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Spectrum of Liver Disease in Type 2Diabetes and Management of Patients

With Diabetes and Liver DiseaseKEITH G. TOLMAN, MD

1,2

VIVIAN FONSECA, MD3ANTHONY DALPIAZ, PHARMD

4

MENG H. TAN, MD5

It is estimated that 20.8 million people,i.e., 7.0% of the U.S. population, havediabetes (1). Type 2 diabetes, with its

core defects of insulin resistance and rel-ative insulin deficiency, accounts for 9095% of those with the disease. Another5.2 million people are estimated to haveundiagnosed type 2 diabetes. It is thesixth leading cause of death (1) in the U.S.

and accounts for 17.2% of all deaths forthose aged 25 years (2).Liver disease is an important cause of

death in type 2 diabetes. In the popula-tion-based Verona Diabetes Study(3), cir-rhosis was the fourth leading cause ofdeath andaccounted for 4.4% of diabetes-related deaths. The standardized mortal-ity ratio (SMR), i.e., the relative rate of anevent compared with the backgroundrate, for cirrhosis was2.52 compared with1.34 for cardiovascular disease (CVD). Inanother prospective cohort study (4), cir-rhosis accounted for 12.5% of deaths in

patients with diabetes.Diabetes, by most estimates, is now

the most common cause of liver disease inthe U.S. Cryptogenic cirrhosis, of whichdiabetes is, by far, the most commoncause, has become the third leading indi-cation for liver transplantation in the U.S.

(5,6). Virtually the entire spectrum ofliver disease is seen in patients with type 2diabetes. This includes abnormal liver en-zymes, nonalcoholic fatty liver disease(NAFLD), cirrhosis, hepatocellular carci-noma, and acute liver failure. In addition,there is an unexplained association ofdiabetes with hepatitis C. Finally, theprevalence of diabetes in cirrhosis is

12.357% (7). Thus, patients with diabe-tes have a high prevalence of liver diseaseand patients with liver disease have a highprevalence of diabetes.

The management of diabetes in pa-tients with liver disease is theoreticallycomplicated by liver-related alterations indrug metabolism, potential interactionsbetween the drugs, and a low, albeit real,incidenceof hepatotoxicity. In this article,we review the spectrum of liver diseasefound in patients with type 2 diabetes andthe management of patients with concur-rent diabetes and liver disease.

METHODS A Medline search with-out limitations of date (as of October2005), language, or humans was carriedout by the authors. The following medicalsubject headings were used: DiabetesMellitus, type 2; Fatty Liver; Hepatitis,

Toxic; Sulfonylurea Compounds;Thiazolidinediones; Rosiglitazone;Pioglitazone; Troglitazone; Hy-droxymethylglutaryl-CoA Reductase In-hibitors; Metformin; Acarbose; andGemfibrozil and free-text terms: fattyliver, steatohepatitis, nonalcoholicsteatohepatitis, nonalcoholic fatty liverdisease, drug-induced hepatitis, eachdrug name and hepat*, and each drugname. When full-text articles were notavailable in the English language, ab-stracts were included in the search. Ab-

stracts from national meetings throughOctober 2006 were included. The Foodand Drug Administration (FDA) Web sitewas searched for hepatotoxicity reportsusing the free-text terms listed above.

SPECTRUM OF LIVER

DISEASE IN TYPE 2

DIABETES The liver diseases seenin type 2 diabetes cover virtually the en-tire spectrum of liver disease.

Abnormal liver enzymesElevation of serumalanine aminotransfer-ase (ALT), while uncommon (0.5%) inapparently normal subjects (7), is com-mon in patients with type 2 diabetes. Infour clinical trials involving 3,701 pa-tients with type 2 diabetes, between 2 and24% of screened patients had liver enzymetestsabovethe upper limitof normal (ULN)(8).In these studies,investigatorsnoted that5% of the patients had concomitant liverdisease at baseline. In anotherreport involv-ing13 clinical trials and 5,003 patientswithtype 2 diabetes, in which patients with se-rum ALT, aspartate aminotransferase(AST), or alkaline phosphatase 2.5times ULN were excluded, 5.6% had se-rum ALT values between 1 and 2.5 timesULN (9). Evaluation of asymptomatic in-dividuals with mild elevations of ALT and

AST reveals that 98% have liver diseasemost commonly, fatty liver disease andchronic hepatitis (10). The most commoncause of a mild elevation of serum ALT isNAFLD (11), the most prevalent liver dis-ease in type 2 diabetes.

