Treatment regimens for non-alcoholic fatty liver disease

BP Lam et al. Treatment regimens for non-alcoholic fatty liver disease Annals of Hepatology 2009; 8(1): Supplement: S51-S59 Treatment regimens for non-alcoholic
fatty liver disease
Abstract
Introduction, epidemiology, and natural history
With the growing epidemic of obesity and diabetes,
Since first described by Ludwig in 1980, non-alcoholic more attention has been placed on metabolic syndrome
fatty liver disease (NAFLD) has progressed from a poorly and its associated hepatic manifestation, non-alcoholic
understood liver disease to one with more well defined fatty liver disease (NAFLD). Within the spectrum of
boundaries. NAFLD is one of the most common causes of clinico-pathologic conditions known as NAFLD, only a
chronic liver disease in the Western world, and its preva- minority of patients has the histological features char-
lence is likely to parallel the increasing prevalence of dia- acteristic of non-alcoholic steatohepatitis (NASH),
betes, obesity, and other components of metabolic syn- which has the potential to progress to cirrhosis and
drome. NAFLD is now accepted as the hepatic component hepatocellular carcinoma. Therefore, diagnosis and
of the metabolic syndrome. NAFLD includes a spectrum of therapy should target patients with NASH. Current
clinicopathologic entities ranging from simple steatosis to treatment recommendations include weight loss and
non-alcoholic steatohepatitis (NASH), with the possibility the reversal of other components of metabolic syn-
of progression to cirrhosis and hepatocellular carcinoma.1,2 drome, but several other treatment modalities are un-
These entities are differentiated by histological features, der investigation. To date, no pharmacologic treat-
and have in common the presence of hepatic steatosis and ment has been reliably shown to be effective for NASH.
the absence of excessive alcohol consumption.
This article reviews all available treatment modalities,
Estimates of the incidence and prevalence of including lifestyle changes, bariatric surgery, weight
NAFLD and NASH are limited by the lack of reliable loss medications, insulin sensitizers, lipid lowering
non-invasive screening modalities. For example, a agents, antioxidants, cytoprotective agents, and other
large proportion of patients with NAFLD and NASH novel treatments.
may have normal transaminase levels. Sonography canoften identify steatosis, but only if it involves 33% or Key words: NAFLD, NASH, treatment.
more of the hepatic parenchyma.3 Sonography is alsosuboptimal for evaluating obese patients. Proton mag-netic resonance spectroscopy is an expensive tool, notsuited for large scale population screening.4 Nonethe-less, estimates of the prevalence of NAFLD in the Center for Liver Diseases at Inova Fairfax Hospital, Falls United States range from 3% to 34% in adults and ap- proximately 10% in children.4,5 Estimates of preva-lence in other parts of the world are as high as 36.9%.6 Abbreviations:Non-alcoholic fatty liver disease (NAFLD); Non-alcoholic The prevalence of NAFLD in morbidly obese patients steatohepatitis (NASH); Tumor necrosis factor (TNF); Thiazolidinedione (TZD); N-Acetyl-cysteine (NAC); Evidence regarding the natural history and progres- Ursodeoxycholic acid (UDCA); Angiotensin receptor blocker sion of NASH indicates that simple steatosis does not (ARB); Homeostatic model assessment (HOMA); Roux-en-Ygastric bypass (RYGB); Laparoscopic adjustable gastric banding typically progress to advanced liver disease. Only a mi- (LAGB); Vertical banded gastroplasty (VBG); Peroxisomal nority of NAFLD patients may have the histologic fea- proliferator activated receptor (PPAR).
tures consistent with steatohepatitis.8-12 Liver-relatedmorbidity and mortality occurs exclusively in cases of Address for correspondence:Zobair M. Younossi, M.D., M.P.H.
