- Email: [email protected]
Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma
Nonalcoholic Fatty Liver Disease/Nonalcoholic S t e a t o h e p a t i t i s an d H e p a t o c e l l u l a r C a rc i n o m a Omar Massoud,
MD
a
, Michael Charlton,
b, MD, FRCP *
KEYWORDS Nonalcoholic steatohepatitis Obesity Hepatocellular carcinoma Metabolic syndrome KEY POINTS The progressive increase in the prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis are likely to make nonalcoholic fatty liver disease/nonalcoholic steatohepatitis the most common predisposing factor of hepatocellular carcinoma in the upcoming decades. The frequency of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis –related hepatocellular carcinoma in the absence of cirrhosis is unclear. Screening and surveillance for hepatocellular carcinoma should, for now, be limited to patients thought to have cirrhosis. Obesity can make screening for hepatocellular carcinoma in patients with nonalcoholic steatohepatitis cirrhosis challenging, increasing the technical failure rate of ultrasound scan as a screening method. The delay in the diagnosis of hepatocellular carcinoma in the setting of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis and the presence of multiple comorbidities in this population negatively impacts prognosis.
INTRODUCTION
The incidence of hepatocellular carcinoma (HCC) in the United States has tripled over the last 3 decades. A recent study using the Surveillance, Epidemiology and End Result (SEER) database found an increase in the incidence rate of HCC from 1.6 per 100000 in 1975 to 4.9 per 100000 in 2000.1 HCC is the fastest growing cause of
The authors have nothing to disclose. a Division of Gastroenterology and Hepatology, University of Alabama, 1720 2nd Avenue South, BDB 380, Birmingham, AL 35233, USA; b Division of Gastroenterology and Hepatology, University of Chicago, Center for Liver Diseases, The University of Chicago Biological Sciences, 5841 South Maryland Avenue, Room M-454, Chicago, IL 60637, USA * Corresponding author. E-mail address: [email protected] Clin Liver Dis 22 (2018) 201–211 http://dx.doi.org/10.1016/j.cld.2017.08.014 1089-3261/18/ª 2017 Elsevier Inc. All rights reserved.
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cancer death in the United States male population.2 The primary risk factor for HCC is cirrhosis, which is present in 70% to 90% of cases.2 The most common causes of cirrhosis are viral hepatitis (hepatitis B and hepatitis C), alcoholic hepatitis, and nonalcoholic steatohepatitis (NASH), the most common cause of liver disease in the West and globally.3–10 However, 15% to 50% of HCC cases occur in patients with cryptogenic cirrhosis without other known chronic liver disease.2 Further, there is a growing body of literature showing that HCC can develop from noncirrhotic NASH or even simple hepatic steatosis.11 In addition, obesity has been established as a risk factor for the development of a variety of malignancies, including liver cancer.12–14 This review discusses the association between HCC and NASH cirrhosis, noncirrhotic NASH/ nonalcoholic fatty liver disease (NAFLD), diabetes, obesity, and metabolic syndrome. This review also discusses the pathogenesis of HCC in cirrhosis and noncirrhosis and reviews the challenges of surveillance for HCC in NASH/NAFLD population. HEPATOCELLULAR CARCINOMA AND NONALCOHOLIC FATTY LIVER DISEASE/ NONALCOHOLIC STEATOHEPATITIS–RELATED CIRRHOSIS
The first report on HCC complicating NASH with cirrhosis was published in the 1990s. Further studies indicated that NASH is a risk factor for the development of cirrhosis and HCC.15 Although most cases of HCC occur in the setting of hepatitis C virus (HCV) or alcoholic cirrhosis, in 15% to 50% of cases, HCC occurs in the setting of cryptogenic cirrhosis.2,10 It is widely believed that cryptogenic cirrhosis represents “burnt out” NASH, bearing metabolic features of metabolic syndrome but no longer having the classic biopsy features of NASH, such as steatosis, which dissipates with more advanced liver disease.14,16 The risk of HCC in NASH-related cirrhosis seems to be lower than in viral or alcohol-related cirrhosis.17 In a large cohort study, HCC was significantly more common in HCV than in NAFLD (6.8% vs 2.4% overall, respectively).18 The perception that HCC is less common in NASH-related cirrhosis has, however, recently been challenged. In a report from England, the overall incidence of HCC increased 1.8fold from 2000 to 2010 with more than 10-fold increase in HCC associated with NAFLD, accounting for 34.8% of all the cases in 2010 and making it the single most common underlying etiology.19 The lower incidence of HCC with NASH cirrhosis may be outweighed by