Volume 42, Issue 4, Pages 272-282 (April 2010)

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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

Accepted 28 January 2010. published online 22 February 2010.

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

Article Outline

• Abstract

• 1. Introduction

• 1.1. Methodology

• 2. Prevalence, incidence and natural history

• 2.1. Prevalence of primary NAFLD/NASH

• 2.2. Incidence of NAFLD/NASH

• 2.3. Natural history

• 3. NALFD, HCV and the metabolic syndrome

• 4. Diagnosis

• 4.1. Clinical presentation

• 4.2. Clinico-laboratory evaluation

• 4.3. Laboratory markers of fibrosis

• 4.4. Clinical scores for fibrosis

• 4.5. Role of imaging studies

• 4.5.1. Ultrasound scanning

• 4.5.2. Computed tomography scanning

• 4.5.3. Magnetic resonance imaging

• 4.6. Transient elastography (FIBROSCAN)

• 4.7. Liver biopsy

• 5. Differential diagnosis with alcoholic fatty liver disease

• 6. Treatment

• 6.1. Non-pharmacologic treatment—lifestyle changes

• 6.2. Anti-obesity drugs

• 6.3. Bariatric surgery

• 6.4. Insulin sensitisers

• 6.5. Lipid lowering agents

• 6.6. Anti-hypertensive agents

• 6.7. Cyto-protective and antioxidant agents

• 6.8. Venesection

• 6.9. Experimental approaches

• 6.10. Conclusions

• 7. Follow-up

• 7.1. Early diagnosis of HCC

• 7.2. Metabolic and cardiovascular risk

• 7.3. Risk of cancer

• 8. Prevention

• 9. NAFLD and orthotopic liver transplantation (OLT)

• 10. Research agenda

• Conflict of interest

• Acknowledgment

• References

• Copyright

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
	I	Evidence from multiple RCTs and or systematic reviews of randomised studies
	II	Evidence from a single well designed controlled trial
	III	Evidence from non-randomised cohort studies with concurrent or historical controls or their metanalytic review
	IV	Evidence from retrospective studies or their metanalytic review
	V	Evidence from case series without a control group
	VI	Evidence 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
	A	Procedure/diagnostic test strongly recommended, supported by good quality scientific evidence, even if not necessarily type I or II
	B	Procedure/diagnostic test not invariably recommended but to be carefully considered
	C	Procedure/diagnostic test surrounded by substantial uncertainty
	D	Procedure not recommended
	E	Procedure strongly advised against

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].


	Aetiology	Prevalence
	NAFLD	Approximately 25%
	HCV	2%
	Alcoholic liver disease	1%
	HBV	0.3–0.4%
	HFE-linked hereditary haemochromatosis	1:200–1:400
	Autoimmune liver disease	Up to 17/100,000
	Alpha1-AT deficiency	1/1500–1/7600
	Wilson's disease	1/30,000

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].

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Fig. 1. The 8–10 year natural history of NAFLD.

Uncomplicated “pure” nonalcoholic fatty liver will rarely (if ever) progress to NASH [41]. In contrast, a proportion of patients with NASH may have cirrhosis at diagnosis or will evolve to cirrhosis during follow-up [33], [34], [35]. Cirrhosis may lead to liver-related death with [36], [37] or without [39] the development of HCC.

Modified from [32], according to Refs. [4], [23], [25], [26], [31], [33], [34], [35], [36], [37], [38], [39], [40], [41].

Level of evidence: II

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

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.

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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]).


History	Physical examination	Laboratory tests
Family occurrence of NAFLD and components of the metabolic syndrome	Height (m)	Blood cell count, PT, PTT, bilirubin, ALT, AST, GGT, ALP, total proteins and serum proteins electrophoresis
Diet	Weight (kg)	Serum levels of total cholesterol, HDL-cholesterol and triglycerides
Alcohol consumption	BMI (kg/m2)	Fasting glucose and insulin
Physical activity	Waist girth	HbsAg, HCV-Ab
Body weight changes	Arterial pressure	Anti-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]).