From the 1Division of Gastroenterology, University of Utah School of Medicine, Salt Lake City, Utah; the2Department of Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah; the 3Division ofEndocrinology, Tulane University, New Orleans, Louisiana; the 4Department of Pharmacy, University Hos-pitals and Clinics, Salt Lake City, Utah; and 5Lilly Research Laboratories, Eli Lilly and Company, Indianap-olis, Indiana.

Address correspondence and reprint requests to Keith G. Tolman, MD, Department of Internal Medicine,University of Utah School of Medicine, 30 N. 1900 East, Salt Lake City, UT 84132. E-mail:[email protected].

Received for publication 21 July 2006 and accepted in revised form 20 November 2006.K.G.T.is on the scientificadvisory boards for TAP Pharmaceuticals, Takada, Santarus,Merck,Johnson &

Johnson, and InterMune and is on the speakers bureau for TAP Pharmaceuticals, Takeda, Schering, Roche,Eli Lilly, Santarus, InterMune, and G.D. Searle. V.F. is a consultant for and on the speakers bureau for EliLilly, Novartis, Takeda, Pfizer, and Sanofi-Aventis and has received grants from GlaxoSmithKline, Novartis,Takeda, AstraZenca, Pfizer, Sanofi-Aventis, Eli Lilly, and the National Institutes of Health.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CVD, cardiovasculardisease; FDA, Food and Drug Administration; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liverdisease; NASH, nonalcoholic steatohepatitis; SMR, standardized mortality ratio; TNF, tumor necrosis factor;TZD, thiazolidinedione; ULN, upper limit of normal.

A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversionfactors for many substances.

DOI: 10.2337/dc06-1539 2007 by the American Diabetes Association.

R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t s

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NAFLDThe most common chronic liver diseasein the U.S. is NAFLD (5). It is defined asfatty liver disease in the absence of20 galcohol/day. NAFLD, which resembles al-coholic liver disease, consists of a spec-trum of liver disease from steatosis (fattyinfiltration of the liver) to nonalcoholic

steatohepatitis (NASH), which consists ofsteatosis plus inflammation, necrosis, andfibrosis. The prevalence of NAFLD in di-abetes is estimated at 3474% (1217)and, in diabetes with obesity, at virtually100% (18). While once considered a be-nign process, NASH has been found tolead to cirrhosis and, in some cases, tohepatocellular carcinoma (13,19 21). Ofpatients with NAFLD, 50% have NASHand 19% have cirrhosis at the time of di-agnosis (18,22,23) While these studiesare subject to selection bias, the preva-

lence is undoubtedly very high.The pathogenesis of NAFLD is onlypartially understood. Hepatic steatosis re-flects an imbalance between the uptakeand synthesis of fatty acids by the liverand their oxidation and export. Patientswith type 2 diabetes have dyslipidemia,which is characterized by elevated plasmatriglycerides, decreased HDL cholesterol,andpredominance of small LDL, a patternalso seen in patients with NAFLD (24). Acentral abnormality in the pathogenesis ofsteatosis appears to be insulin resistanceresulting in lipolysis, which increases cir-

culating free fatty acids (25), which arethen taken up by the liver as an energysource. The fatty acids overload the he-patic mitochondrial -oxidation system,leading to accumulation of fatty acids inthe liver (26). Indeed, some investigatorssuggest NAFLD to be the hepatic manifes-tation of the insulin resistance syndrome(22,2729). NAFLD does not universallyprogress to NASH, and the precise patho-genesis of steatohepatitis is yet to be de-termined. However, dysregulation ofperipheral lipid metabolism seems to be

important.Lipid metabolism is, in part, regu-lated by adipokines, including tumor ne-crosis factor (TNF)- and adiponectin.TNF-, which interferes with insulin sig-naling thereby favoring steatosis, is ele-vated in fatty liver disease albeit notspecific to type 2 diabetes (30,31). TNF-is also proinflammatory and, thus, mayplay a role in the pathogenesis of the in-flammation in NASH (32,33). Adiponec-tin, in contrast to TNF-, is antilipogenicand anti-inflammatory and, thus, mayprotect the liver from lipid accumulation