advanced fibrosis and cirrhosis. Evidence from tertiary Center for Liver Diseases at Inova Fairfax Hospital medical centers, sequential biopsy series, and popula- 3300 Gallows Road, Falls Church, VA 22042 tion-based studies suggest that 10% to 15% of patients Telephone: (703) 776-2540, Fax: (703) 776-4388 with NASH progress to cirrhosis, putting them at risk for liver-related death.1,2 Progressive liver disease also occurs Manuscript received and accepted: 1 February 2009 more frequently in NAFLD patients with components of Annals of Hepatology 8(1) 2009: S51-S59 metabolic syndrome such as insulin resistance.13 Addi- pathogenesis of NAFLD and NASH is a complex process tionally, patients with NAFLD and diabetes mellitus, involving many pathways. Several factors, including med- have more aggressive disease and may be at risk for in- ications, parenteral nutrition, toxins, and certain surgical procedures can lead to the development of fatty liver,sometimes called secondary NAFLD. We focus here on the Identifying treatment candidates
type of NAFLD typically associated with insulin resis-tance, which is sometimes referred to as primary NAFLD.6 Treatment of NAFLD requires a consideration of The "multi-hit" hypothesis of NASH development in which patients require treatment. Because not all cases the setting of insulin resistance includes a hepatic pro- progress to advanced liver disease, and because the goal cess and one or several non-hepatic processes. The "first of treatment is to improve liver-related outcomes from a hit" is a hepatic process involving increased hepatic mac- liver standpoint efforts should be focused on patients rosteatosis due to increased insulin resistance. Three spe- with steatohepatitis and not simple steatosis. Several cific mechanisms are increased de novo hepatic lipogen- approaches have been used to differentiate simple ste- esis, decreased hepatic oxidation of free fatty acids, and atosis and steatohepatitis. The clinical presentation of decreased lipid export from the liver. Proposed "second patients with simple steatosis is similar to the presen- hits" are non-hepatic processes including oxidative tation in NASH, therefore clinical presentation cannot stress, apoptosis, and increased pro-inflammatory cytok- reliably distinguish between the two. Demographic ines. In addition, adipocytes release cytokines such as and clinical parameters such as age, gender, race, body leptin, resistin, interleukin-6, tumor necrosis factor alpha mass index, dyslipidemia, or diabetes cannot reliably (TNF-α), and others. For more details on this topic, read- differentiate between simple steatosis and steatohepati-tis.1 Steatohepatitis cannot be reliably identified by Table I. Potential targets for therapeutic treatment.
simple serum tests, or the current generation of serummarkers of fibrosis, or combination panels for fibrosis.
Several NASH diagnostic biomarker panels have beendeveloped but their accuracy is either limited or yet to Weight loss• Diet with or without exercise be fully validated.14 The few studies that have exam- ined the diagnostic ability of imaging studies have largely concluded that radiological means are insuffi- cient as well.15-19 Measuring liver stiffness by transient elastography may accurately predict hepatic fibrosis in patients with hepatitis C; however, the utility of elas- tography is limited in NASH because obese body habi- tus greatly limits the accuracy of elastography.20,21 Currently, liver biopsy remains the "imperfect gold standard" for diagnosis and staging. Despite the inva- siveness, cost, inconvenience, perioperative risk, and the potential for sampling error, no other modality produces the same measure of detail about the presence and sever- ity of fibrosis. Because standardized pathologic proto- cols for histologic staging of NAFLD have been well de- lineated, liver biopsy continues to be the most reliable diagnostic and prognostic modality. No reliable recom- mendations indicate which NAFLD patients should un- dergo biopsy for diagnoses and staging of NASH, al-though persistent transaminase elevations or the pres- Cytoprotective agents• Ursodeoxycholic acid (UDCA) ence of metabolic syndrome or type 2 diabetes may strengthen the case for biopsy. Weighing the potential risks and benefits of liver biopsy remains in the hands of Identifying therapeutic targets
The following discussion of NAFLD and NASH patho- • ACE inhibitors/ARBs• Incretin analogs genesis briefly identifies areas potentially amenable to in- tervention and reviews potential treatment modalities. The BP Lam et al. Treatment regimens for non-alcoholic fatty liver disease ers are referred to recent review articles on the subject.2 In a similar study in ten obese patients with biopsy- Nevertheless, pathways potentially involved in the proven NASH, Harrison and colleagues found that after pathogenesis of NAFLD are promising targets for thera- six months of orlistat treatment, steatosis improved in some patients.24 Improvements were also noted in bodyweight, hemoglobin A1C, and transaminases. The au- Treatment
thors noted that improvements in steatosis, fibrosis, andhemoglobin A1C were generally associated with a Because insulin resistance participates in the patho- weight loss of 10% or more. A study by Sabuncu and col- genesis of NASH, we first discuss therapies targeting obe- leagues noted improvements in insulin resistance (mea- sity and insulin sensitivity. Several studies examine the sured by HOMA scores), AST, ALT, GGT and sonograph- effect of weight loss on NASH, either by lifestyle, phar- ic findings in a six-month open label trial of sibutramine macologic, or surgical measures. Later we discuss: Lipid or orlistat in combination with a low calorie diet.[74] Lowering Agents, Antioxidants, Cytoprotective Agents, Thirteen patients were treated with sibutramine and Anti-TNF Agents, and Novel Treatments.
