CORRESPONDENCE Need for a Three-Focused Approach to Nonalcoholic Fatty Liver Disease To the Editor: We read with interest the reviews by Ghouri et al.1 and Martinez et al.2 Ghouri et al. analyzed the association of nonalcoholic fatty liver disease (NAFLD) with cardiovascular disease (CVD) and concluded that although a diagnosis of NAFLD should prompt diabetes screening, it is insufficient for considering patients to be at high risk for CVD. Martinez et al. evaluated noninvasive methods for assessing liver fibrosis and recommended that those tests with the highest diagnostic accuracy be validated against liver biopsy to facilitate their implementation in clinical practice. We meta-analyzed prospective data regarding the natural history of NAFLD and studies assessing the diagnostic accuracy of noninvasive methods for liver disease severity against liver biopsy in NAFLD, and we reached the following conclusions3: 1. The two NAFLD histological subtypes, simple steatosis (SS) and nonalcoholic steatohepatitis (NASH), have different risks of liver-related complications: SS progresses to cirrhosis in less than 5% of cases; NASH progresses to cirrhosis in 10% to 15% of cases over 10 years and in 25% to 30% of cases in the presence of advanced fibrosis.3 2. NAFLD patients have a 1.44- to 2.05-fold higher rate of CVD (depending on whether the diagnosis is based on an aminotransferase elevation or radiological/histological criteria) than the general population; restricting the analysis to studies adjusting for metabolic syndrome did not change the risk. Importantly, CVD mortality did not differ among NAFLD histological subtypes.3 3. NAFLD conveys a 2-fold increased risk of developing diabetes in comparison with the general population3; restricting the analysis to studies adjusting for metabolic syndrome did not change the risk. Whether the risk of diabetes differs among NAFLD histological subtypes remains unclear: in a communitybased study, the 13-year incidence of diabetes was 2.98-fold higher in NASH patients versus SS patients.3 According to our analysis, a diagnosis of NAFLD should prompt a thorough three-focus assessment of cardiovascular, metabolic, and liver-related risks (Table 1).4 Liver-related risk assessment remains problematic because it requires liver histology. Three noninvasive methods have been
extensively validated: enzyme-linked immunosorbent assay-detected cytokeratin 18 fragments (9 studies enrolling 856 participants) for the detection of NASH and the NAFLD fibrosis score (13 studies enrolling 3064 participants) and FibroScan (6 studies enrolling 563 participants) for the detection of advanced fibrosis. We believe that these methods should be promptly implemented in diagnostic algorithms to select patients for liver biopsy in routine clinical practice while we continue to search for the ideal noninvasive marker. GIOVANNI MUSSO, M.D.1 ROBERTO GAMBINO, PH.D.2 MAURIZIO CASSADER, PH.D.2 1 Gradenigo Hospital, Turin, Italy 2 Department of Internal Medicine University of Turin, Turin, Italy
References 1. Ghouri N, Preiss D, Sattar N. Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and clinical perspective of prospective data. Hepatology 2011;52:1156-1161. 2. Martinez S, Crespo G, Navasa M, Forns X. Non-invasive assessment of liver fibrosis. Hepatology 2011;52. 3. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med; doi: 10.3109/07853890.2010.518623. 4. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 2008;21: 93-111. C 2011 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24070 Potential conflict of interest: Nothing to report.
Table 1. Suggested Evaluation of Patients With NAFLD Disease Risk
Diabetes
CVD
Liver-related (end-stage liver disease)
NAFLD Assessment
Measure the body mass index, waist circumference, fasting plasma glucose and insulin level, and hemoglobin A1c level.* Perform the 75-g oral glucose tolerance test in NAFLD patients without known diabetes according to standard guidelines (i.e., the American Diabetes Association) to classify their glucose tolerance. Calculate the fasting index of insulin resistance (homeostasis model assessment of insulin resistance), which is associated with the severity of liver disease and has prognostic value in NAFLD. Assess smoking status, measure blood pressure, plasma total cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein(HDL) cholesterol and triglycerides. Calculate the CVD risk score (i.e., Framingham risk score). Perform B-mode carotid ultrasonography in patients without diabetes or established CVD who have intermediate CVD risk (Framingham risk score ¼ 6%-20%) to measure carotid intima-media thickening according to recent guidelines6 (optional). Apply noninvasive tests (i.e., the serum cytokeratin 18 fragment assay, NAFLD fibrosis score, and FibroScan) to screen for the presence of NASH with or without advanced fibrosis. If noninvasive tests yield a high probability of NASH (with or without advanced fibrosis), refer to a gastroenterologist for liver biopsy, the assessment of complications of cirrhosis (hepatic failure, portal hypertension, esophageal varices, and hepatocellular carcinoma), experimental treatments, and tight monitoring. Liver biopsy remains necessary for staging and monitoring the course of liver disease in patients with NASH and if the diagnosis of NAFLD is in doubt.