and inflammation. Adiponectin levels aredecreased in conditions associated withNAFLD, including insulin resistance(34), obesity (35), type 2 diabetes(36,37), and NAFLD (36). Adiponectinand TNF- therefore have opposing ef-fects. The net effect of increased TNF-and decreased adiponectin is prosteatotic

and proinflammatory.The mechanism of cell injury remains

unclear. Fatty acids in theliver inducefor-mation of free radicals (38), which causelipid peroxidation and induce proinflam-matory cytokines (39). The lipid per-o x i d a t i o n l e a d s t o t h e r e l e a s e o f malondialdehyde and 4-hydroxynon-enal, which in turn causes cell death andprotein cross-linkage. This results in theformation of Mallorys hyaline in the he-patocyte (40) and activation of the stellatecells, which leads to collagen synthesis

and fibrosis (41). The net effect of theseprocesses is necrosis, formation of Mal-lorys hyaline, inflammation, and fibro-sisthe characteristic histologic featuresof NASH.

The natural history of NAFLD is sim-ilar to that of alcoholic liver disease. Theprogression from steatosis to steatohepa-titis to cirrhosis and, in some patients, tohepatocellular carcinoma over a period ofmany years is well established (13,42).The prognosis worsens with each stage ofdisease. Why some patients progresswhile most do not is not known. The only

reliable way, to date, of determining thisprogression is liver biopsy, which mayhave significant economic implications(good or bad) for the management of pa-tients with type 2 diabetes.

Cirrhosis in diabetesCirrhosis is an important cause of death indiabetes. An autopsy study in the U.S. hasshown that patients with diabetes have anincreased incidence of severe fibrosis(19). In the Verona study, the SMR forcirrhosis was 2.52, greater than the 1.34

for CVD. If the patient was being treatedwith insulin, the SMR increased to 6.84(3). Cryptogenic cirrhosis, primarily dia-betes 5, is the third leading indication forliver transplantation in this country (6).

The association of cirrhosis and dia-betes is complicated by the fact that cir-rhosis itself is associated with insulinresistance. Impaired glucose tolerance isseen in 60% and overt diabetes in 20% ofpatients with cirrhosis. Insulin-mediatedglucose disposal has been shown to bereduced by 50% in cirrhotic patients(43). However, the onset of type 2 diabe-

tes in cirrhotic patients is associated withdecreased rather than increased insulinsecretion (44). This interplay of associa-tions has made it difficult to sort out thepathogenesis of cirrhosis in diabetes.Nevertheless, the association is incontro-vertible and has implications for the treat-me nt of dia be t e s in pa t ie nt s wit h

cirrhosis.

Hepatocellular carcinoma indiabetesNumerous studies have confirmed a four-fold increased prevalence of hepatocellu-lar carcinoma in patients with diabetes aswell as an increased prevalence of diabe-tes in patients with hepatocellular carci-noma (4548). It is not known whetherthe increased prevalence of hepatocellularcarcinoma is unique to diabetes or the in-creased prevalence of cirrhosis, the pre-

cursor lesion of hepatocellularcarcinoma.The pathogenic sequence of events lead-ing to hepatocellular carcinoma appearsto be insulin resistance, increased lipoly-sis, lipidaccumulation in the hepatocytes,oxidative stress, and cell damage followedby fibrosis and cell proliferation, whichare procarcinogenic (4952).

Acute liver failureThe incidence of acute liver failure ap-pears to be increased in patients with di-abetes: 2.31 per 10,000 person-yearscompared with 1.44 in the background

population (53,54). It remains unclearwhether it is diabetes, medications, orsome other factor that accounts for theincreased risk of acute liver failure. Trogli-tazone was factored out in these studies.

Hepatitis C in diabetesThe prevalence of hepatitis C virus (HCV)is higher in patients with diabetes than inthe general population (5563). Specifi-cally, the prevalence of HCV antibodies is4.2% in the diabetic population com-pared with 1.6% in the comparator

group. The relative odds of HCV-infectedpatients developing diabetes is 2.1 (95%CI 1.123.90) (58). Patients with HCVare more likely to develop diabetes (21%)than patients with hepatitis B (10%), sug-gesting that HCV, rather than liver diseaseper se, predisposes patients to diabetes.Furthermore, patients who are trans-planted for HCV (and universally becomereinfected) are more likely to develop di-abetes than those who are transplantedfor other liver diseases (61). Taken to-gether, these observations suggest thatHCV may play a pathogenetic role in type

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2 diabetes. Recent studies suggest that thecore protein of HCV impairs insulin re-ceptor substrate signaling, which plays animportant role in the metabolic effects ofinsulin (64,65).

