], [62] and increased relapse rate in individuals with genotypes 2 and 3 [63]. The response to Peg-IFN and RBV is lower in patients with a high BMI [64] and elevated insulin resistance [65], [66]. In chronic HCV infection, BMI and IR are risk factors for steatosis and fibrosis [45], [49], [54], [67]. Therefore, the reduction of overweight and IR constitutes an additional rational therapeutic strategy in the treatment of chronic hepatitis C.

Level of evidence: III

Strength of recommendation: A

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4. Diagnosis 

For practical reasons we will first discuss the clinical presentation of NAFLD and then the clinico-laboratory evaluation. Finally, the issue of imaging and invasive diagnostic techniques will be addressed.

Fig. 2 illustrates an integrated diagnostic and therapeutic flow-chart which can be applied in clinical practice.

  • View full-size image.
  • Fig. 2. 

    A practical approach to NAFLD (based on paragraphs 4–6).

  • In the absence of specific chemicals, viral, autoimmune and genetic aetiology, raised liver enzymes are most commonly associated with NAFLD.

  • NAFLD may be suspected owing to increased levels of liver enzymes and/or compatible ultrasonographic findings. Ultrasound scanning should be performed in every patient. History, physical examination and appropriate laboratory tests will reinforce the diagnosis of NAFLD and contribute to ruling out alternative etiologies. The coexistence of specific indicators of the metabolic syndrome will result in enhanced clinical probability of progressive disease (NASH/Fibrosis). Liver biopsy should be reserved to those patients presenting risk factors for NASH/fibrosis such as those listed in Table 3.

  • Lifestyle modification (in the absence of risk factors) and pharmacological therapeutic interventions, possibly in the context of RCTs (in the presence of NASH and fibrosis) may be adopted in the individual patient.

4.1. Clinical presentation 

NAFLD is often diagnosed in asymptomatic patients during the diagnostic work-up for unexplained persistently increased values of serum transaminases and/or gamma-glutamyl-transpeptidase [68], during a routine check-up screening evaluation, and/or during ultrasound evaluation of the abdomen, irrespective of laboratory findings [20]. The upper normal alanine aminotransferase (ALT) limit varies between studies and between tests performed in different laboratories because of technical reasons and different reference populations. The distribution of ALT values in the general population is skewed, the degree of skew being influenced by factors including male gender, obesity, and the different components of the metabolic syndrome. It is now agreed that ALT reference ranges currently used in clinical practice underestimate the actual frequency of liver disease patients as current evidence suggests that existing ‘normal’ ALT thresholds are too high and should be lowered by 25–30%, thus setting the “optimal” ALT threshold at 30U/L for males and 20U/L for females [69], [70].

Usually, NAFLD patients are asymptomatic [5]. In most patients an enlarged liver can be appreciated. Splenomegaly is a rare finding.

Level of evidence: I

4.2. Clinico-laboratory evaluation 

A complete personal and familial medical history should be taken, directed at evaluating and recording the risk factors for NAFLD, alcohol consumption and lifestyle [71]. In young women, changes in the menstrual cycle and hirsutism may suggest the presence of polycystic ovary syndrome, frequently associated with NAFLD [72]. A complete physical examination should be performed, including measurement of height, weight, abdominal circumference, waist-to-hip ratio, and arterial pressure [71].

Strength of recommendation: A

Table 3 (modified from Ref. [71]) lists the specific issues to be addressed in history taking, performing physical examination and selecting laboratory tests. These tests include screening of common causes of chronic liver disease (HBsAg, HCV-Ab, autoimmunity profile, etc.), liver function tests, and metabolic profile.

Table 3. Diagnostic evaluation of patients with NAFLD (modified from Ref. [71]).
HistoryPhysical examinationLaboratory tests
Family occurrence of NAFLD and components of the metabolic syndromeHeight (m)Blood cell count, PT, PTT, bilirubin, ALT, AST, GGT, ALP, total proteins and serum proteins electrophoresis
DietWeight (kg)Serum levels of total cholesterol, HDL-cholesterol and triglycerides
Alcohol consumptionBMI (kg/m2)Fasting glucose and insulin
Physical activityWaist girthHbsAg, HCV-Ab
Body weight changesArterial pressureAnti-smooth muscle Ab (ASMA), anti-nuclear Ab (ANA), anti-liver-kidney microsome (LKM I e II), anti neutrophils cytoplasm (p-ANCA and c-ANCA), anti-transglutaminase Ab and/or anti-endomisial Ab (EMA)
Drugs Serum iron, transferrin and ferritin
Exposure to chemicals and toxins Alfa1-antitrypsin
Alterations of menses Copper, ceruloplasmin
TSH

Strength of recommendation: A

Several tests are available to assess insulin resistance/sensitivity: the glucose euglycaemic clamp, HOMA index, OGIS (oral glucose sensitivity index), fasting glucose and insulin [49], [73], [74]. Fasting glucose and insulin, HOMA and OGIS are more widely available.

4.3. Laboratory markers of fibrosis 

In order to restrict the large number of potential candidates for liver biopsy on the accounts of suspected NAFLD, clinicians have evaluated the utility of several complex, ‘non-invasive’ surrogate biochemical indicators of fibrosis [75]. However, these tests are not available in most laboratories and have not been extensively validated. Therefore, such surrogate indicators do not avoid the need to perform liver biopsy in clinical practice.

Level of evidence: VI

Strength of recommendation: C–D

Studies have attempted to identify specific hormonal factors [76], [77] and genetic polymorphisms [78], [79] which might assist in the diagnosis of NASH.

Although these studies strongly contribute to our understanding of the pathogenesis of NAFLD, further studies are needed before applying these techniques to ascertain the risk in clinical practice.