*According to recent guidelines, hemoglobin A1c can be used for screening for type 2 diabetes. 1773
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Reply: We thank Musso and colleagues for their useful comments on our article. We agree that a comprehensive approach to patients with nonalcoholic fatty liver disease, namely one which considers their diabetes and cardiovascular risk, as well as their long-term liver-related risk, is needed. We wish only to make some points of clarification which will help hepatologists to efficiently assess cardiovascular and diabetes risk in their patients. First, there have been recent calls, recently verified by the World Health Organization, to diagnose diabetes by measurement of hemoglobin A1c (HbA1c), and this measure has the advantage of being measurable on nonfasting samples.1 Of interest, HbA1c is at least as good as fasting glucose at assessing microvascular risk and appears to be the best glycemic predictor of macrovascular risk, performing even better than the 2-hour glucose tolerance test.2 We would therefore argue against routine oral glucose tolerance testing in patients with nonalcoholic fatty liver disease, because of both clinical and economical concerns. Second, the benefit of testing for insulin as a prognostic factor, we believe, remains to be proven. At present, we would advise against measuring insulin routinely, at least until this approach has been shown to be cost-effective. Third, lipid tests to enhance prediction of cardiovascular disease (as part of national cardiovascular risk guidelines or algorithms) also do not require fasting, as recently shown by the Emerging Risk Factor Collaboration group.3 Rather, nonfasting total cholesterol (or low-density lipoprotein cholesterol or non–high-density lipoprotein cholesterol) and high-density lipoprotein cholesterol adequately reflect lipidassociated vascular risk and perform as well as fasting lipids3 for risk prediction. Fasting is therefore not required to test for diabetes, or indeed cardiovascular risk, in the majority of patients. Finally, we have recently proposed4 how combined vascular and diabetes screening may be conducted by simply adding a nonfasting HbA1c test to nonfasting lipids as part of a cardiovascular risk
screen, a simple process which may be easily added to other routine tests conducted in most hepatology and hepatology-related clinics. NAZIM A. GHOURI, M.D. DAVID PREISS, M.D. NAVEED SATTAR, M.D.* Institute of Cardiovascular & Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre University of Glasgow Glasgow, UK *
[email protected]
References 1. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327–1334. 2. Sarwar N, Aspelund T, Eiriksdottir G, Gobin R, Seshasai SR, Forouhi NG, et al. Markers of dysglycaemia and risk of coronary heart disease in people without diabetes: Reykjavik prospective study and systematic review. PLoS Med 2011;7:e1000278. 3. Emerging Risk Factors Collaboration;Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993–2000. 4. Preiss D, Khunti K, Sattar N.Combined cardiovascular and diabetes risk assessment in primary care. Diabet Med 2011;28:19–22. C 2011 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24138 Potential conflict of interest: Nothing to report.
Association Between Virological Response and Decline in Hemoglobin Concentration During Pegylated Interferon and Ribavirin Therapy in HCV Genotype 1: Another Story To the Editor: We read with great interest the article in HEPATOLOGY by Sievert et al.,1 which retrospectively evaluated the CHARIOT study of 871 treatment-naive patients who were infected with hepatitis C virus (HCV) genotype 1 (HCV-1) to determine whether hemoglobin decline is associated with sustained virological response (SVR) achieved through pegylated interferon (PegIFN) and ribavirin treatment. With 16% of patients developing anemia (serum hemoglobin 30 g/L from baseline, SVR rate was higher in anemic patients compared to those without anemia (61% versus 50%, respectively; P ¼ 0.02). The authors concluded that the development of anemia or experience of a decline in hemoglobin of >30 g/L predicts better SVR in HCV-1 patients who receive PegIFN/ ribavirin treatment which has also been reported in the post hoc analysis of the IDEAL study by Sulkowski et al. (74%).2 We examined the 100 Taiwanese HCV-1 patients who received 48-week PegIFN/ribavirin treatment in our randomized trial that enrolled a total of 200 patients.3 The means (6standard deviations) for baseline, lowest, and decline of hemoglobin levels were 146 6 14 g/L, 103 6 17 g/L, and 42 6 14 g/L, respectively. We found 45% of patients developed anemia (serum hemoglobin 30 g/L from baseline. With 79 patients (79%) achieving SVR, the SVR rate was similar between patients with and without anemia (77.8% versus
