non-alcoholic fatty liver disease (nafld): why you should care, when you should worry, what you...

DIABETES/METABOLISM RESEARCH AND REVIEWS R E V I E W A R T I C L EDiabetes Metab Res Rev 2011; 27: 419–424.Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.1198

Proceedings of the First International Congress of the Bildirici DiabetesCenter, Laniado Hospital, Netanya, Israel, December 21–23, 2009. Part 2

Non-alcoholic fatty liver disease (NAFLD): why youshould care, when you should worry, what youshould do

Edward Lebovics∗Jonah Rubin

Sarah C. Upham Division ofGastroenterology &Hepatobiliary Diseases,Department of Medicine,New York Medical College,Valhalla, NY, USA

∗Correspondence to:Edward Lebovics,Sarah C. Upham Division ofGastroenterology &Hepatobiliary Diseases,New York Medical College,Munger Pavilion, Suite 206,Valhalla, NY 10595, USAE-mail:edward [email protected]

Received : 15 March 2011Accepted: 15 March 2011

Summary

For the diabetologist, non-alcoholic fatty liver disease (NAFLD) is importantat both ends of its spectrum. It is an early warning sign of future risk ofmetabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease.It may also lead to late life-threatening sequela of diabetes mellitus inthe event of progression to liver failure or hepatocellular carcinoma. Thisreview will highlight the recent progress in understanding the natural historyof non-alcoholic fatty liver disease and in developing a rational approachto its diagnosis, staging, and management. The pandemic prevalence ofnon-alcoholic fatty liver disease in Western countries necessitates both ahigh index of suspicion to identify cases and a non-invasive approach tostaging, which is best achieved with clinical/biochemical panels and transientelastography. Lifestyle modification is the cornerstone of management.Recent clinical trials provide support for pharmacologic therapies directed atthe metabolic syndrome and at protecting the liver but more data are needed.Bariatric surgery is appropriate for high-risk patients who fail conservativemanagement. Patients with liver failure or hepatocellular carcinoma may becandidates for liver transplantation. Copyright 2011 John Wiley & Sons,Ltd.

Keywords fatty liver; diabetes mellitus; steatosis

Introduction

Non-alcoholic fatty liver disease (NAFLD) has become the focus of intenseinterest because of its pandemic reach in Western countries; relation to themetabolic syndrome, type 2 diabetes mellitus (T2DM), and cardiovasculardisease; and potential for progression to cirrhosis, liver failure, and liver can-cer. NAFLD is characterized by excessive intrahepatic triglyceride content,conventionally defined as steatosis >5% of liver volume or weight, or >5%of hepatocytes containing visible intracellular triglycerides.

Under the broad diagnosis of NAFLD is included a mild form, fatty liver,which is manifest histologically by steatosis alone. Fatty liver may progress toa more severe form, non-alcoholic steatohepatitis (NASH), which is markedby the additional presence of lobar inflammation, hepatocellular balloon-ing, and fibrosis. Fibrosis may advance from centrilobular or periportal(stage 1), to septal (stage 3), and ultimately to cirrhosis (stage 4). Patientswith cirrhosis are at risk for liver failure and hepatocellular carcinoma.

Copyright 2011 John Wiley & Sons, Ltd.

420 E. Lebovics and J. Rubin

This brief review will highlight the recent progress inunderstanding the natural history of NAFLD and in devel-oping a rational approach to its diagnosis, staging, andmanagement. The pathophysiology of NAFLD has beenthoroughly reviewed [1–4] and is beyond the scope ofthis article.

Alanine aminotransferase elevation

Alanine aminotransferase (ALT) elevation, after exclusionof recognized causes of hepatic inflammation, is a markerof NAFLD. In addition, it indicates current or future risk ofmetabolic syndrome, T2DM, and cardiovascular disease.Notably, risk appears to rise with ALT elevation >20 U/Lin females and 30 U/L in males, indicating that these levelsmay represent the true upper limits of normal. Statisticallycorrecting for other known risk factors for T2DM orcardiovascular disease attenuates but does not eliminatethe risk associated with ALT elevation. This suggests thatALT elevation is both a marker of NAFLD (or possiblyectopic fat, with the liver being the most apparent site) asan independent risk factor, as well as a surrogate markerfor adiposity [5–7]. γ -Glutamyl transpeptidase may be amore accurate marker of cardiovascular risk than ALT [8].