Level of evidence: VI

Strength of recommendation: C–D

4.4. Clinical scores for fibrosis 

In order to restrict the large number of individuals potentially susceptible to undergo liver biopsy on the account of suspected NAFLD, clinicians have evaluated the utility of several indices predictors of fibrosis in NAFLD, which are summarised in Table 4 (modified from Ref. [1]) based on Refs. [38], [80], [81], [82], [83], [84], [85], [86].

Table 4. Independent predictors of fibrosis in NAFLD or predictors of NASH and scoring systems proposed to predict NASH/fibrosis (modified from Ref. [1]).
NameBADBAATHAIRBARGNAFLD fibrosis scoreBARDClinical scoring system for predicting NASHELF
Angulo et al. [80]Ratziu et al. [81]Dixon et al.* [82]Harrison et al. [38]Angulo et al.* [83]Harrison et al. [84]Campos et al.* [85]Guha et al.* [86]
BMIYesYes–YesYesYes–Yes
AGEYesYes––Yes–––
AST/ALT–––YesYesYes–Yes
ALT–YesYes––– –
AST Yes
Albumin––––Yes––Yes
Platelets––––Yes––Yes
T2DYes––––YesYes–
HbA1c/glucose–––YesYes––Yes
IR index––Yes–––––
Triglycerides–Yes––––––
Arterial hypertension––Yes–––Yes–
Non-Black race––––––Yes–
Sleep apnea––––––Yes–

The tests result from logistic regression analysis except for those indicated by * which form a true scoring system.

These indices, particularly the NAFLD fibrosis score [80] should be considered in evaluating NAFLD patients for liver biopsy.

Level of evidence: I–II

Strength of recommendation: A–B

4.5. Role of imaging studies 

4.5.1. Ultrasound scanning 

The advantages of ultrasound scanning of the liver include safety, low cost and repeatability [87]. Based on these characteristics, ultrasonography is the first-line imaging technique suitable both in the clinical setting and for epidemiological studies.

Level of evidence: I

Strength of recommendation: A

Limitations of the technique include the relatively low sensitivity in detecting minor degrees of fatty changes, the low accuracy in the obese and meteoric patient, the inability to differentiate simple steatosis from NASH and the operator-dependency [88], [89], [90]. At ultrasound scanning, signs of liver steatosis are the presence of a bright echo pattern of the liver, posterior attenuation and/or skip areas. These are closely related to fatty changes ≥20–30% [91], [92].

Level of evidence: III

Strength of recommendation: B–C

4.5.2. Computed tomography scanning 

Computed tomography (CT) enables the evaluation of the liver-to-spleen attenuation ratio that correlates with the degree of steatosis on histopathology. Patients with NASH have a greater liver span and increased caudate-to-right-lobe-ratio compared with patients with steatosis alone [93]. CT scanning, however, exposes patients to ionising radiation, thus its use is not recommended, particularly in the paediatric population and in follow-up studies.

Level of evidence: III

Strength of recommendation: D

4.5.3. Magnetic resonance imaging 

Although probably the most accurate and fastest method of detecting liver fat, magnetic resonance (MR) spectroscopy is expensive. Moreover, the necessary software is not available in most MR Imaging Units. MR elastography, a new technique to assess liver stiffness, has not been demonstrated to detect NAFLD [90]. MRI techniques are expected to become useful tools in future studies, either in examining the natural history of NAFLD, or in testing new treatment results [94].

Level of evidence: III

Strength of recommendation: B

4.6. Transient elastography (FIBROSCAN) 

Transient elastography measures liver stiffness which is correlated with fibrosis stage in NASH [95], [96], [97]. Transient elastography is, however, influenced by elevated ALT, steatosis [75], [98] and is limited by technical problems in abdominal obesity [99].

Level of evidence: III

Strength of recommendation: B

4.7. Liver biopsy 

Liver biopsy represents the gold standard for the diagnosis and prognosis of NAFLD [5], [7], [100]. Although this invasive technique is not devoid of risks and will not alter the therapeutic strategy in most cases [101], [102], being an irreplaceable diagnostic tool to differentiate NASH from NAFLD, it will help in assessing the liver-related prognosis (Fig. 2).

Level of evidence: VI

Strength of recommendation: B

Pathological findings in NAFLD and NASH have been evaluated and scored in the classification proposed by Brunt et al. [103] and modified by Kleiner et al. [104]. Limitations in the interpretation of liver biopsy derive both from the inter-observer variability in the assessment of pathologic findings and from the inherent inhomogeneous distribution of pathologic changes in NAFLD [104], [105].

Level of evidence: II–III

Strength of recommendation: B

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5. Differential diagnosis with alcoholic fatty liver disease 

In Table 5 [106] the complete pathogenetic spectrum underlying NAFLD in the individual patient is presented. In clinical practice, however, given its common occurrence, the differentiation of NAFLD from AFLD remains a challenge, which can be faced utilising patient interview coupled with laboratory findings.

Table 5. Causes of fatty liver disease [106].
NutritionalDrugsaMetabolic or geneticOther
Protein–calorie malnutritionbGlucocorticoidsbLipodystrophybInflammatory bowel diseaseb
StarvationbSynthetic estrogensbDysbetalipoproteinemiabSmall-bowel diverticulosis with bacterial overgrowthb
Total parenteral nutritionbAspirincWeber–Christian diseasebHuman immunodeficiency
Rapid weight lossbCalcium-channel blockersbWolman's diseasedVirus infectionb
Gastrointestinal surgery for obesitybAmiodaronedCholesterol ester storagedEnvironmental hepatotoxins
TamoxifenbAcute fatty liver of pregnancycPhosphorusc
Tetracyclinec Petrochemicalsb,c
Methotrexateb Toxic mushroomsb
Perhexiline maleated Organic solvents
Valproic acidc Bacillus cereus
Cocainec Toxinsc
Antiviral agents
Zidovudineb
Didanosinec
Fialuridinec

aThis is a partial list of agents that produce fatty liver. Some drugs produce inflammation as well. The association of fatty liver with calcium-channel blockers and valproic acid is weak, whereas the association with amiodarone is strong. Drug-induced fatty liver may have no sequelae (e.g., cases caused by glucocorticoids) or can result in cirrhosis (e.g., cases caused by methotrexate and amiodarone).

bThis factor predominantly causes macrovesicular steatosis (mostly owing to imbalance in the hepatic synthesis and export of lipids).

cThis factor predominantly causes microvesicular steatosis (mostly owing to defects in mitochondrial function).

dThis factor causes hepatic phospholipidosis (mostly owing to the accumulation of phospholipids in lysosomes).

