Insulin Resistance and Microalbuminuria Are Associated with Microvascular Disease in Patients with Cirrhosis

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1 LIVER TRANSPLANTATION 15: , 2009 ORIGINAL ARTICLE Insulin Resistance and Microalbuminuria Are Associated with Microvascular Disease in Patients with Cirrhosis Karen L. Krok, 1,2 Farida Milwalla, 1,2 Anurag Maheshwari, 1,2 Rebecca Rankin, 1,2 and Paul J. Thuluvath 2,3 1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; 2 Institute for Digestive Health and Liver Disease, Mercy Medical Center, Baltimore, Maryland; and 3 Departments of Surgery and Medicine, Georgetown University School of Medicine, Washington, DC Cardiovascular (CV) disease has a significant impact on post liver transplantation (LT) survival. Finding surrogate markers for occult CV disease would improve CV assessment in the LT evaluation. This study was designed to determine the prevalence of microvascular disease (MVD) and the utility of both microalbuminuria and the homeostatic model for insulin resistance (HOMA-IR) for assessing the presence of MVD in potential LT recipients. In this study, we examined the prevalence of MVD in 72 diabetics and 71 nondiabetics; both groups were matched for age, sex, race, and etiology of cirrhosis while awaiting LT. We prospectively collected data including fasting serum insulin and glucose levels, urine creatinine and microalbumin, and macrovascular and microvascular complications. MVD was present in 58 (40.5%) patients; MVD was more common in diabetics (n 45, 62.5%) than nondiabetics (n 13, 18.3%). The presence of diabetes mellitus (DM; P 0.03), insulin use (P 0.002), and duration (months) of DM ( versus , P ), hypertension ( versus , P 0.03), and hypertriglyceridemia ( versus , P 0.04) were associated with MVD. Significant microalbuminuria had a sensitivity of 85%, a specificity of 100%, and a positive predictive value of 100% for the presence of MVD. HOMA-IR also was associated with MVD (P ). In conclusion, at our center, 62.5% of DM patients and 18% of non-dm patients awaiting LT have MVD. Patients with DM, significant microalbuminuria, or an elevated HOMA-IR should undergo rigorous CV assessment prior to LT. Liver Transpl 15: , AASLD. Received November 21, 2008; accepted March 25, Cardiovascular (CV) disease has a significant impact on the long-term survival of patients after liver transplantation (LT). Between 2% and 21% of patients will die of a CV event if they survive more than 1 year after transplantation. 1-3 In most series, CV disease is the third most common cause of death after LT, behind only recurrence of the primary disease/chronic rejection and malignancy. 1,2,4 The incidence of CV-related events and deaths is more common in LT recipients than a matched nontransplant population. 3,5 After LT, CV risk factors, including hyperlipidemia, hypertension, obesity, and diabetes mellitus (DM), are more prevalent. 3,6-11 We have previously shown that, in comparison with nondiabetic post-lt patients, the development of new onset DM after transplantation is associated with an increased risk of cardiac (47.8% versus 23.9%) and vascular complications (15.2% versus 5.4%). 12 Additionally, the presence of pretransplant DM is associated with significantly lower long-term patient and graft survival. 13,14 Despite the thorough CV screening that patients with DM undergo prior to transplant, there is this increase in CV morbidity and mortality that is most likely related to occult microvascular disease (MVD), which is not detected with the standard CV screening methods employed by transplant centers. Abbreviations: Alb, albumin; BMI, body mass index; CAD, coronary artery disease; Cr, creatinine; CV, cardiovascular; DM, diabetes mellitus; ESLD, end-stage liver disease; HBV, hepatitis B virus; HCV, hepatitis C virus; HOMA-IR, homeostatic model for insulin resistance; HTN, hypertension; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; MVD, microvascular disease; NASH, nonalcoholic steatohepatitis; NS, not significant; PVD, peripheral vascular disease; TIA, transient ischemic attack. Karen L. Krok is a recipient of the American Association for the Study of Liver Diseases Advanced Hepatology Fellowship. Address reprint requests to Paul J. Thuluvath, M.D., F.R.C.P., Institute for Digestive Health and Liver Disease, Mercy Medical Center, #718, 301 St. Paul Place, Baltimore, MD Telephone: ; thuluvath@gmail.com DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 INSULIN RESISTANCE AND MICROALBUMINURIA 1037 As the overall survival rate for LT has improved to almost 80% at 5 years, it is important to assess a patient s long-term survival prior to transplantation. DM and coronary artery disease (CAD) are closely associated with each other, and the combination of these 2 diseases incurs even greater post-lt mortality. 