507239

research-article2013

AOPXXX10.1177/1060028013507239Riche et alAnnals of Pharmacotherapy

Case Report

Resistant Nonalcoholic Fatty Liver Disease Amelioration With Rosuvastatin and Pioglitazone Combination Therapy in a Patient With Metabolic Syndrome

Annals of Pharmacotherapy 2014, Vol. 48(1) 137­–141 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013507239 aop.sagepub.com

Daniel M. Riche, PharmD1,2, Joshua W. Fleming, PharmD1, Scott S. Malinowski, PharmD1, Catherine A. Black, PharmD3, Kristen H. Miller, MD2, and Marion R. Wofford, MD, MPH2

Abstract Objective: To report a case describing resolution of persistently elevated aminotransferases in a patient with severe, resistant nonalcoholic fatty liver disease (NAFLD) using combination therapy. Case Summary: A 47-year-old obese male patient presented with a history of elevated aminotransferases and numerous statin intolerances. In addition to worsening control of diabetes and dyslipidemia, severe NAFLD was confirmed. Rosuvastatin was started, which induced short-term elevations in aminotransferases resulting in patient discontinuation. Biochemical markers of NAFLD worsened over time. Therefore, both rosuvastatin 20 mg daily and pioglitazone 15 mg daily were started simultaneously to potentially blunt the early increase in transaminases seen with rosuvastatin. At 2 weeks, the patient’s alanine aminotransferase (ALT) and aspartate aminotransferase (AST) had decreased 57% and 56% from baseline, respectively. By 9 months, the patient’s ALT and AST serum concentrations had normalized. Repeat liver ultrasound demonstrated improvement in steatosis grading and reduction in liver size. These improvements occurred despite a 4.5-kg weight gain since starting rosuvastatin and pioglitazone. Discussion: Pharmacotherapy in NAFLD is not well validated, particularly combination therapy. Medications that target obesity-related consequences are commonly used, although evidence regarding biochemical and histological improvement is inconclusive. Consideration should be given to the use of combination of thiazolidinediones and statins for rapid biochemical improvement and long-term histological impact. Conclusions: The improvement in this patient’s biochemical and ultrasonographic markers of resistant, severe NAFLD was rapid and sustained with combination therapy. This case represents a potential solution for initiating or maintaining statin therapy in patients with NAFLD who are at high cardiovascular risk. Keywords fatty liver, NAFLD, pioglitazone, antioxidants, statin

Introduction Nonalcoholic fatty liver disease (NAFLD) is the accumulation of lipids in hepatocytes causing steatosis. NAFLD is one of the most common causes of elevated aminotransferases, affecting up to 46% of adults in the general population and up to 75% of patients considered to be obese.1 NAFLD can double the risk of cardiovascular disease (CVD) mortality independent of common comorbid conditions, including metabolic syndrome. Obesity is the primary risk factor for NAFLD followed by type 2 diabetes mellitus (DM2), atherogenic dyslipidemia, and advanced age.2,3 Patients are typically asymptomatic but can exhibit mild generalized symptoms (eg, malaise and fatigue).1

The most effective treatment for NAFLD, particularly in obese patients, is weight loss, with a goal of 7% weight reduction.4 In addition to lifestyle intervention, a variety of pharmacological agents (eg, statins, thiazolidinediones, metformin, and vitamin E) have been studied in the treatment of NAFLD, with varying results.5 Unfortunately, 1

University of Mississippi, Jackson, MS, USA University of Mississippi Medical Center, Jackson, MS, USA 3 Walgreen’s, Nashville, TN, USA 2

Corresponding Author: Daniel M. Riche, PharmD, University of Mississippi Medical Center, 2500 North State Street, PH225, Jackson, MS 39216-4505, USA. Email: [email protected]

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combination pharmacological therapies that target comorbid conditions (eg, obesity, hyperlipidemia, and DM2) are lacking robust evidence.5 It is well known that the mainstay of pharmacotherapy for lipid disorders is statins, but many providers shy away from using statins in patients with transient, mild aminotransferase elevations (3 times the upper limit of normal). Gastroenterology worked the patient up for potential causes of liver abnormalities. This evaluation included a hepatitis panel, antimitochondrial antibody, ceruloplastin, α-antitrypsin 1, and iron studies, which were all normal. Liver ultrasound was performed confirming severe NAFLD.10 At the next clinic appointment, the patient was started on a trial of vitamin E at a recommended dose of 800 international units daily. After approximately 12 months on vitamin E, the patient showed no improvement in aminotransferases and presented with a low-density lipoprotein (LDL) level of 217 mg/dL, an alanine aminotransferase (ALT) of 148 U/L, and an aspartate aminotransferase (AST) of 88 U/L.

Table 1.  Laboratory Values for the Patient With NAFLD.