Occult alcohol abuse should be ruled out in subjects with fatty liver disease, particularly in elderly males [20].

Level of evidence: II–III

Strength of recommendation: A

The threshold for hepatotoxicity in a free-living population in Italy is 30g/die [107]. An Italian Expert Panel suggested 20/30g daily (women/men) as the level of “moderate alcohol consumption”, to be consumed during meals, and not to be exceeded (www.inran.it). This threshold is also acknowledged in clinical practice to differentiate AFLD from NAFLD [108].

Level of evidence: III

Strength of recommendation: A

The potential of modest alcohol consumption (<70g/week) being associated with a reduced risk of increased transaminases and steatosis in patients without other liver conditions [109], [110], [111] needs to be evaluated in additional studies before it can be translated in clinical practice.

Level of evidence: III–IV

Strength of recommendation: D

Not only the amount of alcohol consumed, but also the composition of the diet and the pattern of drinking are important determinants in the risk of liver disease [107], [112]. Drinking on an empty stomach and/or drinking multiple types of alcoholic beverages, independent of the amount drunk is associated with an increased prevalence of alcoholic liver disease [107].

Advice for hepatological lower-risk drinking habits should take into account the results of the above studies.

Level of evidence: III–IV

Strength of recommendation: A

Obese subjects are likely to be exposed to more severe alcohol hepatotoxicity [113], [114].

Obese subjects should be discouraged from drinking alcohol.

Level of evidence: IV–V

Strength of recommendation: A

Table 6 summarises the characteristics of currently used biomarkers of alcoholism [115]. Owing to alcohol's short half-life [116] serum and urine alcohol levels cannot be utilised for the diagnosis of alcoholic liver disease. The combination of physician interview, questionnaire and laboratory markers is necessary for the diagnosis of alcoholism [117].

Table 6. Biomarkers in alcoholism [115].
MarkerAbbreviationHalf-life/elimination rateClinical characteristics
Blood ethanolEtOH1g/1h/10kgLevels exceeding 1.5‰ without evidence of intoxication or 3‰ at any time indicate ethanol tolerance typically found in alcohol abusers and alcohol-dependent patients. Suitable for emergency clinics.
Gamma-glutamyltransferaseGGT2–3 weeksA sensitive and inexpensive marker. Age-dependent. Specificity decreased by obesity, diabetes, nonalcoholic liver diseases, pancreatitis, hyperlipidemia, cardiac insufficiency, severe trauma, medications (barbiturates, drugs for epilepsy, anticoagulants), nephrotic syndrome, renal rejection.
Mean corpuscular volume of erythrocytesMCV2–4 monthsMore sensitive in women. Specificity decreased by vitamin B12 or folic acid deficiency, liver diseases, haematological diseases, hypothyroidism, reticulocytosis, smoking.
Carbohydrate-deficient transferrin (desialotransferrin)CDT2–3 weeksMost specific of the currently available methods. Specificity decreased by genetic variants of transferrin on rare occasions.
GGT–CDT combinationGGT–CDT (γ-CDT)2–3 weeksA mathematically formulated combination, which is easy to manage in hospital laboratories. Improves sensitivity without a loss of specificity. Good correlation with the amount of recent ethanol intake. Suitable for routine use.
AminotransferasesAST, ALT2–3 weeksAST/ALT-ratio over 2 suggests alcoholic aetiology in liver disease patients.

The most sensitive and specific of the commonly used biomarkers of alcohol intake are carbohydrate-deficient transferrin (CDT) and the combination of GGT and CDT [118]. One of the postulated advantages of CDT over many other markers is that it is not influenced by the presence of liver disease [119], [120]. CDT alone or combined with GGT is more sensitive in males than in females, in those older than 35 years of age and in those who drink more than 60g alcohol per day [115], [120], [121].

Level of evidence: II–III

CDT is the only test approved by the FDA for the identification of heavy alcohol use [122]. Its use in this specific subset of individuals is recommended although the procedure is not widely available.

Level of evidence: III–IV

Strength of recommendation: B

Due to the lack of specificity, GGT is a poor marker when alcohol consumption needs to be screened in patients with NAFLD or other liver diseases and in hospitalised patients [115]. The test is not recommended in the differential diagnosis of alcoholic liver disease.

Level of evidence: III–IV

Strength of recommendation: D

Macrocytosis is not specific but there is a dose dependent response between erythrocytes and the amount of ethanol intake [115].

Level of evidence: V

Thrombocytopenia is one of the most common laboratory abnormalities in alcoholic patients [115].

Level of evidence: VI

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6. Treatment 

6.1. Non-pharmacologic treatment—lifestyle changes 

Non-pharmacologic interventions aimed at correcting unhealthy lifestyles simultaneously treat all the clinical manifestations of the metabolic syndrome, and are an effective treatment option in NAFLD. Lifestyle changes include weight loss, dietary changes, reduction of sedentarity and physical exercise. They are best accomplished through cognitive-behaviour therapy, which should always be implemented as first-line therapeutic option, regardless of the severity NAFLD/NASH [123], [124], [125].