14 The aim of our current study was to determine whether the microalbuminuria ratio and the homeostatic model for insulin resistance (HOMA-IR) could be used as surrogate markers to predict CV disease prior to LT in a more objective manner. PATIENTS AND METHODS Patients All patients referred to the Johns Hopkins Hospital for LT evaluation between October 2005 and July 2007 were eligible for enrolment. We prospectively enrolled 143 patients, 72 with DM and 71 without DM, in this study. Both groups were matched on the basis of age ( 4 years), sex, race, and etiology of liver disease. During this period, 118 LT procedures were performed at our institution. A patient was considered to have DM if he was currently taking insulin or an oral hypoglycemic agent, if he was carrying a diagnosis of DM that was being controlled by diet, or if he had a fasting serum glucose level 126 mg/dl on 2 separate occasions. Inclusion criteria included age 21 years and cirrhosis as confirmed by clinical, imaging, biochemical, or histological parameters. Exclusion criteria included age 21 years, being positive for human immunodeficiency virus, the presence of hepatocellular carcinoma, being on hemodialysis, and being on an insulin pump. Although we attempted to include all potential recipients, we could not do this for many reasons; a few patients were not seen in the transplant clinic, a few were not obvious transplant candidates, and a few had exclusion criteria. We also excluded a few patients as we were trying to get equal numbers of diabetics and nondiabetics in our cohort for long-term follow-up studies. The following demographic and clinical data were obtained from all patients by both chart review and direct questioning: age, gender, race, body mass index, etiology of liver disease, duration of end-stage liver disease, and date of first decompensation. The existence of MVD, defined as the presence of neuropathy, retinopathy, or nephropathy, was ascertained. We assessed each of the components in the definition of MVD as follows. For retinopathy, patients were asked if they had seen an ophthalmologist and if they had laser treatment or were told that they had any evidence of retinopathy. We relied mostly on patients reports. For neuropathy, we did not perform monofilament testing on patients as part of this protocol, but they were asked a battery of questions to determine if they had symptoms of peripheral neuropathy. We could have missed subclinical neuropathy by this method. For nephropathy, if a patient had seen a nephrologist, we examined his report and noted if the nephrologist had stated that the patient had evidence of diabetic nephropathy. Otherwise, as in the majority of patients, we based the definition of nephropathy on the presence of proteinuria [microalbuminuria 30 mg of albumin (Alb)/g of creatinine (Cr)], regardless of the baseline Cr. We did not use baseline Cr to diagnose nephropathy as Cr may be elevated for many reasons in patients with end-stage liver disease, such as hepatorenal syndrome, which would not produce microalbuminuria. Limitations of these definitions are discussed later. CV risk factors were assessed by the determination of the following: duration of DM, need for insulin, family history of DM, family history of premature CAD (for men, 55 years, and for women, 65 years), history and duration of hypertension, tobacco use and packyear history, history and duration of hyperlipidemia, and history and duration of hypertriglyceridemia. In addition to these data, patients were asked if they had a history of any macrovascular complications (stroke, transient ischemic attack, CAD, and peripheral vascular disease). Laboratory tests including the fasting serum insulin level, Alb, Cr, blood urea nitrogen, fasting glucose, international normalized ratio, total bilirubin, and hemoglobin A1c were done prospectively. We used the fasting insulin and fasting glucose to determine the HOMA-IR score [fasting glucose (mg/dl) fasting insulin ( U/ ml)/405]. Urine Cr and microalbumin were obtained in order to calculate the Alb/Cr ratio. Significant microalbuminuria was defined as a ratio 30 mg of Alb/g of Cr. Statistical Analysis Data were compared with the Wilcoxon-Mann-Whitney test for continuous variables and the chi-square test or Fisher s exact test for categorical variables. Logistic regression was used to identify independent predictors for microvascular MVD in all patients (diabetics and nondiabetics). A P value 0.05 was considered statistically significant. All confidence intervals are given as 95%. Results are expressed as the mean standard deviation or frequency or median as appropriate. Cases with missing data for any particular measurement were omitted from analyses involving that measurement. The data analysis was generated with SAS software, version 9.1.3, of the SAS System for Windows (SAS Institute, Inc.). Institutional Board Approval The study was approved by the institutional review board at the Johns Hopkins School of Medicine (reference number NA_ ). RESULTS One hundred forty-three patients (male/female 79/ 64) with a mean age of (range, 26-73) years were enrolled during the study period. The majority were Caucasian (113 patients or 79.02%), but the cohort included 23 (16.1%) African Americans, 5 (3.5%)

3 1038 KROK ET AL. Hispanics, and 2 (1%) classified as other. Sixty-one patients (42.7%) had hepatitis C virus (HCV) cirrhosis, 24 patients (16.8%) had alcohol-induced cirrhosis, 17 patients (11.9%) had HCV- and alcohol-induced cirrhosis, 8 patients (5.6%) had an autoimmune cause for their cirrhosis (autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis), 31 patients (21.7%) had either nonalcoholic steatohepatitis or cryptogenic cirrhosis, and 2 patients (1.4%) had chronic hepatitis B. Significant microalbuminuria ( 30 mg of Alb/g of Cr) was seen in 18 (25%) patients with DM and 9 (12.7%) without DM. As expected, HOMA-IR was higher in DM patients compared to non-dm patients ( versus ); HOMA-IR was between 2 and 3.9 in 15 patients with DM and in 21 patients without DM and 4 in 55 patients with DM and in 33 patients without DM. A significant proportion (46.5%) of non-dm patients had marked insulin resistance (HOMA-IR 4) as measured by HOMA-IR. Microvascular Complications MVD, defined as the presence of neuropathy (n 38), retinopathy (n 15), or nephropathy (n 29), was present in 58 (40.6%) patients; 45 (31.5%) patients with DM and 13 (9.1%) without DM had MVD. More than 1 microvascular complication was seen in 24 patients. Characteristics of patients with and without MVD are listed in Table 1. As would be expected, MVD was more common in patients with DM (P 0.03). The duration (months) of DM ( versus , P ), hypertension ( versus , P 0.03), and hypertriglyceridemia ( versus , P 0.04) was significantly associated with the presence of MVD, as was the need for insulin to treat DM (P 0.002). In the entire cohort of patients, a hemoglobin A1c level 7.0% was associated with a lower prevalence of MVD. Caucasians and those with alcohol-related liver disease or autoimmune disease were less likely to have MVD (Table 1). HCV did not incur any increased risk for the presence of MVD unless the patient also had DM. In fact, the only 2 liver diseases that were associated with MVD in patients without DM were nonalcoholic steatohepatitis and cryptogenic cirrhosis (P 0.007; Table 2). In the entire cohort of patients, a low serum Alb ( versus g/dl, P 0.03), elevated Cr ( versus mg/dl, P 0.002), and elevated blood urea nitrogen ( versus mg/dl, P ) were independent risk factors associated with MVD (Table 1). When the diabetic patients were examined separately, only elevated Cr ( versus mg/dl, P 0.05) remained significant, whereas in the nondiabetic population, all 3 laboratory abnormalities continued to represent an increased