Weight (kg) BMI (kg/m2) LDL (mg/dL) HDL (mg/dL) TG (mg/dL) Hemoglobin A1c (%) AST (U/L) ALT (U/L)

Preintervention (April 8, 2011)

Postintervention (February 20, 2012)

139 37.3 217 23 173 9.2 146 88

143.2 38.3 101 35 99 7.2 29 38

Abbreviations: NAFLD, nonalcoholic fatty liver disease; BMI, body mass index; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglycerides; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

After pharmacist and physician risk-benefit counseling, the patient agreed to a trial of rosuvastatin 20 mg and pioglitazone 15 mg, and all other medications including vitamin E and fish oil were continued. At 2 weeks, the patient’s ALT and AST decreased to 63 U/L and 39 U/L, respectively. The patient was satisfied with the results and continued the regimen, ultimately leading to a 2.2% hemoglobin A1C reduction, a 58% lowering of LDL, and stabilization of ALT and AST serum concentrations at 3 months (see Table 1 and Figure 1). ALT and AST serum concentrations normalized to 38 U/L and 29 U/L, respectively, 9 months after starting rosuvastatin and pioglitazone. Additionally, a repeat liver ultrasound demonstrated improvement in steatosis grading from severe to moderate-severe as well as a reduction in size over the right upper lobe by 0.55 cm.10 These improvements occurred despite a 4.5-kg weight gain (not related to fluid retention) since starting rosuvastatin and pioglitazone, excluding weight loss as a reason for improvement in NAFLD.

Discussion The treatment with the strongest evidence for a NAFLD patient is targeted lifestyle modifications, emphasizing diet and exercise.3 Unfortunately, this patient was unwilling or unable to make sufficient changes to diet and exercise to achieve meaningful weight reduction. We considered pharmacological agents that targeted NAFLD, and addressed individualized metabolic syndrome components. The patient presented in this case report had persistent elevations in AST and ALT serum concentrations despite being treated with olmesartan and metformin—therapies that have been used to treat NAFLD.11,12 In this patient olmesartan and metformin were being used for blood pressure and diabetes, respectively, long before development of NAFLD, thus likely having little bearing on improving his

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Figure 1.  Aminotransferase response to pharmacological intervention. Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase.

aminotransferases. Vitamin E was chosen as an initial attempt to improve AST and ALT because it has demonstrated improvements in histological composite scores versus placebo.12 Despite the clinical trial evidence, vitamin E therapy in this patient for more than 12 months with questionable adherence had resulted in no improvement in aminotransferases. Given this patient’s past medical history, our primary treatment goal was reduction of CVD risk with a statin; however, the patient was refusing a statin based on his previous intolerances to statins. In the presence of elevated aminotransferases secondary to NAFLD, many health care providers and patients are hesitant to initiate statin therapy regardless of indication. Studies in patients with elevated baseline aminotransferases and suspected NAFLD have shown no significant differences in the incidence and magnitude of elevated aminotransferases between statin users and nonusers.13,14 The United States Food and Drug Administration has provided further support for the safety of statins with a recent product information change recommending aminotransferase monitoring only at baseline and as clinically indicated rather than routinely. This change reflects the published literature, which reports that serious hepatotoxicity is rare and unpredictable in patients on statin therapy.15

Because hypercholesterolemia plays a major role in NAFLD, several statins have been evaluated for use in treatment of NAFLD.5 In general, statins have not been associated with consistent improvement on the basis of ultrasonic evidence related to NAFLD.16,17 Rosuvastatin 10 mg has demonstrated an approximate 45% to 47% improvement in aminotransferase within 2 months and normalization within 8 months in a small, prospective study.18 Prior to referral to our clinic, our patient experienced an increase in aminotransferases with rosuvastatin monotherapy (see Figure 1). Though AST began to decrease, ALT continued to rise, resulting in rosuvastatin discontinuation after 6 months. Pioglitazone has shown mixed results as monotherapy in the treatment of NAFLD. In a long-term randomized trial in nondiabetic patients, pioglitazone reduced AST by approximately 20 U/L and ALT by 35 U/L within 24 weeks at a dose of 30 mg per day. In addition, there was improved insulin sensitivity and improved steatohepatitis, but there was no improvement in fibrosis score compared with placebo.12 When studied in patients with impaired glucose tolerance or DM2, pioglitazone demonstrated similar improvements with an approximate 20 U/L and 37 U/L decrease in AST and ALT, respectively, within 24 weeks at

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a dose of 45 mg/d. Additional benefits included improved hepatic insulin sensitization as well as reduction in hepatic fat content with pioglitazone compared with placebo.19 In our patient, with a primary goal of CVD risk reduction, initiation of a statin was thought to be prudent. We elected to use rosuvastatin 20 mg because we needed >50% reduction in LDL to achieve his goal of

Resistant nonalcoholic fatty liver disease amelioration with rosuvastatin and pioglitazone combination therapy in a patient with metabolic syndrome.

To report a case describing resolution of persistently elevated aminotransferases in a patient with severe, resistant nonalcoholic fatty liver disease...
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