ALT elevation, however, has poor sensitivity for NAFLD.Most patients with NAFLD, even in morbidly obese cohortswith >50% of the liver replaced by fat, have normal ALT.While patients with NAFLD with elevated ALT have moreadvanced pathology compared to patients having normalALT, normal ALT levels are not grounds for complacency.In a study of patients selected for liver biopsy because ofsevere steatosis on ultrasonography or high serum ferritin,of the patients with normal ALT levels, 59% had NASHand 24% had stage 2–4 fibrosis [9].

Epidemiology and natural history

In Western countries, the approximate prevalence ofNAFLD is 25% and that of NASH is 3%. In patientswith obesity or T2DM, up to 85% have NAFLD and overhalf may have NASH. Of great concern is the presence ofNAFLD in over half of obese children. Obesity, however,is not a pre-requisite for NAFLD. In developing countries,most patients with NAFLD are not overweight [10,11].

Emerging data has shed light on the vexing issue ofthe natural history of NAFLD [12–16]. Most studieshave confirmed that patients with NASH, but not fattyliver, are subject to increased liver-related and all-causemortality [15]. The NHANES III registry indicated thatliver-related and all-cause mortality adjusted for age,gender, race, education, income, and metabolic syndromewas increased for the overall population of patients withNAFLD as well [14]. Over a follow-up of 10–15 years,about 20% of patients with fatty liver will progress toNASH and about 10% of patients with NASH will progressto cirrhosis. For patients with NASH and cirrhosis, the10-year liver-related mortality is about 15% and all-cause

mortality about 20%. The mortality for NASH with cirrho-sis approximates that of chronic hepatitis C with cirrhosis[17].

A dramatic rise in the incidence of hepatocellular car-cinoma has been observed in recent years. Patients withT2DM have doubled the incidence of hepatocellular carci-noma compared with controls [18]. An alarming findingthat 65% of hepatocellular carcinoma lesions in patientswith metabolic syndrome were found in pre-cirrhotic liv-ers (stage 0–2 fibrosis) [19], if confirmed, implies thatcurrent surveillance standards limiting interval hepaticimaging to cirrhotic patients may be inadequate.

Diagnosis and staging

The gold standard for the diagnosis of NAFLD is liverbiopsy, which also differentiates fatty liver from NASH,a critical prognostic determination. It is possible thatthe grade of inflammation is a more important pathologicpredictor of fibrosis progression [20]. Because of the enor-mous prevalence of NAFLD in Western countries and theinvasiveness and expense of liver biopsy, much effort isbeing expended on developing non-invasive alternatives.

Ultrasound and computerized tomography, which oftenbring the patient to the hepatologist’s attention, are insen-sitive to fatty infiltration of <30% and lack specificity.Magnetic resonance imaging, particularly dual gradientecho magnetic resonance imaging, has superior accuracy,can quantify and map steatosis, and is appropriate for lon-gitudinal evaluations because of lack of radiation [21,22].Cost and availability are issues. No radiological study hasbeen validated to differentiate fatty liver and NASH orstage fibrosis.

Various clinical and biochemical parameters have beenexplored as predictors of fibrosis in patients with NAFLD.The presence of T2DM, hypertension, obesity, and amino-transferase elevation are predictors of fibrosis [23,24].Elevated serum ferritin does not indicate iron overload inpatients with NAFLD but is a marker of fibrosis. Hepato-cellular iron accumulation is associated with fibrosis butdoes not correlate with HFE mutations [25,26]. Hype-ruricaemia is associated with cirrhosis-related death orhospitalization [27]. Recently, the hepatocyte apoptosismarker cytokeratin-18 was shown to differentiate fattyliver and NASH [28].

Several fibrosis scores have been developed to pre-dict fibrosis and obviate the need for biopsy. The FIB4index requires only age, AST, ALT, and platelet count.The NAFLD fibrosis score additionally includes body massindex, presence of T2DM, and albumin. The EnhancedLiver Fibrosis panel uses the tissue inhibitor of matrixmetalloproteinase 1, hyaluronic acid, and the aminoter-minal peptide of procollagen III. These panels have beenused in combination with better accuracy [27,29–31].Three studies have now shown transient elastography, anon-invasive technique that measures liver stiffness, to bea valid predictor of fibrosis in NAFLD [32–34]. The limi-tation that liver stiffness measurement with the standard

Copyright 2011 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2011; 27: 419–424.DOI: 10.1002/dmrr

Fatty Liver Disease 421

probe fails in up to 25% of obese patients is overcometo a large extent by the development of the new XLprobe [35]. Experience with chronic viral hepatitis sug-gests that the best results for non-invasive staging will beachieved by combining a clinical/biochemical index withelastography.