Name	BAD	BAAT	HAIR	BARG	NAFLD fibrosis score	BARD	Clinical scoring system for predicting NASH	ELF
	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]
BMI	Yes	Yes	–	Yes	Yes	Yes	–	Yes
AGE	Yes	Yes	–	–	Yes	–	–	–
AST/ALT	–	–	–	Yes	Yes	Yes	–	Yes
ALT	–	Yes	Yes	–	–	–		–
AST							Yes
Albumin	–	–	–	–	Yes	–	–	Yes
Platelets	–	–	–	–	Yes	–	–	Yes
T2D	Yes	–	–	–	–	Yes	Yes	–
HbA1c/glucose	–	–	–	Yes	Yes	–	–	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

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].


Nutritional	Drugsa	Metabolic or genetic	Other
Protein–calorie malnutritionb	Glucocorticoidsb	Lipodystrophyb	Inflammatory bowel diseaseb
Starvationb	Synthetic estrogensb	Dysbetalipoproteinemiab	Small-bowel diverticulosis with bacterial overgrowthb
Total parenteral nutritionb	Aspirinc	Weber–Christian diseaseb	Human immunodeficiency
Rapid weight lossb	Calcium-channel blockersb	Wolman's diseased	Virus infectionb
Gastrointestinal surgery for obesityb	Amiodaroned	Cholesterol ester storaged	Environmental hepatotoxins
	Tamoxifenb	Acute fatty liver of pregnancyc	Phosphorusc
	Tetracyclinec		Petrochemicalsb,c
	Methotrexateb		Toxic mushroomsb
	Perhexiline maleated		Organic solvents
	Valproic acidc		Bacillus cereus
	Cocainec		Toxinsc
	Antiviral agents
	Zidovudineb
	Didanosinec
	Fialuridinec

This 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).

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

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

This 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].


Marker	Abbreviation	Half-life/elimination rate	Clinical characteristics
Blood ethanol	EtOH	1g/1h/10kg	Levels 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-glutamyltransferase	GGT	2–3 weeks	A 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 erythrocytes	MCV	2–4 months	More sensitive in women. Specificity decreased by vitamin B12 or folic acid deficiency, liver diseases, haematological diseases, hypothyroidism, reticulocytosis, smoking.
Carbohydrate-deficient transferrin (desialotransferrin)	CDT	2–3 weeks	Most specific of the currently available methods. Specificity decreased by genetic variants of transferrin on rare occasions.
GGT–CDT combination	GGT–CDT (γ-CDT)	2–3 weeks	A 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.
Aminotransferases	AST, ALT	2–3 weeks	AST/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

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

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

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

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

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.

Conflict of interest

None declared.

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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a 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

b Dipartimento di Medicina Interna ed Epatologia, Seconda Università di Napoli, Naples, Italy

c Centro studi Fegato, Gastroenterologia, Ospedale “Ramazzini” di Carpi, Modena, Italy

d Divisione di Gastro-Epatologia, Ospedale San Giovanni Battista, Università di Torino, Turin, Italy

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

f Dipartimento di Medicina Interna, Fondazione Policlinico, Mangiagalli e Regina Elena, IRCCS, Università di Milano, Milan, Italy

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

h Centro Interuniversitario per Ricerche su Alimenti, Nutrizione e Apparato Digerente, Naples, Italy

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

j Dipartimento di Medicina Interna, Azienda Ospedaliera Universitaria Careggi, Università di Firenze, Florence, Italy

k Unità di Medicina Interna ed Epatologia, Seconda Università di Napoli, Naples, Italy

l Dipartimento di Medicina Trasfusionale e di Ematologia dell’Ospedale “Alessandro Manzoni, Lecco, Italy

m Centro di Medicina Trasfusionale, Terapia Cellulare e Criobiologia, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

n Dipartimento di Gastroenterologia, Università della Marche – Politecnico, Ancona, Italy

Corresponding author. Tel.: +39 059 3961801/422580; fax: +39 059 3961335.

PII: S1590-8658(10)00045-9

doi:10.1016/j.dld.2010.01.021

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