There are other peculiarities in theHCV-diabetes connection including HCVgenotype specificity. There are six geno-

types of HCV, with genotype 1 being themost prevalent in the U.S. The prevalenceof fatty liver disease is disproportionatelyhigh in HCVgenotype 3 (66), presumablysecondary to insulin resistance (67,68).Patients with hepatitis C and fatty liverdisease have elevated levels of TNF- andreduced levels of adiponectin, which incombination are proinflammatory andprosteatotic (69,70), leading to oxidativestress in mitochondria (71) and steatosisin many genotype 3 patients (7274). Fi-nally, there is an association of diabetes

with

-interferon treatment of HCV infec-tion. Type 1 diabetes occurs more fre-quently in patients treated with interferonfor HCV versus other conditions (75).The latency of diabetes ranges from 10days to 4 years after starting treatment.

The interaction between HCV infec-tion, diabetes, and interferon is the sub-

ject of intensive investigation. In themeantime, given the strong epidemio-logic evidence for the increased preva-lence of HCV in diabetes, it seemsreasonable that all patients with type 2diabetes and persistently elevated serum

ALT should be screened for HCV.

TREATMENT OF PATIENTS

WITH TYPE 2 DIABETES

AND LIVER DISEASE T h e s e -verity of type 2 diabetes and the type andseverity of liver disease influence the ther-apy. There are few clinical trials that spe-cifically target patients with coexistentdiabetes and liver disease, and all are lim-ited by small numbers of patients. We willreview the management of type 2 diabetesin patients with liver disease as well as the

management of liver disease specificallyassociated with type 2 diabetes.

MANAGEMENT OF

DIABETES IN PATIENTS

WITH CONCOMITANT

LIVER DISEASE

Lifestyle modificationTreatment of type 2 diabetes in patientswith liver disease may be compromisedby poor nutritional status and generalhealth. More than 50% of patients withsevere liver disease are malnourished. A

number of uncontrolled studies indicatethat weight loss decreases hepatic steato-sis (7678). The durability of weight losson hepatic steatosis remains to be deter-mined (79). Low-glycemic, low-caloriediets with a weight loss of 12 kg/weekseem reasonable. Low-fat diets should beavoided (80,81). Some have suggested

that a Mediterranean diet (i.e., high com-plex carbohydrates, high monounsatu-rated fats, moderate amounts of wine, andlow amounts of red meat) is preferred inpatients with type 2 diabetes and NAFLD(82,83). Exercise improves peripheral in-sulin sensitivity (84), albeit not specific topatients with diabetic liver disease. Alco-hol should be avoided not only because ofits toxic effects on the liver, but also be-cause of its high caloric content and poten-tial interaction with sulfonylureas (85,86).

Pharmacologic therapyPharmacologic therapy of type 2 diabetesin patients with liver diseases is, for themost part, the same as that without liverdisease. While there are theoretical con-cerns about altered drug metabolism andhepatotoxicity, only patients with evi-dence of liver failure such as ascites, co-agulopathy, or encephalopathy havealtered drug metabolism. Furthermore,there is no evidence that patients withliver disease are predisposed to hepato-toxicity (87). Underlying liver disease,however, may compromise the diagnosis

and increase the severity of drug-inducedliver disease.

First-line therapy with metformin isappropriate in most patients but not rec-ommended in patients with advanced he-patic disease because of a perceivedincreased risk of lactic acidosis. Recenttrials have shown some benefit in patientswith fatty liver and type 2 diabetes (8891). Given that insulin resistance is thecore defect in fatty liver disease, the casecan be made for thiazolidinediones(TZDs) as front line therapy in these pa-

tients. Recent trials with pioglitazone androsiglitazone have shown improvementin ALT and liver histology (9297).