prevalence of MVD (Table 2). There was no association between the Model for End-Stage Liver Disease score and the risk of MVD (P 0.11). DM was present in 72 (50.3%) patients (Table 2). Diabetes was a significant risk factor for MVD (P 0.03). In patients with DM, HCV was an additional risk factor for the presence of MVD (P 0.006). Patients who required insulin (P 0.002) and patients with both DM and hypertension (P 0.02) or hypertriglyceridemia (P 0.05) had a higher prevalence of MVD. In patients with DM, the presence of a significant microalbuminuria ratio (P ) or an elevated HOMA-IR (P 0.048) predicted the presence of MVD. When patients with retinopathy (n 15) were analyzed separately, an elevated microalbuminuria ratio was significantly higher in this group in comparison with those (n 128) without retinopathy ( versus , P 0.002). Macrovascular Complications Macrovascular complications were defined as a history of stroke, transient ischemic attack, CAD, or peripheral vascular disease. Most patients with macrovascular complications had DM (15/19, 79%), and a majority of patients with macrovascular complications (14/19, 74%) also had MVD. It is important to note that there were very few patients in this study with macrovascular disease secondary to the selective nature of this population; patients with significant macrovascular disease generally are excluded from transplant evaluation. For this reason, we cannot postulate on the use of the microalbuminuria ratio and HOMA-IR as surrogate markers for the presence of macrovascular complications. Microalbuminuria and MVD Significant microalbuminuria ( 30 mg of Alb/g of Cr) had a sensitivity of 85% and a specificity of 100% for the presence of MVD, with a positive predictive value of 100% (P ). This was true in both the diabetic and nondiabetic populations (Table 2). The average values for the microalbuminuria ratio in patients with and without MVD were and g/ml, respectively (P ). More importantly, a microalbuminuria ratio 20 mg of Alb/g of Cr was predictive of the absence of MVD in patients without DM (P 0.001) but not in patients with DM (P 0.47). HOMA-IR and MVD An elevated HOMA-IR was associated with the presence of MVD [ ( 7.8) versus ( 4.2), P ] when the entire cohort was included. DISCUSSION In this study, we prospectively evaluated 143 patients presenting to our institution for an LT evaluation and assessed them for CV disease risk factors and the presence of MVD. MVD was present in 40.5% of our patients, and 18.9% (25% with DM and 12.7% without DM) had significant microalbuminuria. We found that the presence of DM alone should be enough to encourage the physician to more aggressively screen for CV disease, as MVD and macrovascular complications were present in 62.5% and 20.8% of patients with dia-

4 INSULIN RESISTANCE AND MICROALBUMINURIA 1039 TABLE 1. Demographic Data for Patients With and Without MVD MVD Present (n 58) MVD Absent (n 85) P Value Age NS Male/female 32/26 47/ Race Caucasian Black Other 2 5 BMI , , 28.4 NS Etiology HCV Alcohol HCV alcohol NASH/cryptogenic HBV Autoimmune diseases Duration of ESLD (months) NS Diabetes present Duration of diabetes (months) Family history of diabetes NS Family history of CAD NS Insulin required Diabetes control HgbA1C 7.0% HgbA1C % HgbA1C 8.5% Macrovascular complications Stroke TIA CAD PVD HTN present NS Duration of HTN (months) Hyperlipidemia present 8 9 NS Duration of hyperlipidemia (months) NS Hypertriglyceridemia present 12 7 NS Duration of hypertriglyceridemia (months) Pack years of tobacco use Microalbuminuria ratio 0-19 mg of Alb/g of Cr mg of Alb/g of Cr mg of Alb/g of Cr HOMA-IR , , Serum Alb (g/dl) Serum Cr (mg/dl) MELD score Abbreviations: Alb, albumin; BMI, body mass index; CAD, coronary artery disease; Cr, creatinine; ESLD, end-stage liver disease; HBV, hepatitis B virus; HCV, hepatitis C virus; HgbA1C, hemoglobin A1c; HOMA-IR, homeostatic model for insulin resistance; HTN, hypertension; MELD, Model for End-Stage Liver Disease; MVD, microvascular disease; NASH, nonalcoholic steatohepatitis; NS, not significant; PVD, peripheral vascular disease; TIA, transient ischemic attack. betes, respectively. The presence of an elevated microalbuminuria ratio ( 30 mg of Alb/g of Cr) was an important surrogate marker for the presence of MVD. A significant proportion (46.5%) of patients without known DM had evidence of marked insulin resistance as assessed by HOMA-IR. It is well established that microalbuminuria is associated with an increased risk of all-cause mortality (hazard ratio of 1.48) and mortality from CV disease (hazard ratio of 2.03) in patients without liver disease Moreover, prospective studies have shown that the presence of significant microalbuminuria may identify patients at the greatest risk of fatal CV events along with the conventional CV risk factors (DM, hypertension, family history, age, and tobacco use). However, until this study, it was not known whether microalbuminuria could predict vascular disease in patients with chronic liver diseases. Although our study was not designed to assess mortality, we found that patients with cirrhosis with significant microalbuminuria ( 30 mg of

5 1040 KROK ET AL. TABLE 2. Demographic Data for Patients Based on Both the Presence and Absence of Diabetes Mellitus and MVD Diabetes Present Diabetes Absent MVD Present (n 45) MVD Absent (n 27) P Value MVD Present (n 13) MVD Absent (n 58) P Value Age NS NS Male/female 25/20 13/14 7/6 34/24 Race Caucasian Black/other 8/2 2/2 NS 4/0 9/3 NS BMI NS NS Etiology HCV Alcohol HCV alcohol NASH/cryptogenic HBV Autoimmune diseases HCV present Duration of ESLD (months) NS NS Duration of diabetes (months) Family history of diabetes Family history of CAD Diabetes control HgbA1C 7.0% HgbA1C % HgbA1C 8.5% Macrovascular complications NS Stroke TIA CAD PVD HTN present Duration of HTN (months) NS NS Hyperlipidemia present Duration of hyperlipidemia (months) Hypertriglyceridemia present Duration of hypertriglyceridemia (months) NS NS Pack years of tobacco use NS NS Microalbuminuria ratio 0-19 mg of Alb/g of Cr mg of Alb/g of Cr mg of Alb/g of Cr HOMA-IR , , , , Serum Alb (g/dl) Serum Cr (mg/dl) MELD score Abbreviations: Alb, albumin; BMI, body mass index; CAD, coronary artery disease; Cr, creatinine; ESLD, end-stage liver disease; HBV, hepatitis B virus; HCV, hepatitis C virus; HOMA-IR, homeostatic model for insulin resistance; HTN, hypertension; MELD, Model for End-Stage Liver Disease; MVD, microvascular disease; NASH, nonalcoholic steatohepatitis; NS, not significant; PVD, peripheral vascular disease; TIA, transient ischemic attack. Alb/g of Cr) had a higher risk of MVD. A urine microalbumin/cr ratio 30 mg of Alb/g of Cr had a positive predictive value of 100% for the presence of MVD, with a sensitivity of 85% and a specificity of 100%. Additionally, 6 of 8 patients (75%) with moderate microalbuminuria (ratio 20 mg of Alb/g of Cr but 30 mg of Alb/g of Cr) had MVD, and this suggests that even these patients should be screened more aggressively for serious CV diseases. In patients with DM, the presence of significant microalbuminuria alone was sufficient to predict MVD. The use of HOMA-IR for assessing MVD is a novel approach in patients prior to LT. HOMA-IR is a method used to quantify insulin resistance and beta-cell func-

6 INSULIN RESISTANCE AND MICROALBUMINURIA 1041 tion in patients with and without liver disease; a score 4 denotes significant insulin resistance. Insulin resistance plays a primary role in the development of type 2 DM and can precede the onset of DM by 10 to 20 years. 18 Multiple studies have used the HOMA-IR to assess for insulin resistance in patients with HCV and nonalcoholic steatohepatitis, as both HCV and fatty liver disease are associated with the development of insulin resistance. 19,20 In our study, 46.5% of our patients without established DM had significant insulin resistance (HOMA-IR 4). Determining CV risk prior to LT is extremely important as the presence of CV disease has a significant impact on outcomes after LT. Multiple studies have found that between 2% and 21% of patients will die of a CV event if they survive more than 1 year after transplant. 