Level of evidence: II

Strength of recommendation: A

The diet of NASH patients is richer in saturated fats and cholesterol and poorer in poly-unsaturated fats, fibers and antioxidants (vitamin C and E) [126]. A link was suggested between fructose overconsumption, dyslipidemia, insulin resistance and ectopic lipid deposition [127], [128], [129].

All NAFLD patients should receive counselling for a low carbohydrate and low saturated fat diet, avoidance of fructose-enriched soft drinks and increased consumption of fruits and vegetables. Overweight individuals and those with visceral obesity should follow a hypocaloric diet aimed at 0.5kg/week weight loss [130], [131].

Level of evidence: II

Strength of recommendation: A

Most NAFLD patients fail to meet current recommendations for physical activity [132]. Daily physical activity should be measured in each patient and counselling for exercise should be provided. Training improves cardio-respiratory fitness, insulin resistance and liver enzymes, independent of weight loss [133]. Any increase in physical activity over baseline or even avoidance of sedentariness is desirable, but vigorous exercising should be avoided in individuals known to be prone to cardiovascular disease [28], [134], [135].

Level of evidence: II

Strength of recommendation: A

6.2. Anti-obesity drugs 

Drug therapy of obesity (orlistat and sibutramine) [136] has not shown a direct beneficial effect on the liver independent of the beneficial effect of weight loss. However, these drugs may enhance the beneficial effects of behavioural therapy. The finding that psychiatric side-effects outweighed the metabolic benefits resulted in the discontinuing of all trials with commercially available CB1 receptors blockers [137].

Level of evidence: III–II

Strength of recommendation: C

6.3. Bariatric surgery 

Although bariatric surgery is not specifically indicated in NAFLD, it may be useful in morbidly obese patients. A metanalytic review has reported improved liver histology following gastric by-pass and LAP-banding [138]. However, a recent Cochrane database systematic review reported that the lack of randomised clinical trials precludes the assessment of benefits and harm of bariatric surgery as a therapeutic approach for patients with NASH [139].

Level of evidence: IV

Strength of recommendation: B–C

6.4. Insulin sensitisers 

Insulin sensitisers such as metformin and glitazones are associated with normalisation of transaminases in 50% of cases, decreased steatosis (evaluated through ultrasonography and MR spectroscopy), a partial improvement in necro-inflammation and, less evident, in fibrosis [140] in a 1-year follow-up. Longer duration of treatment does not increase the success rate [141]. Liver enzymes will invariably return to pre-treatment values and liver histology will rapidly deteriorate after cessation of treatment [140], [142]. In addition, cardiovascular side-effects have been reported following administration of glitazones [143]. In NAFLD, their use should be restricted to randomised controlled trials in non-responders to standard lifestyle changes.

Level of evidence: II–III

Strength of recommendation: B

6.5. Lipid lowering agents 

Lipid lowering drugs such as fibrates, statins, omega-3s produce a partial improvement in transaminases. However, they have no advantage over lifestyle changes [140], [108].

Level of evidence: III–IV

Strength of recommendation: C

6.6. Anti-hypertensive agents 

Blood pressure control is aimed at reducing cardiovascular risk and the effects on liver disease are uncertain. However, angiotensin-receptor blockers have favourable metabolic effects, and a pilot study with losartan [144] showed moderate effects on hepatic histology. The use of these drugs should be restricted to NAFLD subjects with arterial hypertension until more evidence will be available.

Level of evidence: III

Strength of recommendation: C

6.7. Cyto-protective and antioxidant agents 

Cyto-protective and antioxidant agents do not have substantial advantages compared with behavioural changes on modification of biochemical parameters [108]. Conflicting data have been reported with UDCA [145], [146].

Level of evidence: II–III

Strength of recommendation: C

Supplementation with vitamin E and C, which have mainly been tested in paediatric NAFLD, were reported as ineffective on biochemical and histological outcomes [140], [108]. Positive results have been demonstrated for vitamin E in association with UDCA [147] and additional data (the large PIVENS trial of the NASH CRN Research Group), which will soon be released, are eagerly awaited.

Level of evidence: III

Strength of recommendation: C

6.8. Venesection 

Particularly in subjects with elevated ferritin levels, or with HFE gene mutations indicative of hereditary haemochromatosis, iron depletion through venesection can be proposed [148].

Level of evidence: IV

Strength of recommendation: B

6.9. Experimental approaches 

Experimental approaches include anti-TNFalfa, and caspases inhibitors [140], [108]. Moderately encouraging results including histological outcomes have been reported in pilot studies with pentoxiphylline [149]. The use of drugs belonging to this class should be limited to controlled studies.

Level of evidence: VI

Strength of recommendation: C

6.10. Conclusions 

In conclusion, as shown in Fig. 2, owing to the lack of hard data, administration of drug agents or the practice of surgical interventions should be reserved to controlled studies of evolutive NAFLD, unless otherwise motivated by other health requirements.

It is recommended that such therapeutic studies be designed and performed with the aim of providing clinically useful information. To this end, liver biopsy at entry and second biopsy at scheduled interval should be performed.

Level of evidence: III

Strength of recommendation: A

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7. Follow-up 

Natural history data have shown that individuals with uncomplicated nonalcoholic steatosis should be reassured about the benign course of disease [25], [26].

Based on these data it is advisable that patients with steatosis undergo a “low intensity” surveillance schedule. Patients with NASH should be monitored as patients with chronic viral hepatitis.

Level of evidence: III

Strength of recommendation: A

7.1. Early diagnosis of HCC 

Individuals with NASH-cirrhosis are at risk of developing HCC [36] and, by inference extrapolated from studies conducted in patients with cirrhosis due to other etiologies [150], [151], should undergo systematic follow-up aimed at the early diagnosis of HCC.