Weight gain is a concern with TZDs, andcost is prohibitive for many patients. Ifmetformin or TZDs are contraindicated,pharmacotherapy can begin with a secre-tagogue such as a sulfonylurea with rapidadvancement to insulin if glycemic con-trol is not achieved.Insulin secretagogues. Sulfonylureasare generally safe in patients with liverdisease but may not overcome the insulinresistance and defects in insulin secretion

seen in patients with coexistent alcoholicliver disease and pancreatic damage (84).Sulfonylureas with a short half-life such asglipizide or glyburide are preferred inthese patients. Patients with decompen-sated cirrhosis, i.e., encephalopathy,ascites, or coagulopathy, may have a re-duced ability to counteract hypoglyce-

mia, and thus, the response to therapyshould be monitored closely. Historically,chlorpropamide (84,98100) was associ-ated with hepatitis and jaundice.

Clinical trials assessing the efficacy ofmeglitinides in the treatment of patientswith liver disease have not been reported.The pharmacokinetics and tolerabilityof nateglinide in patients with cirrhosisis not significantly different than in con-trol subjects (101). Repaglinide andnateglinide have not been associated withhepatotoxicity.

Biguanides. Metformin may be particu-larly useful in obese patients in whom itmay cause mild weight loss (102). It isrelatively contraindicated in patients withadvanced liver disease or in binge drink-ers because it may predispose to lactic ac-idosis. It is unclear whether the liverdisease or alcohol is the predisposing fac-tor. Metformin has not been reported tocause hepatotoxicity and has shown somebenefit in patients with NAFLD (8891).-Glucosidase inhibitors. The -gluco-sidase inhibitors may be particularly use-ful in patients with liver disease because

they act directly on the gastrointestinaltract to decrease carbohydrate digestionand thus glucose absorption, thereby de-creasing postprandial hyperglycemia

A randomized double-blind trial eval-uated the use of acarbose for the control ofpostprandial hyperglycemia in 100 pa-tients with compensated liver cirrhosisand type 2 diabetes treated with insulin(103). Glycemic control improved signif-icantly in both the fasting and postpran-dial state. In a recent placebo-controlledcross-over trial in patients with hepatic

encephalopathy, acarbose significantlydecreased fasting and postprandial glu-cose as well as A1C (104). There was alsoa reduction in blood ammonia levels,which paralleled an increase in bowelmovement frequency. It was speculatedthat the increased bowel frequency favoredthe proliferation of saccharolytic bacteriawhile reducing the proliferation of proteo-lytic bacteria, resulting in a reduction inintestinal ammonia production.

Acarbose frequently causes mild tran-sient elevations of ALT and, on rare occa-sions, severe liver disease (105107).

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While the labeling of acarbose has a warn-ing for patients with liver disease, it ap-pears to be safe and effective in patientswith hepatic encephalopathy and type 2diabetes. Miglitol, another -glucosidaseinhibitor, has not been associated withhepatotoxicity.TZDs. TZDs may be especially useful be-

cause they enhance insulin sensitivity, theunderlying defect in NAFLD. There hasbeen concern about their potential hepa-totoxicity because of the experience withtroglitazone (since withdrawn from theU.S. market). However, in pre-approvalclinical trials of rosiglitazone and piogli-tazone, threefold elevations of ALT wereseen with the same frequency for rosigli-tazone (0.26%), pioglitazone (0.2%), andplacebo (0.2 and 0.25%) (PhysiciansDesk Reference 2005, Avandia Tabletsand Actos Tablets). Lebovitz et al. (9)

have reported that there was no differencein the incidence of liver abnormalities inpatients treated with rosiglitazone, pla-cebo, metformin, or a sulfonylurea intrials involving 5,000 patients. Rosigli-tazone, in fact, decreased serum ALT by amean of 5 units/l (9), as did pioglitazonein another trial (8). Furthermore, in thelatter trial (8), serum ALT three timesULN occurred less frequently in the piogli-tazone group (0.9%) than in the metformin(1.9%) or gliclazide (1.9%) groups.

The risk of acute liver failure with ros-iglitazone and pioglitazone is much less

than that with troglitazone (108,109). Atthe time of that review (109), 68 cases ofhepatitis or acute liver failure due torosiglitazone and 37 cases due to piogli-tazone had been reported to the Food andDrug Administration (110116). How-ever, attestation as to cause was not pro-vided, and many cases were confoundedby concomitant medications and cardio-vascular events (fluid retention and heartfailure).