the progressive increase in NASH-related cirrhosis.17 Ascha and colleagues20 compared the incidence of HCV- and NASH-related cirrhosis. Among 510 patients with cirrhosis, 196 had underlying NASH, whereas 315 had cirrhosis secondary to HCV. Median follow-up of 3.2 years found an annual cumulative HCC incidence of 2.6% for NASH-related cirrhosis compared with 4% for HCV-related cirrhosis cases. Despite the estimated low HCC incidence rate of 2.6% in patients with NASH-related cirrhosis, the surge in the number of cases with NAFLD is projected to lead to an increase in the number of patients with NASH-related HCC.10 A recent study found a 4-fold increase in the prevalence of NASH-related HCC among liver transplant recipients since the implementation of the model for end-stage liver disease in 2002. In this large US population-based study, which used the United Network for Organ Sharing database from 2002 to 2012, Wong and colleagues21,22 reported 10,061 patients with HCC among 61,868 liver transplant recipients. To achieve a more accurate assessment of the true prevalence of NASH, the investigators created a modified NASH category, which included patients with a formal diagnosis of NASH and obese patients (body mass index [BMI] more than 30 kg/m2) with cryptogenic cirrhosis and obese patients with unknown etiology of HCC. The proportion of HCC patients undergoing liver transplantation increased from 3.3% in 2000 to 13.5% in 2012 (Table 1). Although HCV remained the leading
NAFLD/NASH and HCC
Table 1 The etiologies of liver disease among hepatocellular carcinoma–related liver transplant recipients after the implementation of MELD in 2002 Etiology of HCC
2002
2007
HCV (%)
43.4
46.3
2012 49.9
NASH (%)
0
4
6
Modified NASH (%)
8.3
10.3
13.5
etiology of HCC, NASH was found to be the second leading cause of HCC in patients undergoing liver transplantation. With the growing burden of obesity and diabetes mellitus (DM) in the developed countries leading to NAFLD and NASH, there is cumulative evidence suggesting that NASH may account for a large portion of idiopathic or cryptogenic cirrhosis.16,23 NASH-related HCC patients undergoing liver transplantation have significantly higher rates of DM and higher BMI.22 Similar to the NASH population, patients with cryptogenic cirrhosis have a high prevalence of obesity and DM. Additionally, a significant number of liver transplant recipients with cryptogenic cirrhosis go on to have NAFLD (25.4%) or NASH (15.7%) within 2 years after transplant surgery.24 This finding provides further support that patients with end-stage or burnt out NASH are potentially being misclassified with cryptogenic cirrhosis.25 HEPATOCELLULAR CARCINOMA AND NONCIRRHOTIC NONALCOHOLIC FATTY LIVER DISEASE/NONALCOHOLIC STEATOHEPATITIS
NAFLD, the most common liver disorder in the United States and other industrialized countries, affects between 25% and 45% of the US population. NASH affects 5% of the population.26–29 Although HCC almost always occurs in adults in the setting of cirrhosis, there is growing evidence that HCC can develop in the setting of noncirrhotic NAFLD.11 Since 2004, several reports have described the development of HCC in noncirrhotic NAFLD.14,30–43 The largest study was from Japan and included 87 patients who had HCC in the setting of NAFLD. Forty-three of these patients did not have cirrhosis.43 In 2008 Guzman and colleagues37 published a small case series of 3 patients with noncirrhotic HCC in the setting of NAFLD. All had at least 2 features of metabolic syndrome with a mean BMI of 33.5. More recently, Perumpail and colleagues26 published a case series of 9 patients who had HCC in the absence of cirrhosis. Of these, 1 patient had chronic hepatitis B virus (HBV), 1 had chronic HCV infection, and 1 had the fibrolamellar variant of HCC. Six patients (66.7%) had either NASH/NAFLD or at least 2 features of metabolic syndrome without underlying liver disease. The mean age of the 6 patients was 72 8 years. One patient had NASH, 2 had NAFLD, and 3 had no known liver disease. All 6 patients had at least 2 of the features of metabolic syndrome; all 6 had hypertension, and 5 had dyslipidemia. All 6 had either type II diabetes or evidence of insulin resistance. The mean BMI was 29.4, with 2 patients meeting criteria for severe obesity (BMI, 35–39.9), 1 for obesity (BMI, 30–34.9), 2 for overweight (BMI, 25–29.9), and 1 for normal weight. Patients with HCC in the setting of noncirrhotic NAFLD were older in age and mostly men.26 HCC was more likely to be well differentiated, and many developed in a preexisting liver cell adenoma.38 Although the growing body of evidence suggesting HCC can develop in the setting of NAFLD without cirrhosis deserves particular attention, current guidelines recommend HCC screening only in patients with cirrhosis, with the exception of patients with chronic HBV.14