Level of evidence: III

Strength of recommendation: A

7.2. Metabolic and cardiovascular risk 

Given these patients’ increased risk of developing diabetes and MS [30], [31], laboratory parameters exploring common metabolic disorders should be repeated at timed intervals (6–12 months). The interval between check-ups should keep into account the severity of liver disease and the metabolic risk in the individual patient.

Based on the evidence of early atherosclerosis [28], [134] and increased cardiovascular mortality [26] particularly in the 45–54 year age group [29], NASH patients should undergo periodic non-invasive evaluation of their cardiovascular risk.

Level of evidence: III

Strength of recommendation: A

7.3. Risk of cancer 

Similar to those with obesity [152] and diabetes [153], hospitalised individuals with fatty liver have been reported to be at increased risk for some extra-hepatic cancers [154] and cancer was the first cause of death in a population based cohort study [4].

Based on the above studies, generalised cancer screening programs cannot be proposed to all NAFLD patients. However, tailored screening strategies may be discussed on an individual basis on the grounds of familial and personal risk of cancer and on patient's informed consent.

Level of evidence: V–VI

Strength of recommendation: B–C

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8. Prevention 

No specific studies about NAFLD prevention are available. However, given the association of NAFLD with poor physical fitness and diets rich in soft drinks, fructose, carbohydrates and saturated fatty acids [126], [133], [155], [156] it is reasonable to speculate that a policy reducing the consumption of these risk factors may result in a decreased incidence of NAFLD in cohorts at high risk.

Level of evidence: VI

Strength of recommendation: A

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9. NAFLD and orthotopic liver transplantation (OLT) 

Steatosis <30% in the donor's liver does not affect the success rate of the transplant [157]. Steatosis risk factors that are present pre-OLT in the recipient will often worsen after OLT [158].

Level of evidence: III

Strength of recommendation: B

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10. Research agenda 

Based on the present document, the Expert Committee recommends priority for the following research items:

•Epidemiology: Multi-centre prospective long-term (≥20 years) follow-up studies. Genetic characterisation, particularly in subjects with no risk factors.

•NAFLD, HCV and the metabolic syndrome: Impact of “metabolic” therapeutic strategies associated with virologic schedules. Study of the host's genetic features.

•Clinical manifestations: Registry of cryptogenic cirrhosis; characterisation of non-insulin-resistant cases of NAFLD or insulin-resistant NAFLD without risk factors.

•Diagnosis: Sample variability of liver biopsy. Genetic and endocrine determinants of progressive disease.

•Treatment: Controlled large-scale studies with histological end-points.

•Follow-up: Study of non-invasive predictors of early cirrhosis (e.g., scores, laboratory and imaging, transient elastography). Assessment of cancer risk: affected organs and assessment of risk rate.

•Prevention: Effectiveness of prevention strategies, particularly in children, teen-agers and young adults.

•OLT: Steatosic liver as marginal graft. Recurrence of NASH in the post-transplant setting.

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Conflict of interest 

None declared.

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Acknowledgements 

We acknowledge all the colleagues who helped us in writing, revising, and editing the manuscript and particularly Dr. Ester Vanni.

The dedicated secretarial assistance of Elisa Gibertini is also gratefully acknowledged.