It is currently recommended that se-rum ALT levels be evaluated before the

initiation of rosiglitzone and pioglitazonetherapy andthat therapy not be initiatedifthere is evidence of active liver disease orif the serum ALT level exceeds 2.5 timesULN (product labeling, 2005). Monitoringis recommended periodically thereafter asclinically indicated rather than every 2months as previously recommended. Para-doxically, TZDs are emerging as the treat-ment of choice for NASH (9297).Insulin. Insulin treatment is frequentlyrequired in patients with diabetes andliver disease. Insulin requirements, how-ever, may vary. For example, in patients

with decompensated liver disease, the re-quirement may be decreased due to re-duced capacity for gluconeogenesis andreduced hepatic breakdown of insulin.However, patients with impaired hepaticfunction may have an increased need forinsulin due to insulin resistance (43).Thus, careful glucose monitoring and fre-

quent dose adjustments of insulin may benecessary.

In patients with hepatic encephalop-athy who require high-carbohydratediets, resulting in postprandial hypergly-cemia, rapid-acting insulin analogs suchas insulin lispro, aspart, or glulisine maybe particularly useful.

Other drugs used in the managementof disorders associated with type 2diabetesStatins are frequently used in patients

with type 2 diabetes to treat hyperlipid-emia and prevent cardiovascular events.Statin therapy, like all cholesterol-lowering therapy including bariatric sur-ge ry (117,118), c a use s minor buttransient elevations in liver enzymes(119). However, the liver adapts withcontinuing therapy, and there are nolong-term consequences of these abnor-malities. Severe liver damage and liverfailure are very rare (119). Paradoxically,statins are currently used to treat NAFLD(120,121), and recent studies suggest thatstatins are hepatoprotective in patients

with HCV (122).All of the ACE inhibitors have been

implicated in hepatic injury including ful-minant hepatic failure (123126). The re-actions are mostly hepatocellular, butcholestatic reactions have also been re-ported. Although losartan has been asso-ciated with hepatotoxicity (127) it hasalso been used to treat fatty liver disease(128). There are no current recommenda-tions for hepatic monitoring of these id-iosyncratic events.

Even aspirin is potentially hepato-

toxic albeit at very high doses. Hepatotox-icity has not been described at doses usedfor cardioprotection.

MANAGEMENT OF LIVER

DISEASE IN PATIENTS

WITH CONCOMITANT TYPE

2 DIABETES AND LIVER

DISEASE

Abnormal liver function testsGiven the fact that at least 50% of patientswith type 2 diabetes have NAFLD, all pa-tients with type 2 diabetes should have an

ALT and AST test done as part of theirinitial evaluation. At least 95% of patientswith a confirmed minor elevation of ALTor AST have chronic liver disease inde-pendent of the degree of elevation. Thus,it is always necessary to obtain a specificdiagnosis (10). The most likely etiologiesof minor elevations of ALT/AST are

NAFLD, hepatitis C, hepatitis B, and alco-hol. Moderate social drinking, i.e., 20g/day, does not cause an elevation of liverenzymes. The initial workup should in-clude testing for hepatitis C (anti-HCV orHCV PCR), hepatitis B (HBV surface an-tigen), hemochromatosis (iron and ironsaturation), and an abdominal ultra-sound. Patients with hepatitis C, hepatitisB, and increased iron saturation need re-ferral for further workup and treatment.Ultrasound has a positive predictive valueof 96% for detecting NAFLD in the ab-

sence of other liver diseases (129). Unfor-tunately the negative predictive value isonly 19%; thus, patients with a negativeultrasound will also need referral. Theim-pact of this approach on cost of care andmanpower is not known, and the cost-effectiveness of screening ALT has notbeen established, although the American

Association for the Study of Liver Diseaseis now recommending yearly ALT screen-ing for everyone.

Fatty liver diseaseThe diagnosis of NAFLD or NASH should

be suspected in any patient with type 2diabetes, especially if there are abnormalliver function tests. It should be specifi-cally looked for in all obese patients withtype 2 diabetes. ALT is typically elevatedtwo- to threefold above ULN but is oftennormal. Mild elevations of serum alkalinephosphatase and glutamyl transferasemay be present. Serum ferritin levels arefrequently elevated, while iron and iron-binding capacity are normal (42,130).