Currently, non-invasive panels and transient elastog-raphy are not widely available commercially, leavingclinicians in a quandary as to when to obtain a liverbiopsy. A rational approach is to select patients identifiedas being at increased risk for progressive fibrosis, who areyoung and motivated, and in whom the biopsy may leadto more aggressive intervention at a reversible stage. Onetypical example would be a 35-year-old obese, hyperten-sive diabetic patient, with elevated ALT and ferritin butnormal platelet count, who is undecided about bariatricsurgery. Of course, when the diagnosis of NAFLD is uncer-tain, liver biopsy may be essential to confirm NAFLD oran alternative diagnosis.

Genetic and early developmentalfactors

A mutation in the gene encoding patatin-like phospho-lipase domain-containing 3 protein, the I148M allele,confers pre-disposition to and predicts severity of NAFLD,despite the fact that it accounts for only about 5%of the hepatic steatosis. This association is indepen-dent of body mass index, diabetes, alcohol consump-tion, and ancestry [36–38]. Apolipoprotein C3 genevariants (single-nucleotide polymorphisms C482T andT455C) are associated with NAFLD and insulin resistance[39].

The roles of nature and nurture were explored in a studyof cross-fostering offspring mice of lean and obese dams.Offspring of obese dams had a dysmetabolic, insulin-resistant and NAFLD phenotype compared with offspringof lean dams. However, offspring of lean dams suckledby obese dams showed an exaggeration of this pheno-type with increased body weight, insulin, leptin, AST,interleukin-6, tumour necrosis factor α, liver triglycerides,histologic steatosis, and hepatic fibrogenesis. Obese damshad increased breast milk leptin levels compared withlean dams. The study concluded that maternal obesityprograms the development of a dysmetabolic and NAFLDphenotype which is critically dependent on the earlypost-natal period [40].

Management: lifestyle modification

A modest, gradual weight reduction of 10% of bodyweight decreases ALT and hepatic steatosis. Low car-bohydrate diets are superior to low-fat diets. Fructoseconsumption is associated with less steatosis but morefibrosis in patients with NAFLD [41,42]. Patients withNAFLD consume more soft drinks than controls, inde-pendent of the presence of metabolic syndrome [42].

Consumption of one glass of wine per day is safe forpatients with NAFLD [43]. No pharmacologic weightreduction agents have been demonstrated to be effec-tive for NAFLD. Exercise improves ALT and steatosis; thiseffect is independent of weight loss [44,45].

Management: pharmacologic therapy

Pharmacologic therapy can be divided into treatmentsdirected at the metabolic syndrome and those directed atprotecting the liver. Metformin is commonly used as thefirst-line drug for insulin resistance in NAFLD. Advantagesare that it is cheap, promotes weight loss, and can be usedin combinations. In the largest randomized controlledtrial (RCT) to date, a 12-month open-label study, met-formin 2 g/day normalized aminotransferase levels anddecreased liver steatosis, necroinflammation, and fibrosis,more effectively than vitamin E or diet [46]. Of note, therehave been no RCTs of metformin specifically for NASH orfor NAFLD in the setting of T2DM.

Pioglitazone for NASH has been subjected to threeRCTs [47]. In a 6-month study of patients with T2DM orimpaired glucose tolerance, pioglitazone decreased ALT,decreased hepatic fat content, increased hepatic insulinsensitivity, and improved steatosis, ballooning necrosis,and necroinflammation, but reduction in fibrosis did notdiffer significantly from that in the placebo group [48].A 12-month study of diabetic patients showed reductionof fibrosis as well [49]. However, in the PIVENS trial,a 24-month RCT of NASH without T2DM, pioglitazonefailed the primary outcome of an improvement in histo-logic features as assessed by a composite of scores forsteatosis, lobular inflammation, hepatocellular balloon-ing, and fibrosis (although the absence of ballooning atbaseline in a higher percentage of patients randomizedto pioglitazone may have confounded this finding). ALT,insulin resistance, steatosis, and lobular inflammation didimprove [50]. In addition, pioglitazone was associatedwith weight gain in all of these studies. At this time,risk:benefit assessment does not favour pioglitazone as afirst-line agent for NAFLD.