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HEPATOCELLULAR CARCINOMA AND OBESITY, DIABETES, AND METABOLIC SYNDROME
The prevalence of obesity, type II diabetes, and metabolic syndrome has been increasing at alarming rates, both in the United States and worldwide. Obesity affects more than one-third of the population of the USA.44 Type II diabetes affects one in ten middle-aged adults.27,45 Metabolic syndrome, as defined by the presence of at least 3 of the following risk factors: central obesity, elevated triglycerides, hypertension, impaired fasting glucose, and reduced high-density lipoprotein cholesterol, affects up to 25% of the US population.46,47 In a prospectively studied population of more than 900,000 US adults, who were free from cancer at enrollment in 1982, Calle and colleagues13 identified 57,145 deaths from cancer during 16 years of follow-up. The investigators examined the relation in men and women between the BMI in 1982 and the risk of death from all cancers and from cancers at individual sites, while controlling for other risk factors in multivariate and proportional-hazards models. The study found that individuals with BMI of at least 40 had death rates from all cancers combined of 52% higher (for men) and 62% higher (for women) than the rates in men and women of normal weight. The relative risk of death was 1.52 for men and 1.62 for women. In both men and women, BMI was significantly associated with higher rates of death from cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney. On the basis of associations observed in this study, the authors estimated that current patterns of overweight and obesity in the United States could account for 14% of all deaths from cancer in men and 20% of those in women. Other studies confirmed the association between obesity and the increase in the risk of cancer. In a Swedish population-based cohort of 28,129 hospital patients, Wolk and colleagues48 reported a 33% increase in the incidence of cancer in obese persons compared with nonobese persons. In a Danish cohort of 43,965 obese persons, Moller and colleagues49 observed increased incidences of liver cancer (58 cases; relative risk, 1.9) compared with the general population. In a prospective study of 771 French patients with well-compensated alcoholic and hepatitis C–related cirrhosis, BMI was found to have a positive linear relationship with incidence of HCC over the follow-up period of up to 7 years. In this study, BMI between 25 and 30 kg/m2 was associated with a hazard ratio of 2, whereas BMI of 30 kg/m2 or greater was associated with a hazard ratio of 2.8.50 An association between HCC and diabetes has been reported as early as 1986.51,52 El-Serag and colleagues,53 in a study that included 823 patients, found an increase in the risk of HCC in diabetics. In a large prospective study, investigators found that patients with diabetes were more than twice as likely as controls to have chronic nonalcoholic liver disease or HCC.54 A large population-based study, which used the SEER database, showed a 2.87 odds ratio of HCC among older patients with DM without other risk factors for chronic liver disease.55 Diabetes was also found to be an independent risk factor for HCC in the setting of cryptogenic cirrhosis.16 The association between HCC and diabetes was confirmed in many other studies.14,16,56,57 A systematic review and meta analysis of the studies published between 1966 and 2005 also found a significant association of diabetes and HCC in 9 of 13 case-controlled studies (pooled odds ratio, 2.5) and 7 of 13 cohort studies (pooled odds ratio, 2.5).55 The association between HCC and metabolic syndrome is more difficult to assess because of the lack of uniform diagnostic criteria for the metabolic syndrome. The most widely used criteria for diagnosis are those set by the US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) (Table 2).58
NAFLD/NASH and HCC
Table 2 National Cholesterol Education Program Adult Treatment Panel III definition for metabolic syndrome (2001) Three or More of the Following Risk Factors Fasting plasma glucose
5.6 mmol/L (100 mg/dL)
Blood pressure
130/85 mm Hg
Triglycerides
1.7 mmol/L (150 mg/dL)
High-density lipoprotein cholesterol
Men: <1.03 mmol/L (40 mg/dL) Women: <1.29 mmol/L (50 mg/dL)
Obesity
Men: waist circumference >102 cm Women: waist circumference >88 cm
Data from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Treatment of high blood cholesterol in, executive summary of the third report of The National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001:285(19);2486–97.