twelve patients were treated with orlistat. Liver biopsieswere not performed.
Weight loss by lifestyle changes
Weight loss by surgical measures
Patients with NAFLD or metabolic syndrome are en- couraged to adopt a program of diet and exercise with the Most of the work on histological improvement after goal of weight loss as a first step in their treatment. Many weight loss relies on patients who have had bariatric sur- studies have examined the effects of weight loss achieved gery. Jejunoileal bypass for treatment of obesity has by diet with or without exercise; however, most enrolled largely been abandoned due to poor postoperative out- fewer than 50 subjects. A relatively large study by Suzuki comes. Jejunoileal bypass has been associated with high and colleagues examined the effect of weight loss due to rates of mortality, more often than not due to liver fail- lifestyle change upon elevated ALT levels.22 Records ure. Biliopancreatic diversion with or without duodenal from annual employee health checkups showed that 348 switch is the only form of bariatric surgery still in use men out of 1,546 employees had elevated ALT in the ab- that aims at effecting weight loss through malabsorption sence of concomitant liver disease. Weight loss of at least of macronutrients. A single observational study involv- 5% was significantly associated with improved ALT lev- ing 104 patients who had liver biopsies at time of initial els, and maintaining this 5% weight loss was significantly surgery and at surgical revision showed that overall fi- associated with sustained ALT improvement. However, brosis scores were unchanged in the majority of patients histologic criteria were not used to diagnose NAFLD and but decreased in 11 patients found to have cirrhosis upon only 6% of the cohort was able to achieve a weight loss of 5% or more; for these reasons, the conclusions may not be Roux-en-Y gastric bypass (RYGB), gastroplasty, and applicable to most NAFLD patients. Because lifestyle laparoscopic adjustable gastric banding (LAGB) are changes associated with diet and exercise are so difficult presently the most common surgeries for weight loss. At to maintain for most patients, attention has turned to other least five small studies have examined the effect of means of achieving sustainable weight loss.
RYGB on NASH patients.26-30 Paired liver biopsies dur-ing and after RYGB were performed in a total of 108 pa- Weight loss by pharmacologic measures
tients. No worsening of liver disease was reported. Allfive studies reported varied measures of histological im- The medications orlistat and sibutramine are used for provement, with NASH resolving in up to 89%.29 Gas- the treatment of obesity and have been studied for their troplasty techniques, such as vertical banded gastro- effects on steatohepatitis. Hussein and colleagues con- plasty (VBG) with or without gastric sleeve are not used ducted an open-label study in which fourteen patients as commonly as RYGB or LAGB. RYGB tends to yield underwent liver biopsy before and after treatment with better results, although the adjustable features of LAGB six months of orlistat 120 mg tid.23 At the end of six are attractive. At least four studies have examined the months, ten patients (70%) had reduced fatty infiltration, effect of gastroplasty on NAFLD.31-34 Improved steatosis and inflammation improved by two grades in 22% and was reported in all four studies, but the reports regard- one grade in 50% of patients. Fibrosis improved two ing inflammation and fibrosis are mixed. Reports on pa- grades in three patients (21%) and one grade in seven pa- tients with paired liver biopsies with LAGB are limited.