A variety of hepatoprotective agents have been stud-ied for NAFLD. The anti-oxidant vitamin E, at a dose of800 IU daily, appears most promising with the PIVENStrial showing improvement in ALT, steatosis, lobularinflammation, hepatocyte ballooning, and the compos-ite histologic score [50]. Recent trials of betaine [51] andursodeoxycholic acid [52] showed no significant benefit.The angiotensin II receptor blocker losatran, in a smallstudy of patients with NASH and hypertension, improvedhepatic necroinflammation and fibrosis in most patients[53]. An RCT comparing angiotensin receptor blockerstelmisartan, characterized by peroxisome proliferator-activated receptor-γ modulatory effects, and valsartan,for hypertension-associated NASH revealed greater reduc-tion in fibrosis and NASH activity score in the telmisartangroup [54]. l-Carnitine, 1000 mg twice daily, in anRCT, improved AST, ALT, γ -glutamyl transpeptidase,



cholesterol, low-density lipoprotein, high-density lipopro-tein, HOMA-IR, and the histologic features of steatosis,hepatocyte injury, fibrosis, and NASH activity score [55].

While the available data certainly provides directionfor the clinician treating NAFLD, valid evidence formost agents is lacking. A comprehensive meta-analysisof randomized trials for NAFLD [56] concluded that‘well-designed RCTs of adequate size and duration, withhistologic endpoints, are needed to assess long-term safetyand efficacy of proposed treatments on patient-orientedclinical outcomes.’

Perhaps the most common question regarding patientswith NAFLD addressed to hepatologists by referring physi-cians is whether HMG-CoA reductase inhibitors (‘statins’)can be used. Statins are not contraindicated in patientswith chronic liver disease including NAFLD. The mild ALTelevation associated with statins is a class effect that is notindicative of liver injury and does not necessitate discon-tinuation. As such, statins may be used in patients withNAFLD for the standard indication of hyperlipidaemiaeven in the setting of baseline elevation of ALT. Currently,there is no convincing evidence that statins are beneficialfor NAFLD. However, statin use does reduce the risk ofhepatocellular carcinoma in diabetic patients [57].

Management: surgical therapy

Results of bariatric surgery for NASH are very encour-aging, with nearly all studies showing improvement insteatosis, hepatocyte ballooning, and inflammation andmost showing improvement in fibrosis. Results are betterwith procedures that include a malabsorptive element,such as Roux-en-Y gastric bypass, compared with that ofpurely restrictive procedures, such as placement of anadjustable gastric band [58]. Endoscopic approaches toweight reduction, including intragastric balloon place-ment, endoscopic suturing for vertical gastroplasty,transoral gastroplasty sleeve stapling, and duodenoje-junal bypass sleeve placement, are currently undergoingevaluation [59].

Patients with NASH who progress to decompensatedcirrhosis or develop hepatocellular carcinoma may be

candidates for liver transplantation. As histopathologicevidence of NASH may not be apparent with progressionto advanced cirrhosis, cases categorized as cryptogeniccirrhosis may, in fact, be ‘burnt-out’ NASH. Epidemiologicstudies suggest that this is the true for the majority.Post-transplant, steatosis recurs in up to 70% of patientsand NASH develops in up to 25% [ [60,61].

Conclusion

For the diabetologist, NAFLD is important at both endsof its spectrum. It is an early warning sign of futurerisk of metabolic syndrome, T2DM, and cardiovasculardisease and a call to therapeutic action. It can alsolead to life-threatening sequela of diabetes mellitus inthe event of progression to liver failure or hepatocellu-lar carcinoma. The pandemic prevalence of NAFLD inWestern countries necessitates both a high index of sus-picion to identify cases and a non-invasive approach tostaging, which will be facilitated by the anticipated com-mercial availability of clinical/biochemical panels andtransient elastography. Lifestyle modification is the cor-nerstone of management. Metformin remains the first-lineagent for insulin resistance. Vitamin E and L-carnitineappear to provide benefit without known significantrisk and are appropriate for the motivated patient. Inpatients with NAFLD, telmisartan is the preferred agentfor hypertension and statins should not be withheldif indicated for hyperlipidaemia. For high-risk patientswho do not improve with conservative management,bariatric surgery should be strongly encouraged. Thereis a great need for translational research that will leadto safe and effective treatments for NAFLD. It is pro-jected that unless effective therapies for NAFLD aredeveloped, NASH will become the leading indicationfor liver transplantation in the United States within10–20 years.

Conflict of interest

None declared.

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