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References 

  1. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43(2 Suppl. 1):S99–S112
  2. Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis. 2008;28:339–350
  3. Baumeister SE, Völzke H, Marschall P, et al. Impact of fatty liver disease on health care utilization and costs in a general population: a 5-year observation. Gastroenterology. 2008;134:85–94
  4. Adams LA, Lymp JF, St. Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–121
  5. American Gastroenterological Association . American Gastroenterological Association medical position statement: nonalcoholic fatty liver disease. Gastroenterology. 2002;123:1702–1704
  6. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202–1219Review. Erratum in: Hepatology 2003; 38: 536
  7. Farrell GC, Chitturi S, Lau GK, et al. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary. J Gastroenterol Hepatol. 2007;22:775–777
  8. Zeng MD, Fan JG, Lu LG, et al. Chinese National Consensus Workshop on Nonalcoholic Fatty Liver Disease. Guidelines for the diagnosis and treatment of nonalcoholic fatty liver diseases. J Dig Dis. 2008;
  9. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–152
  10. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in non-alcoholic fatty liver disease. Semin Liver Dis. 2008;28:370–379
  11. Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res. 2009;48:1–26
  12. Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010;5:145–171
  13. Centre for EBM (CEBM) of Oxford and CEVEAS - Piano nazionale linee guida http://www.pnlg.it/.
  14. Angulo P. GI epidemiology: nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2007;25:883–889
  15. Loria P, Lonardo A, Bellentani S, et al. Non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease: an open question. Nutr Metab Cardiovasc Dis. 2007;17:684–698
  16. Lonardo A, Carani C, Carulli N, et al. ‘Endocrine NAFLD’ a hormonocentric perspective of nonalcoholic fatty liver disease pathogenesis. J Hepatol. 2006;44:1196–1207
  17. Harmon RC, Caldwell SH. Propensity for non-alcoholic fatty liver disease: more evidence for ethnic susceptibility. Liver Int. 2009;29:4–5
  18. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106–1110
  19. Yu AS, Keeffe EB. Elevated AST or ALT to nonalcoholic fatty liver disease: accurate predictor of disease prevalence?. Am J Gastroenterol. 2003;98:955–956
  20. Bedogni G, Miglioli L, Masutti F, et al. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005;42:44–52
  21. Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37:1286–1292
  22. Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008;48:792–798
  23. Bedogni G, Miglioli L, Masutti F, et al. Incidence and natural course of fatty liver in the general population: the Dionysos study. Hepatology. 2007;46:1387–1391
  24. Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med. 2005;143:722–728
  25. Dam-Larsen S, Franzmann M, Andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–755
  26. Ekstedt M, Franzén LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–873
  27. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2008;(November):
  28. Gastaldelli A, Kozakova M, Højlund K, et al. Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology. 2009;49:1537–1544
  29. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am J Gastroenterol. 2008;103:2263–2271
  30. Friis-Liby I, Aldenborg F, Jerlstad P, et al. High prevalence of metabolic complications in patients with non-alcoholic fatty liver disease. Scand J Gastroenterol. 2004;39:864–869
  31. Adams LA, Waters OR, Knuiman MW, et al. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol. 2009;104:861–867
  32. de Alwis NM, Day CP. Non-alcoholic fatty liver disease: the mist gradually clears. J Hepatol. 2008;48(Suppl. 1):S104–S112
  33. Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11:74–80
  34. Teli MR, James OF, Burt AD, et al. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. 1995;22:1714–1719
  35. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419
  36. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140
  37. Ratziu V, Bonyhay L, Di Martino V, et al. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology. 2002;35:1485–1493
  38. Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol. 2003;98:2042–2047
  39. Hui JM, Kench JG, Chitturi S, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 2003;38:420–427
  40. Fassio E, Alvarez E, Domínguez N, et al. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40:820–826
  41. Day CP. Natural history of NAFLD: remarkably benign in the absence of cirrhosis. Gastroenterology. 2005;129:375–378
  42. Lonardo A, Loria P, Adinolfi LE, et al. Hepatitis C and steatosis: a reappraisal. J Viral Hepat. 2006;13:73–80
  43. Adinolfi LE, Gambardella M, Andreana A, et al. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33:1358–1364
  44. Rubbia-Brandt L, Quadri R, Abid K, et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol. 2000;33:106–115
  45. Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology. 2003;38:75–85
  46. Conjeevaram HS, Kleiner DE, Everhart JE, et al. Race, insulin resistance and hepatic steatosis in chronic hepatitis C. Hepatology. 2007;45:80–87
  47. Adinolfi LE, Ingrosso D, Cesaro G, et al. Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients. Hepatology. 2005;41:995–1003
  48. Zampino R, Ingrosso D, Durante-Mangoni E, et al. Microsomal triglyceride transfer protein (MTP)-493G/T gene polymorphism contributes to fat liver accumulation in HCV genotype 3 infected patients. J Viral Hepat. 2008;15:740–746
  49. Svegliati-Baroni G, Bugianesi E, Bouserhal T, et al. Post-load insulin resistance is an independent predictor of hepatic fibrosis in virus C chronic hepatitis and in non-alcoholic fatty liver disease. Gut. 2007;56:1296–1301
  50. Targher G, Bertolini L, Padovani R, et al. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C. J Hepatol. 2007;46:1126–1132
  51. Tsochatzis E, Patheodoridis GV, Manesis EK, et al. Metabolic syndrome is associated with severe fibrosis in chronic viral hepatitis and non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2008;27:80–89
  52. Lonardo A, Ballestri S, Adinolfi LE, et al. Hepatitis C virus-infected patients are ‘spared’ from the metabolic syndrome but not from insulin resistance. A comparative study of nonalcoholic fatty liver disease and hepatitis C virus-related steatosis. Can J Gastroenterol. 2009;23:273–278
  53. Fartoux L, Poujol-Robert A, Guéchot J, et al. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54:1003–1008
  54. Leandro G, Mangia A, Hui J, et al. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology. 2006;130:1636–1642
  55. Westin J, Nordlinder H, Lagging M, et al. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients. J Hepatol. 2002;37:837–842
  56. Castéra L, Hézode C, Roudot-Thoraval F, et al. Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies. Gut. 2003;52:288–292