Ultrasound studies may reveal a dif-fuse increase in echogenicity, so-called

bright liver. The sensitivity of ultra-sound in patients with elevated ALT is89% with a specificity of 93% for detect-ing steatosis (131). If the ultrasound re-veals fatty liver, it is appropriate to lookfor etiologies other than diabetes such asdyslipidemia. There are shortcomings tothis approach. The sensitivity of ultra-sound decreases greatly as hepatic steato-sis decreases to 30% or less (132). Mostpatients with NAFLD found incidentallyor by screening ultrasound have a normal

ALT. These observations suggest that thesensitivity of ultrasound overall is really




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not very high. In patients with abnormalALTs and other diseases ruled out, thepositive predictive value of ultrasound is96% but the negative predictive valueonly 19% (129). Magnetic resonancespectroscopy is capable of quantitative as-sessment of steatosis (133) but is not in-dicated for routine clinical practice. Thus,

the gold standard for diagnosis of NAFLDremains the liver biopsy. Furthermore,the diagnosis of progressive liver disease(i.e., NASH), the precursor of cirrhosis,can only be made by liver biopsy. How-ever, certain patients including those withreversed ALT-to-AST ratio, hypertriglyc-eridemia, and thrombocytopenia are ath i g h r i s k f o r p r o g r e s s i v e d i s e a s e(134,135).

Treatment of NAFLDMost patients do not need to be treated.

Only patients with biopsy-proved NASHor the risk factors listed above should betreated. Whether or not all patients need aliver biopsy is controversial in that thesensitivity of the risk factors for progres-sive disease is not known. It is also notknown whether treatment, other thanbariatric surgery, affects the ultimateprognosis. The treatment consists of mea-sures to lose weight as well as pharma-cologic intervention. There are no FDA-approved treatments and, in fact, no FDAguidelines for approving drugs for NAFLD.Exercise and weight reduction. The

initial treatment of NASH consists ofweight loss and exercise, which enhanceinsulin sensitivity and result in reductionof steatosis (136141). Rapid weight re-duction, however, may increase ne-c rosis, infla mma t ion, a nd fibrosis(117,118,142). This paradoxical effect isthought to be due to an increase in circu-lating free fatty acids due to increased li-polysis seen with fasting. The ideal rate ofweight loss is not known, but l.5 kg/weekhas been recommended (143). The idealcontent of the diet is not known. How-

ever, saturated fatty acids increase insulinresistance, and for that reason a Mediter-ranean diet, i.e., a diet enriched withmonounsaturated fatty acids and low-glycemic carbohydrates, seems reason-a ble (82,83). Re c e nt st udie s ha vedemonstrated that bariatric surgery eitherimproves or completely reverses steatosisin patients with obesity with or withoutdiabetes (141,144).Pharmacologic therapy. Pharmacologictherapy of NAFLD is evolving. Whilemany studies have shown improvementin steatosis, there are neither long-term

studies to determine whether they alterthe natural history of thedisease nor stud-ies to indicate whether relapse occurs af-ter treatment withdrawal. Gemfibrozil(145), vitamin E (146), metformin (8891), betaine (147), pioglitazone (9296),rosiglitazone (97), atorvastatin (120,121), losartan (128), orlistat (148), and

pentoxifylline (149) have all been triedand have all been shown in small trials toimprove liver enzymes. Modest histologicimprovement over 612 months is seenwith some of the agents. Long-term out-come trials with the various treatmentmodalities are yet to be completed.

Given that insulin resistance is centralto the pathogenesis of NAFLD, insulin-sensitizing agents should have utility(even in the absence of diabetes), andthere is increasing evidence that they do(8090,9297). Five studies using piogli-

tazone from 16 to 48 weeks have beenpublished, and a large multicenter place-bo-controlled trial is near completion(94). All have shown improvement in se-rum ALT and most in histology (9296).One study showed an increase in adi-ponectin, a decrease in A1C, enhancedinsulin sensitivity, and improved hepatichistologyincluding steatosis, inflammation,and fibrosis (150). There have been threetrials including a placebo-controlled trialwith rosiglitazone (97,151,152). A 24-week study with rosiglitazone showedhistologic improvement (97). In another

study of 30 patients treated with rosigli-tazone 8 mg/day for 48 weeks, there wassignificant improvement in ALT, AST,-glutamyl transferase, and insulin sensi-tivity. Of the 22 patients who had histo-logic evaluation, steatosis improved in 13,and fibrosis improved in 8 (152). Thisstudy was confounded by the use of st-atins. Interestingly, in the recently pre-sented French multicenter trial known asFLIRT (French Multicenter Trail), 50%of the patients had ALT and/or histologicimprovement, but nondiabetic patients

were more likely than diabetic patients torespond (153).Metformin has shown mixed results

in human trials (8891) with some im-provement in ALT but not in histology.Two long-term trials initiated by the Na-tional Institutes of Health are underway.