tients (50%). Improvement was also noted in transami- Two published studies by Dixon and coworkers showed nases levels, total cholesterol, triglycerides, LDLs, and improved steatosis after LAGB.35,36 Features of fibrosis insulin resistance index. Although the size of the cohort improved in most patients. One study showed that of 23 was small, the findings include histological data from patients with NASH upon initial biopsy, only four showed findings of NASH on subsequent biopsy.35 The Annals of Hepatology 8(1) 2009: S51-S59 other study showed that 30 of 60 patients had NASH mechanisms of action include decreasing hepatic gluco- findings upon initial biopsy, whereas only 6 showed neogenesis, increasing peripheral and hepatic insulin these findings upon subsequent biopsy.36 In a review of sensitivity, slowing intestinal glucose absorption, and re- 19 studies on the histological effects of gastric bypass ducing serum lipid levels and hepatic fatty acid oxida- on NAFLD, Verna and Berk reported that bariatric sur- tion. At least seven trials have examined the effect of gery usually improves steatosis,37 but the evidence for metformin upon NAFLD and NASH.47-53 Only the trials by improvement in NASH features was less uniform. These Uygun et al., and Bugianesi et al., were randomized con- authors also noted occasional reports of regressed cir- trolled trials48,51. The study by Uygun et al, randomized 36 patients to either caloric restriction alone or caloric re- On the other hand, some authors are still concerned striction plus metformin.48 Significant improvement in that, the risk of liver disease progression due to rapid transaminases, insulin, and C-peptide levels were noted weight loss within the first few postoperative months in the metformin group, and although more improvement makes the role of bariatric surgery in the treatment of in necroinflammatory activity was noted in the metform- NAFLD and NASH unclear. Nevertheless, further study of in group, the difference was not statistically significant.
this issue requires trials with larger numbers of paired bi- Bugianesi and colleagues randomized 55 patients to re- opsies, clearer indications, follow-up liver biopsies, and ceive metformin 2000 mg daily for 12 months, 28 pa- tients to receive vitamin E 800 IU daily, and 27 patientsto diet alone.51 Due to concerns raised by the ethics com- Insulin sensitizing agents
mittee, only 17 patients treated with metformin under-went biopsy at the end of treatment, but significant de- Among the insulin sensitizing agents used for the creases in steatosis, necroinflammation, and fibrosis were treatment of NASH, thiazolidinediones (TZDs) have reported. Several studies have reported improved inflam- been studied the most and have shown the most favor- mation but not much improvement in fibrosis. Again, the able results. TZDs such as pioglitazone and rosiglita- strength of these conclusions about metformin’s efficacy zone act as peroxisomal proliferator activated receptor- is limited by the lack of adequately powered, random- γ (PPAR-γ) agonists. Studies have also been conducted ized, placebo controlled trials with histological data with troglitazone, which has since been withdrawn from the market due to issues of hepatotoxicity.38 TZDs in-crease fatty acid oxidation and decrease fatty acid pro- Lipid lowering agents
duction within the liver. Insulin sensitivity is improvedboth peripherally and within the liver. Several studies Interest in the use of antihyperlipidemic agents for on the effects of TZDs on NAFLD and NASH report fa- NAFLD stems from the role of dyslipidemia in metabolic vorable results,39-46 including improved transaminases syndrome and its association with NAFLD. Fatty acid and steatosis. A large, recently published study by metabolism abnormalities are likely to contribute to the Aithal and colleagues randomized 74 nondiabetic, bi- development of NAFLD. Statins competitively inhibit opsy-proven NASH patients to receive pioglitazone 30 hepatic hydroxymethyl-glutaryl coenzyme A (HMG- mg qd or placebo with standard diet and exercise for 12 CoA) reductase, thereby decreasing cholesterol produc- months.39 Sixty-one patients (30 placebo, 31 pioglita- tion and reducing serum cholesterol. The use of statins in zone) had follow-up biopsies, and pioglitazone treated patients with chronic liver disease has raised concerns patients showed significant improvements in hepatocel- about the potential for of hepatotoxicity, but most agree lular injury, Mallory bodies, and fibrosis. Improved that the incidence of significant hepatotoxicity is ex- necroinflammation is a common finding in such studies, ceedingly rare and statin use in the setting of compensat- with the exception of a 48-week placebo-controlled trial ed liver disease is essentially safe.54-56 of rosiglitazone by Ratziu and colleagues.40 The effect Only a few studies have examined the efficacy of st- of TZDs on fibrosis is variable, improving in some, un- atins for NAFLD treatment. A pilot study by Rallidis and changed in others, but not worsening.