80%, P ¼ 0.786). Also, the SVR rate in patients with hemoglobin decline >30 g/L was similar compared to patients without hemoglobin decline >30 g/L (78.2% versus 81.8%, P ¼ 1.000). The means (6standard deviations) for baseline, lowest, and decline of hemoglobin level were similar between patients with and without SVR (146 6 13 g/L versus 143 6 15 g/L, P ¼ 0.286; 104 6 17 versus 102 6 19 g/L, P ¼ 0.670; 43 6 14 versus41 6 14 g/L, P ¼ 0.600). The treatment-related anemia seems to play a minimal role in predicting SVR in Taiwanese patients infected with HCV-1. We showed the percentage of hemoglobin decline >30 g/L (78%) in Taiwanese patients who received PegIFN/ribavirin treatment without erythropoietin was similar to reports by Sievert et al. (76%) and Sulkowski et al. (74%). Nevertheless, we reported a higher percentage (45%) of anemia (serum hemoglobin 30 g/L from baseline had higher sustained virological response (SVR) rates compared to those who did not experience similar hematological changes. A similar outcome was reported from the IDEAL (Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) study of 3023 patients.2 Both study populations were primarily Caucasian. Yu and colleagues examined a subset of 100 patients from a total study population of 200 Taiwanese patients treated with pegylated interferon and ribavirin for 48 weeks and found a higher rate of anemia development (45%) and a similar rate of patients with a hemoglobin decline of >30 g/L from baseline (78%). There was no significant difference in SVR rates between patients with and patients without the hematological changes. We therefore further analyzed the CHARIOT study population stratified by ethnicity (Asian, n ¼ 118 versus non-Asian, n ¼ 778). Asian patients were more likely to develop anemia than non-Asians (27% versus 14%, P < 0.001) but had a similar likelihood of hemoglobin decline >30 g/L from baseline (71% versus 74%, P ¼ 0.494). Within the Asian population, SVR rates were not significantly higher for those with anemia (71% versus 59%, P ¼ 0.188) or those with hemoglobin decline >30 g/L from baseline (74% versus 66%, P ¼ 0.379). Within the non-Asian population, SVR rates were higher for those with anemia (57% versus 46%, P ¼ 0.036) and those with hemoglobin decline >30 g/L from baseline (51% versus 36%, P < 0.001). These contrasting levels of significance may relate to sample size, because the SVR differential for the impact of anemia was similar in the Asian (12%) and non-Asian (11%) populations. An alternative explanation, as proposed by Yu et al., may relate to the higher proportion of patients with a favorable interleukin28B (IL28B) genotype,3 leading to an overall higher SVR rate. Although the SVR rate within the CHARIOT Asian population was not as high as in the Taiwanese study (79%) it was significantly higher than the non-Asian population (68% versus 47%, P < 0.001). Ultimately, multivariate analysis including IL28B genotype and on-treatment anemia in a large treatment population will be required to conclusively demonstrate the relative influence of each factor on treatment outcome.4 WILLIAM SIEVERT, M.D.1 GREGORY J. DORE, B.SC., M.B., B.S., PH.D.2 STUART K. ROBERTS, M.D.3 On behalf of the CHARIOT Study Group 1 Gastroenterology and Hepatology Unit Monash Medical Centre and Centre for Inflammatory Diseases Monash University, Melbourne, Australia 2 National Centre in HIV Epidemiology and Clinical Research University of New South Wales and St Vincent’s Hospital Sydney, Australia 3 Alfred Hospital, Melbourne, Victoria, Australia
References 1. Sievert W, Dore GJ, McCaughan GW, Yoshihara M, Crawford DH, Cheng W, et al. Virological response is associated with decline in hemoglobin concentration during pegylated interferon and ribavirin therapy in HCV genotype 1. HEPATOLOGY 2011; doi:10.1002/hep.24180. 2. Sulkowski M, Shiffman M, Afdhal N, Reddy K, McCone J, Lee W, et al. Hepatitis C virus treatment-related anemia is associated with higher sustained virologic response rate. Gastroenterology 2011;139:1602-1611. 3. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399-401.
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4. Thompson AJ, Muir AJ, Sulkowski M, Ge D, Fellay J, Shiana KV, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2011;139:120-129.
C 2011 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24250 Potential conflict of interest: Nothing to report.
Patatin-Like Phospholipase Domain Containing 3 Sequence Variant and Hepatocellular Carcinoma To the Editor: In a recent article in HEPATOLOGY, Valenti et al.1 reported an association of the patatin-like phospholipase domain containing 3 (PNPLA3) isoleucine-to-methionine substitution at position 148 (I148M; rs738409) with hepatitis C virus (HCV)-related chronic liver disease. In particular, they showed this genetic variant was associated with fatty liver and fibrosis progression in two independent cohorts of Caucasians with chronic HCV. In one study cohort, they also reported an independent association with hepatocellular carcinoma (HCC) in homozygous 148M carriers.1 Our goal was to examine the latter association in a cohort of individuals with HCV-related cirrhosis, comparing those with and without HCC. We genotyped a total of 221 (male/female ¼ 141/80) Caucasians at the Department of Gastroenterology, ‘‘Sapienza’’ University of Rome, Italy, for the PNPLA3 148M allele. Inclusion criteria were presence of clinical cirrhosis, HCV RNA positivity, surveillance for HCC for at least 2 years, and alcohol consumption of