In a population-based study, using the SEER-Medicare database, Welzel and colleagues59 identified 3649 HCC cases. Metabolic syndrome, defined by the NCEP ATP III, was significantly more common among persons who had HCC (37.1%) than the comparison group (17.1%; P<.0001). In an adjusted multiple logistic regression analysis, metabolic syndrome remained significantly associated with increased risk of HCC (odds ratio, 2.13; confidence interval, 1.96–2.31; P<.0001).59 More recently, Perumpail and colleagues26 published a case series of 6 patients who had HCC in the absence of cirrhosis, HBV, or HCV infection. All 6 patients had at least 2 or more features of metabolic syndrome; all 6 had hypertension, all 6 had either type 2 diabetes or evidence of insulin resistance, and 5 had dyslipidemia. MECHANISM OF HEPATOCELLULAR CARCINOMA IN THE SETTING OF NONALCOHOLIC FATTY LIVER DISEASE/NONALCOHOLIC STEATOHEPATITIS
The mechanism of HCC arising in the setting of cirrhosis has been extensively studied. It is generally characterized by cycles of hepatocellular death and compensatory regeneration, accompanied by constant cell growth and proliferation that favor tumor development.16 The mechanisms of HCC in the setting of NAFLD, in the absence of cirrhosis, are less well understood. These mechanisms involve 3 groups of factors: proinflammatory cytokines, diet and gut microbiomes, and genetic factors. Proinflammatory Cytokines
Insulin resistance, in the setting of obesity, is characterized by low-grade inflammation that is associated with macrophage activation with release of proinflammatory cytokines including tumor necrosis factor alpha (TNF-a) and interleukin 6 (IL-6).60 TNF-a interacts with the nuclear factor kappa-B kinase beta subunit (NF-kB) to promote apoptosis, inflammation, proliferation, and angiogenesis.61 IL-6 activates the signal transducer and activator of transcription 3 (STAT3), which promotes cell growth and differentiation. STAT3 is also involved in other tumor pathogenesis.62 Diet and Gut Microbiome
A diet with high fat content increases the expression of TNF-a and IL-6 and activates NF-kB. All are involved in angiogenesis and cell differentiation.63 Fructose stimulates hepatic lipogenesis, which amplifies lipotoxic injury. Lipogenesis downregulates the expression of sirtuin-1, which is involved in the regulation of cellular survival.64 Obesity
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is associated with changes in composition of the gut microbiota, which produces reactive oxygen species leading to DNA damage and release of senescenceassociated secretory phenotype from hepatic stellate cells.65 Genetic Factors
Romeo and colleagues66 described a single-nucleotide polymorphism in the patatinlike phospholipase domain–containing 3 (PNPLA3) gene, which encodes the triglycerides lipase adiponutrin. The PNPLA3 rs738409 [G] risk allele increases the risk of HCC development by 12-fold. Further, GG homozygosity is associated with the development of HCC in younger age, and more diffuse nature at the diagnosis.67 SURVEILLANCE FOR HEPATOCELLULAR CARCINOMA IN THE SETTING OF NONALCOHOLIC FATTY LIVER DISEASE/NONALCOHOLIC STEATOHEPATITIS
US and European societies recommend regular surveillance for HCC in patients with cirrhosis every 6 months.68,69 Ultrasound scan is the recommended method of surveillance.68–70 There are data suggesting that HCC surveillance in cirrhotic patients in general is inadequate71 but much less used in patients with cirrhosis secondary to NASH.72 A retrospective analysis of a cohort with 1500 HCC patients from Veterans Administration hospitals found that patients with NAFLD HCC underwent less frequent surveillance (43.3%) in the 3 years before HCC diagnosis than patients with alcohol(59.8%) or HCV-induced (86.7%) HCC.73 The basis for the lower frequency of screening among patients with NAFLD cirrhosis is not clear. The lower US screening rate is compounded by the higher technical failure rate of US