colleagues examined pravastatin use in four NASH pa- The favorable results observed with TZDs requires tients for six months; they found improvement in inflam- prospective, randomized, controlled trials before these mation in three patients and improvement in steatosis in agents can be routinely recommended. Side effects one patient.57 Ekstedt and colleagues retrospectively re- must also be kept in mind, as mild weight gain and viewed initial and follow-up liver biopsies of 68 NAFLD lower extremity edema have been reported.39 The re- patients, 17 of whom began treatment with statins at some cent controversy over the possibility of increased car- point after the initial biopsy.58 The time between biopsies diac risk with use of rosiglitazone also must be taken ranged from 10.3 to 16.3 years. Although patients treated with statins showed greater body mass index (BMI) and Several studies have examined the utility of metform- insulin resistance at initial and follow-up biopsies com- in in the management of NAFLD and NASH. Metformin’s pared to patients without statins, greater improvements in BP Lam et al. Treatment regimens for non-alcoholic fatty liver disease hepatic steatosis were noted in the patients treated with st- heterogeneous to conflicting. A large randomized, multi- atins. The study also reported that only four of the 17 pa- center, double-blinded, placebo-controlled trial of piogl- tients treated with statins showed progression of their fi- itazone and Vitamine E is currently in progress by inves- brosis stage on follow-up biopsy. These findings are pre- tigators from NASH Network.69 These researchers have liminary and the number, size, and design of the studies enrolled 247 patients who will receive pioglitazone 30 are suboptimal. No conclusions can yet be drawn about mg qd, vitamin E 800 IU qd or placebo for 96 weeks. The the efficacy of metformin for NAFLD treatment.
primary outcome, improvement according to defined his- There is some suggestion that fibrates, such as clofi- tological criteria, will be based on paired liver biopsies.
brate, gemfibrozil, and fenofibrate may have some ben- The results are expected to shed more light on the effica- efit in NAFLD treatment. A 12-month pilot study com- paring 24 NASH patients treated with ursodeoxycholic Other antioxidants such as betaine and N-acetyl-cys- acid (UDCA) to 16 biopsy-proven NASH patients treat- teine (NAC) have also been studied for their purported ed with clofibrate noted significant improvement in antifibrotic effects.72-75 Betaine, a metabolite of choline, ALT, GGT, and histologic amounts of steatosis with increases S-adenosyl-L-methionine (SAM) levels, which UDCA. Significant improvements in alkaline phos- contributes to cellular membrane integrity and protects phatase levels were only noted with Clofibrate.59 A against fatty infiltration in animal models.70,71 Abdel- four-week study showed that gemfibrozil improved ALT malek and colleagues examined the effects of betaine an- levels, but histological data was not obtained.60 Be- hydrous for oral solution bid for 1 year in 10 patients cause pioglitazone, a PPAR-γ agonist with weak PPAR- with biopsy proven NASH.72 Seven patients completed α activity, has shown some benefit in NAFLD treat- the study, and although statistically significant improve- ment, it is possible that fenofibrate may have some ben- ments were noted in transaminases levels, the improve- efit as well, due to its PPAR-α activity; this however has ment in the amount of steatosis, histological inflamma- tion and fibrosis were not statistically significant. In asubsequent study by the same investigators, betaine was Antioxidants
not shown to be efficacious (personal communicationwith Dr. Abdelmalek 2008).