  57. Cross TJ, Quaglia A, Hughes S, et al. The impact of hepatic steatosis on the natural history of chronic hepatitis C infection. J Viral Hepat. 2009;16:492–499
  58. Ohata K, Hamasaki K, Toriyama K, et al. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer. 2003;97:3036–3043
  59. Pekow JR, Bhan AK, Zheng H, et al. Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis. Cancer. 2007;109:2490–2496
  60. Takuma Y, Nouso K, Makino Y, et al. Hepatic steatosis correlates with the postoperative recurrence of hepatitis C virus-associated hepatocellular carcinoma. Liver Int. 2007;27:620–626
  61. Tanaka A, Uegaki S, Kurihara H, et al. Hepatic steatosis as a possible risk factor for the development of hepatocellular carcinoma after eradication of hepatitis C virus with antiviral therapy in patients with chronic hepatitis C. World J Gastroenterol. 2007;13:5180–5187
  62. Harrison SA, Brunt EM, Qazi RA, et al. Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2005;3:604–609
  63. Mangia A, Minerva N, Bacca D, et al. Determinants of relapse after a short (12 weeks) course of antiviral therapy and re-treatment efficacy of a prolonged course in patients with chronic hepatitis C virus genotype 2 or 3 infection. Hepatology. 2009;49:358–363
  64. Bressler BL, Guindi M, Tomlinson G, et al. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology. 2003;38:639–644
  65. Romero-Gómez M, Del Mar Viloria M, Andrade RJ, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636–641
  66. D'Souza R, Sabin CA, Foster GR. Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am J Gastroenterol. 2005;100:1509–1515
  67. Adinolfi LE, Durante-Mangoni E, Zampino R, et al. Review article: hepatitis C virus-associated steatosis—pathogenic mechanisms and clinical implications. Aliment Pharmacol Ther. 2005;22(Suppl. 2):52–55
  68. Loguercio C, De Simone T, D’Auria MV, et al. Non-alcoholic fatty liver disease: a multicentre clinical study by the Italian Association for the Study of the Liver. Dig Liver Dis. 2004;36:398–405
  69. Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1–10
  70. Zeuzem S, Alberti A, Rosenberg W, et al. Review article: management of patients with chronic hepatitis C virus infection and “normal” alanine aminotransferase activity. Aliment Pharmacol Ther. 2006;24:1133–1149
  71. Loria P, Lonardo A, Carulli N. Should nonalcoholic fatty liver disease be renamed?. Dig Dis. 2005;23:72–82
  72. Setji TL, Holland ND, Sanders LL, et al. Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:1741–1747
  73. Ferrannini E. Insulin resistance, iron, and the liver. Lancet. 2000;355:2181–2182
  74. Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42:987–1000
  75. Pinzani M, Vizzutti F, Arena U, et al. Technology Insight: non-invasive assessment of liver fibrosis by biochemical scores and elastography. Nat Clin Pract Gastroenterol Hepatol. 2008;5:95–106
  76. Charlton M, Angulo P, Chalasani N, et al. Low circulating levels of dehydroepiandrosterone in histologically advanced nonalcoholic fatty liver disease. Hepatology. 2008;47:484–492
  77. Loria P, Carulli L, Bertolotti M, et al. Endocrine and liver interaction: the role of endocrine pathways in NASH. Nat Rev Gastroenterol Hepatol. 2009;6:236–247
  78. Wilfred de Alwis NM, Day CP. Genes and nonalcoholic fatty liver disease. Curr Diab Rep. 2008;8:156–163
  79. Kotronen A, Peltonen M, Hakkarainen A, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009;137:865–872
  80. Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30:1356–1362
  81. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118:1117–1123
  82. Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001 Jul;121:91–100
  83. Angulo P, Hui JM, Marchesini G, Bugianesi E, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–854
  84. Harrison SA, Oliver D, Arnold HL, et al. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57:1441–1447
  85. Campos GM, Bambha K, Vittinghoff E, et al. A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients. Hepatology. 2008;47:1916–1923
  86. Guha IN, Parkes J, Roderick P, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008;47:455–460
  87. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123:745–750
  88. Mathiesen UL, Franzén LE, Aselius H, et al. Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/moderate abnormalities of liver transaminases. Dig Liver Dis. 2002;34:516–522
  89. Strauss S, Gavish E, Gottlieb P, et al. Interobserver and intraobserver variability in the sonographic assessment of fatty liver. Am J Roentgenol. 2007;189:W320–W323
  90. Roldan-Valadez E, Favila R, Martínez-López M, et al. Imaging techniques for assessing hepatic fat content in nonalcoholic fatty liver disease. Ann Hepatol. 2008;7:212–220
  91. Palmentieri B, de Sio I, La Mura V, et al. The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. Dig Liver Dis. 2006;38:485–489
  92. Dasarathy S, Dasarathy J, Khiyami A, et al. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J Hepatol. 2009;51:1061–1067
  93. Oliva MR, Mortele KJ, Segatto E, et al. Computed tomography features of nonalcoholic steatohepatitis with histopathologic correlation. J Comput Assist Tomogr. 2006;30:37–43
  94. Mehta SR, Thomas EL, Bell JD, et al. Non-invasive means of measuring hepatic fat content. World J Gastroenterol. 2008;14:3476–3483
  95. Yoneda M, Yoneda M, Fujita K, et al. Transient elastography in patients with non-alcoholic fatty liver disease (NAFLD). Gut. 2007;56:1330–1331
  96. Yoneda M, Yoneda M, Mawatari H, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD). Dig Liver Dis. 2008;
  97. Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology. 2008;134:960–974
  98. Wong GL, Wong VW, Choi PC, et al. Assessment of fibrosis by transient elastography compared with liver biopsy and morphometry in chronic liver diseases. Clin Gastroenterol Hepatol. 2008;6:1027–1035
  99. Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology. 2009;(November):
  100. Brunt EM. Pathology of fatty liver disease. Mod Pathol. 2007;20(Suppl. 1):S40–S48
  101. Campbell MS, Reddy KR. Review article: the evolving role of liver biopsy. Aliment Pharmacol Ther. 2004;20:249–259
  102. Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology. 2009;49:1017–1044
  103. Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94(September):2467–2474
  104. 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
  105. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–1906
  106. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;18:1221–1231
  107. Bellentani S, Saccoccio G, Costa G, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut. 1997;41:845–850
  108. Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology. 2009;49:306–317
  109. Suzuki A, Angulo P, St. Sauver J, et al. Light to moderate alcohol consumption is associated with lower frequency of hypertransaminasemia. Am J Gastroenterol. 2007;102:1912–1919