At this time, treatment with metformin isnot recommended outside of clinical tri-als. In the meantime, it seems reasonableto treat patients with NASH and type 2diabetes with TZDs, recognizing that thepatients may gain weight. In the absenceof a histologic diagnosis of NASH, only

those with risk factors for progressive dis-ease as mentioned above should betreated. TZDs, despite shortcomings, areemerging as the treatment of choice evenin the absence of diabetes.

Three prospective controlled studiesusing ursodeoxycholic acid, which re-duces apoptosis and has cytoprotective

properties, have been conducted. The re-sults have been mixed (121,154,155).There is increasing interest in this agentbecause of its antiapoptotic effect as non-specific or add-on therapy.

Statins may reducehepatic fat contentin patients with hyperlipidemia andNASH (120,121). Atorvastatin and ur-sodeoxycholic acid were evaluated in asmall comparative trial of 44 obese adultswith NASH, including 10 patients withdiabetes. Normolipidemic patients re-ceived ursodeoxycholic acid, 1315 mg

kg

1

day

1

, and hyperlipidemic pa-tients received atorvastatin, 10 mg dailyfor 6 months. Liver chemistries improvedin both groups; however, an increase inliver density, suggesting a decrease in fatcontent, occurred only in the atorvastatingroup.

Oxidative stress has been shown to beimportant in the pathogenesis of NASH. Itseems reasonable, therefore, to try ther-apy with antioxidants. Pilot studies withv i t a m i n E h a v e b e e n c o n d u c t e d(146,156158) with promising results,but a meta-analysis of high-dose vitamin

E revealed an increase in overall mortality(159).

TNF- is proinflammatory and in-creased in NASH. Pentoxifylline is amethylxanthine compound that inhibitsTNF-. It is used in the treatment of alco-holic hepatitis. A pilot study (149) hasshown improvement in liver enzymes inpatients with NASH. However, the highincidence of side effects led to early with-drawal in many patients, and it seems un-likely that it will find a place in thetreatment of NASH.

In summary, the ideal therapy forNAFLD is yet to be identified, and no ev-idence-based recommendations can bemade. Outside of clinical trials, therapyshould be directed toward the underlyingetiology.Hepatitis C. The most effective treat-ment of HCV is a combination of pegy-lated -interferon and ribavirin (160).Interferon, however, affects insulin sensi-tivity and glucose tolerance. Studies innondiabetic patients report that inter-feron impairs glucose tolerance (161163). A recent trial, however, failed to




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detect a difference in insulin sensitivityand glucose tolerance after 6 months ofinterferon treatment (164), while anotherstudy reported that fasting plasma glu-cose and fasting immunoreactive insulindecreased during interferon treatment(72). The practical implications of the ob-served changes in glucose homeostasis in

patients being treated with interferon arenot known. Given the unpredictable ef-fect of interferon in diabetes, it is reason-able to monitor diabetes carefully whenusing interferon.

SUMMARY Type 2 diabetes is as-sociated with a large number of liver dis-orders including elevated liver enzymes,fatty liver disease, cirrhosis, hepatocellu-lar carcinoma, and acute liver failure. Inaddition, there is an unexplained associa-tion with HCV. The SMR for cirrhosis is

higher than that for CVD in type 2 diabe-tes. Many consider NAFLD to be part ofthe insulin resistance syndrome. How-ever, the presence of liver disease (unlessdecompensated) has little implication forthe specific treatment of diabetes, and thepresence of diabetes has little implicationfor the specific treatment of liver disease.Patients with decompensatedliver diseasearemore susceptible to hypoglycemiaandrequire careful monitoring. There contin-ues to be a need for long-term placebo-controlled trials for the treatment ofNAFLD and for the treatment of diabetesin patients with liver disease.

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