Oxidative stress is considered a major contributor as Gulbahar and colleagues conducted a small study on the "second hit" in the pathogenesis of NAFLD and the effects of NAC in 11 patients and reported improve- NASH, justifying the study of several antioxidants in ments in transaminases, but no histological data was ob- NAFLD treatment. Many of these studies have examined tained.74 NAC shows some benefit in a variety of liver the effects of vitamin E. Alpha-tocopherol, the form of vi- conditions, reports of its use in NASH treatment are tamin E that is preferentially metabolized in humans, in- hibits transforming growth factor beta1, which is thought Some researchers have surmised that endotoxins pro- to contribute to fibrosis progression; six of the nine stud- duced by gut flora may also contribute to oxidative stress ies reviewed showed improved transaminases.44,62-66 How- in the liver, and that alterations in that flora may have ever, only three of the studies examined histological beneficial effect upon the liver. Most of the support changes. Hasegawa’s one-year study of open-label vita- comes from results in animal models.76,77 Only two small min E in 10 patients with NAFLD and 12 patients with open label studies have been conducted with probiotics NASH reported improvement in transaminases and histo- in patients with NAFLD.78,79 A study by Loguercio and logical findings in the NASH cohort.63 Kugelmas’ pilot colleagues showed that VSL#3 is well-tolerated in pa- study of diet and aerobic exercise with or without vita- tients with NAFLD, alcoholic cirrhosis, and chronic hep- min E in 16 patients showed no additional benefit with atitis C.79 Various serum markers of hepatic damage vitamin E.64 A small pilot study by Sanyal and col- showed improvement after 120 days of treatment, but no leagues showed that vitamin E alone was not as effective biopsies were performed. Oligofructose, an indigestible as vitamin E with pioglitazone. Significant improve- insulin-type fructan, decreases hepatic uptake of tria- ments in steatosis, ballooning and pericellular fibrosis cylglycerol in rats.80 An eight-week double-blind cross- were noted on the follow-up biopsies of the 10 patients over pilot study by Daubioul et al. randomized seven pa- treated with vitamin E and pioglitazone.45 A placebo- tients with biopsy-proven NASH to receive either oligof- controlled double-blind study by Harrison and col- ructose or maltodextrine, which served as a placebo.81 leagues randomized 49 patients with biopsy-proven Insulin levels improved after four weeks of therapy and NASH to receive either vitamin E 1,000 IU qd and vita- transaminases improved after eight weeks.
min C 1,000 mg qd or placebo for 6 months. On follow-up biopsy, a statistically significant improvement was Cytoprotective agents
noted in fibrosis score, although inflammation grade re-mained unchanged.68 So far, these data are of mixed qual- Several studies have examined the effects of ur- ity; the study sizes are small and the results range from sodeoxycholic acid (UDCA) in NAFLD and NASH pa- Annals of Hepatology 8(1) 2009: S51-S59 tients. UDCA is a naturally occurring bile acid be- according to Brunt’s criteria was noted in 67% of patients, lieved to have cytoprotective and immunomodulator and fibrosis improved in four out of the six patients with properties and may decrease apoptosis.82 UDCA has fibrosis at baseline. Further investigation with larger, well- long been used in the treatment of primary sclerosing designed clinical trials would be helpful.
cholangitis and primary biliary cirrhosis, and its ad-verse effect profile is generally benign. Initial pilot Other novel treatments
studies showed improvements in transaminases andsteatosis;83-85 however, these results were not con- Attempts to find other safe and efficacious treatments firmed in a large randomized placebo-controlled trial for NAFLD and NASH include investigations of the an- by Lindor and colleagues.86 One hundred sixty-six bi- giotensin receptor blockers (ARB) telmisartan and irbe- opsy-proven NASH patients were randomized to re- sartan. The insulin sensitizing properties of these agents ceive either UDCA at 13-15 mg/kg daily for two years; results from stimulation of PPARγ.95 In a study by Yoko- 126 patients completed the two year study and 107 hama et al., seven patients with NASH and hypertension follow-up biopsies were performed. Histological im- were treated with 50 mg daily of the ARB losartan for 48 provement was not significantly different between the weeks.96 Significant improvements were noted in the lev- two groups. Other studies have also reported that els of transforming growth factor beta1, serum markers of UDCA monotherapy is no better than placebo.87,88 A hepatic fibrosis, and ferritin. Five patients showed de- six-week, double-blind, placebo-controlled trial by creased necroinflammation upon follow-up biopsy and Mendez-Sanchez and colleagues randomized 14 obese four patients showed decreased fibrosis.