  110. Dunn W, Xu R, Schwimmer JB. Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease. Hepatology. 2008;47:1947–1954
  111. Gunji T, Matsuhashi N, Sato H, et al. Light and moderate alcohol consumption significantly reduces the prevalence of fatty liver in the Japanese male population. Am J Gastroenterol. 2009;104:2189–2195
  112. Corrao G, Zambon A, Bagnardi V, et al. Nutrient intakes, nutritional patterns and the risk of liver cirrhosis: an explorative case-control study. Eur J Epidemiol. 2004;19:861–869
  113. Naveau S, Giraud V, Borotto E, et al. Excess weight risk factor for alcoholic liver disease. Hepatology. 1997;25:108–111
  114. Ruhl CE, Everhart JE. Joint effects of body weight and alcohol on elevated serum alanine aminotransferase in the United States population. Clin Gastroenterol Hepatol. 2005;3:1260–1268
  115. Niemelä O. Biomarkers in alcoholism. Clin Chim Acta. 2007;377:39–49
  116. Ferreira MP, Weems MK. Alcohol consumption by aging adults in the United States: health benefits and detriments. J Am Diet Assoc. 2008;108:1668–1676
  117. Musshoff F, Daldrup T. Determination of biological markers for alcohol abuse. J Chromatogr B: Biomed Sci Appl. 1998;713:245–264
  118. Hannuksela ML, Liisanantti MK, Nissinen AE, et al. Biochemical markers of alcoholism. Clin Chem Lab Med. 2007;45:953–961
  119. Nalpas B, Hispard E, Thépot V, et al. A comparative study between carbohydrate-deficient transferrin and gamma-glutamyltransferase for the diagnosis of excessive drinking in a liver unit. J Hepatol. 1997;27:1003–1008
  120. Hock B, Schwarz M, Domke I, et al. Validity of carbohydrate-deficient transferrin (%CDT), gamma-glutamyltransferase (gamma-GT) and mean corpuscular erythrocyte volume (MCV) as biomarkers for chronic alcohol abuse: a study in patients with alcohol dependence and liver disorders of non-alcoholic and alcoholic origin. Addiction. 2005;100:1477–1486
  121. Huseby NE, Nilssen O, Kanitz RD. Evaluation of two biological markers combined as a parameter of alcohol dependency. Alcohol Alcohol. 1997;32:731–737
  122. Das SK, Dhanya L, Vasudevan DM. Biomarkers of alcoholism: an updated review. Scand J Clin Lab Invest. 2008;68:81–92
  123. Bellentani S, Dalle Grave R, Suppini A, et al. Behavior therapy for nonalcoholic fatty liver disease: the need for a multidisciplinary approach. Hepatology. 2008;47:746–754
  124. Neuschwander-Tetri BA. Lifestyle modification as the primary treatment of NASH. Clin Liver Dis. 2009;13:649–665
  125. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–129
  126. Musso G, Gambino R, De Michieli F, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003;37:909–916
  127. Lê KA, Ith M, Kreis R, et al. Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. Am J Clin Nutr. 2009;89:1760–1765
  128. Abid A, Taha O, Nseir W, et al. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol. 2009;51:918–924
  129. Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009;119:1322–1334
  130. Ryan MC, Abbasi F, Lamendola C, et al. Serum alanine aminotransferase levels decrease further with carbohydrate than fat restriction in insulin-resistant adults. Diabetes Care. 2007;30:1075–1080
  131. Gasteyger C, Larsen TM, Vercruysse F, et al. Effect of a dietary-induced weight loss on liver enzymes in obese subjects. Am J Clin Nutr. 2008;87:1141–1147
  132. Krasnoff JB, Painter PL, Wallace JP, et al. Health-related fitness and physical activity in patients with nonalcoholic fatty liver disease. Hepatology. 2008;47:1158–1166
  133. St. George A, Bauman A, Johnston A, et al. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology. 2009;50:68–76
  134. Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol. 2008;49:600–607
  135. Helmerhorst HJ, Wijndaele K, Brage S, et al. Objectively measured sedentary time may predict insulin resistance independent of moderate- and vigorous-intensity physical activity. Diabetes. 2009;58:1776–1779
  136. Neff LM, Aronne LJ. Pharmacotherapy for obesity. Curr Atheroscler Rep. 2007;9:454–462
  137. Lee HK, Choi EB, Pak CS. The current status and future perspectives of studies of cannabinoid receptor 1 antagonists as anti-obesity agents. Curr Top Med Chem. 2009;9:482–503
  138. Mummadi RR, Kasturi KS, Chennareddygari S, et al. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2008;6:1396–1402
  139. Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, et al. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev. 2010;1:CD007340
  140. Moscatiello S, Marzocchi R, Villanova N, et al. Which treatment for nonalcoholic fatty liver disease?. Mini Rev Med Chem. 2008;8:767–775
  141. Ratziu . Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: Results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology. 2009;epub October 31
  142. Lutchman G, Modi A, Kleiner DE, et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology. 2007;46:424–429
  143. Taylor C, Hobbs FD. Type 2 diabetes, thiazolidinediones, and cardiovascular risk. Br J Gen Pract. 2009;59:520–524
  144. Yokohama S, Yoneda M, Haneda M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004;40:1222–1225
  145. Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770–778
  146. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23:1464–1467
  147. Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2006;4:1537–1543
  148. Valenti L, Fracanzani AL, Dongiovanni P, et al. Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case–control study. Am J Gastroenterol. 2007;102:1251–1258
  149. Satapathy SK, Sakhuja P, Malhotra V, et al. Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis. J Gastroenterol Hepatol. 2007;22:634–638
  150. Bolondi L, Sofia S, Siringo S, et al. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut. 2001;48:251–259
  151. Sangiovanni A, Del Ninno E, Fasani P, et al. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology. 2004;126:1005–1014
  152. Calle EE. Obesity and cancer. Br Med J. 2007;335:1107–1108
  153. Brun E, Nelson RG, Bennett PH, et al. Diabetes duration and cause-specific mortality in the Verona Diabetes Study. Diabetes Care. 2000;23:1119–1123
  154. Sørensen HT, Mellemkjaer L, Jepsen P, et al. Risk of cancer in patients hospitalized with fatty liver: a Danish cohort study. J Clin Gastroenterol. 2003;36:356–359
  155. Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol. 2007;47
  156. Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48:993–999
  157. Nocito A, El-Badry AM, Clavien PA. When is steatosis too much for transplantation?. J Hepatol. 2006;45:494–499
  158. Forman LM. Metabolic syndrome in liver transplantation: the elephant in the room. Liver Transplant. 2008;14:1245–1248

PII: S1590-8658(10)00045-9

doi:10.1016/j.dld.2010.01.021

Digestive and Liver Disease
Volume 42, Issue 4 , Pages 272-282, April 2010

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