1-3 Even more patients (up to 24%) will have a nonfatal CV event after LT. 21 Interestingly, there are more CV-related events and deaths in LT recipients than in a matched nontransplant population despite pretransplant screening and surviving a major surgery such as LT. 3,5 The accelerated rate of macrovascular complications in patients after LT probably is multifactorial. Many of these patients may have occult disease prior to LT, as shown in our study. Obesity and hyperlipidemia are 2 other major risk factors in this group. About 20% of patients undergoing LT are severely or morbidly obese prior to LT, and a significant number (approximately 25%) of nonobese patients will become obese within 3 years after LT. 22,23 Immunosuppression (steroids, calcineurin inhibitors, and sirolimus) causes hyperlipidemia, often by direct effects on cholesterol synthesis. In 1 series, posttransplant metabolic syndrome was present in 69 of 188 patients (58%), with an increased risk of vascular complications in the posttransplant metabolic syndrome group (30% versus 8%, respectively, P 0.003) in comparison with the non metabolic syndrome group. 24 For these reasons, it is important to screen patients for CV disease aggressively prior to LT. Unfortunately, the current methods of screening, including stress echocardiogram, do not adequately detect microvascular or macrovascular disease In this exploratory study, we have shown that HOMA-IR and the microalbuminuria ratio are good surrogate markers for MVD. These inexpensive tests could be used in clinical practice to risk-stratify patients prior to LT. In our study, as in the general population, the presence of MVD strongly predicted the presence of macrovascular disease. Patients who present to transplant evaluation with a history of myocardial infarction, CAD, or stroke or the classic symptoms of peripheral vascular disease obviously need to be assessed aggressively for the presence of significant CV disease. Additionally, we believe that an elevated microalbuminuria ratio could predict those who are at high risk of vascular disease. These patients should undergo rigorous pretransplant assessment and treatment as appropriate. There are a few caveats to our observations. We could not assess the use of HOMA-IR or microalbuminuria in patients with end-stage liver disease and macrovascular complications, as we had only a small number of patients with any macrovascular disease (19/143). This was a selected population of patients being referred for LT evaluation, and we presume that most patients with significant CAD, peripheral vascular disease, or a history of a stroke were not referred or evaluated for LT. In addition, we based our observations on the basis of a history of retinopathy or neuropathy, and we did not objectively document the presence of retinopathy and neuropathy. More importantly, significant microalbuminuria is considered a sign of MVD by convention, but this may not be applicable to this patient population. Similarly, neuropathy is common in liver disease and may be multifactorial in origin. 28 These are some of the major limitations of this study. As expected, microalbuminuria was significantly higher in the subgroup with retinopathy than in those without retinopathy. Future studies should prospectively evaluate whether there is an association between pretransplant and posttransplant morbidity and mortality and HOMA-IR and microalbuminuria. To our knowledge, this is the first study that has assessed the role of HOMA-IR and the microalbuminuria ratio in predicting the presence of MVD in a pre-lt population. On the basis of this study, we recommend assessing the microalbuminuria ratio and HOMA-IR in all patients undergoing LT evaluation, even in the absence of DM. In patients undergoing LT evaluation, the presence of an elevated microalbuminuria ratio or an elevated HOMA-IR alone is an excellent marker for MVD. All patients with a microalbuminuria ratio should be more rigorously screened for CV disease prior to LT and be more aggressively treated for CV risk factors before and after LT. The rigorous screening may include carotid duplex, adequate dobutamine stress echo, coronary calcium score, coronary computed tomography (CT) angiography, or cardiac catheterization. This approach may reduce posttransplant morbidity and mortality in patients undergoing LT, especially those with DM and other high-risk patient populations. 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