women to receive UDCA 1200 mg qd and 13 to re- Preliminary studies with animal models and case reports ceive placebo.87 All patients were also placed on a in humans show that incretin analogs may also be of benefit 1200-calorie diet. UDCA and dietary restriction were in NAFLD treatment. Incretin analogues, such as exenatide not superior to dietary restriction alone. These results and sitagliptin, increase glucose-dependant insulin secre- with cytoprotective agents have been disappointing, tion, decrease inappropriate glucagon secretion, and in- but UDCA may have some benefit when used in com- crease satiety by delaying gastric emptying.97,98 bination with other agents such as vitamin E.89 Studies Second generation sulfonylureas, such as repaglinide are also underway to determine whether higher dosag- ESTE DOCUMENTO ES ELABORADO POR MEDI-
and nateglinide, have also been considered as possible es of UDCA are as safe and might be more efficacious.
NAFLD treatment options. Ten diabetic patients with bi- UDCA’s benign side effect profile suggests that further opsy-proven NASH were randomized by Morita and col- study of its use as an adjunct in NASH treatment leagues to receive nateglinide 270 mg daily with diet should be conducted. The potential benefits of other and exercise or diet and exercise alone for 20 weeks.99 In cytoprotective agents such as lecithin, silymarin, beta- the nateglinide group, improvements were noted in post- carotene, and metadoxine might also be examined.
prandial glucose, hemoglobin A1C, glucose tolerancetest results, liver function tests, and imaging and histo- Anti-TNF agents
logical findings of NAFLD. Suffice it to say, these andother possible treatment options require further study and Other potential components targeting the "second hit" in the pathogenesis of NAFLD include those agents im-proving necrosis, inflammation, and fibrogenesis caused Conclusion
by a number of pro-inflammatory adipocytokines, in-cluding tumor necrosis factor alpha (TNF-α).90 Pentoxi- Despite more than a decade of research and clinical fylline, a xanthine derivative that affects blood viscosi- trials, no single intervention has been proven effective ty, is currently approved for the treatment of claudica- for the treatment of NAFLD and NASH in all important tion. It has also been shown to inhibit TNF-α.91 Two outcomes. While some promising results are seen with small open-label trials have examined the safety and effi- certain types of bariatric surgery and medications such cacy of pentoxifylline in NASH patients. These initial tri- as TZDs and vitamin E, these results have not been vali- als show improvement in transaminases after 12 months dated with larger, well-designed studies. With most of of open-label pentoxifylline, with 18 patients in a trial the trials that have been conducted to date, conclusions by Satapathy and colleagues and 20 patients in a trial by have been limited by methodological flaws such as the Adams and colleagues.92,93 Satapathy and colleagues ob- lack of randomization, small sample size, and failure to tained histological evidence of improvement in 2007, in address multiple pathogenic pathways. Additionally, a trial treating 9 patients with biopsy-proven NASH with because NAFLD and NASH are chronic in nature, as pentoxifylline 400 mg tid for 12 months.94 Significant with other components of metabolic syndrome, long- transaminase improvement was again noted. Upon follow- term treatment is likely to be required. This poses a up liver biopsy, improvement in steatosis and lobular in- methodological dilemma for clinical trials of shorter du- flammation was noted in 55% of patients, decreased stages ration. As it stands today, no single medication can be BP Lam et al. Treatment regimens for non-alcoholic fatty liver disease recommended for routine use in clinical practice. For 17. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radio- now, clinicians may focus on treating the comorbid con- logical imaging in nonalcoholic fatty liver disease. Gastroenter-ology 2002; 123: 745-750.
ditions associated with metabolic syndrome and revers- 18. Brunt EM, Neuschwander-Tetri BA, Oliver D, et al. Nonalcoholic ing factors that predispose patients for NAFLD and steatohepatitis: histologic features and clinical correlations with 30 NASH. In the absence of clearly superior treatments, blinded biopsy specimens. Hum Pathol 2004; 35: 1070-1082.
NAFLD and NASH patients may appropriately be re- 19. Ataseven H, Yildirim MH, Yalniz M, et al. The value of ultra- sonography and computerized tomography in estimating the his- topathological severity of nonalcoholic steatohepatitis. ActaGastroenterol Belg 2005; 68: 221-225.
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