examinations of the liver in patients with BMI greater than 25 kg/m2. The fact that HCC can develop in the absence of cirrhosis adds uncertainty to who should undergo surveillance. Another challenge of surveillance in patients with NASH is that obesity can reduce the sensitivity of ultrasound examination. An Italian study found that a BMI greater than 25 was significantly associated with ultrasound surveillance failure.74 Computed tomography scans or MRIs are more accurate in this setting, but they may not be cost effective or appropriate for initial surveillance.75 A recent study suggested that alpha-fetoprotein has a better sensitivity and specificity in NAFLD cirrhosis patients than in HCV cirrhosis patients with a sensitivity of 89.7% and a specificity of 85.1% at a cutoff value of 20 ng/mL in NAFLD patients.76 Whether noncirrhotic NAFLD/ NASH patients should be screened for HCC and the best method for screening are still to be determined. PREVENTION
Metformin may have antineoplastic effects through both insulin-dependent and insulin-independent mechanisms.77 A meta-analysis including 22,650 cases of HCC in 334,307 patients with type 2 diabetes concluded that incidence of HCC was reduced by 50% with metformin use, increased with sulfonylurea or insulin, and unchanged with glitazones.78 Statins may also decrease the risk of cancers through antiproliferative, proapoptotic, anti-angiogenic, and immunomodulatory effects.17 A systematic meta-analysis of 26 randomized controlled trials, including almost 1.5 million patients and 4298 cases of HCC, found that the use of statins was associated with a 37% reduction in HCC incidence after adjusting for potential confounders.79 It is conceivable that controlling risk factors for metabolic syndrome would decrease the risk of HCC. The role of bariatric surgery in reducing the risk of HCC is to be determined.
NAFLD/NASH and HCC
SUMMARY
The progressive increase in the prevalence of NAFLD and NASH are likely to make NAFLD/NASH the most common predisposing factor of HCC in the upcoming decades. The frequency of NAFLD/NASH-related HCC in the absence of cirrhosis is unclear. Screening and surveillance for HCC should, for now, be limited to patients thought to have cirrhosis. Obesity can make screening for HCC in patients with NASH cirrhosis challenging, increasing the technical failure rate of ultrasound scan as a screening method. The delay in the diagnosis of HCC in the setting of NAFLD/NASH and the presence of multiple comorbidities in this population negatively impacts prognosis. A better understanding of the mechanisms involved in the development of NAFLD/NASH-related HCC will allow the discovery of new targets for therapeutic and preventive intervention. REFERENCES
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54. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126(2):460–8. 55. El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006;4(3):369–80. 56. Caldwell SH, Oelsner DH, Iezzoni JC, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999;29(3):664–9. 57. Poonawala A, Nair SP, Thuluvath PJ. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology 2000;32(4 Pt 1):689–92. 58. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Treatment of high blood cholesterol in, executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486–97. 59. Welzel TM, Graubard BI, Zeuzem S, et al. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology 2011;54(2):463–71. 60. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology 2007;132(6):2169–80. 61. Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature 2002;420(6913):333–6. 62. Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 2005;41(16):2502–12. 63. Vanni E, Bugianesi E. Obesity and liver cancer. Clin Liver Dis 2014;18(1): 191–203. 64. Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005;115(5):1343–51. 65. Dongiovanni P, Romeo S, Valenti L. Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors. World J Gastroenterol 2014;20(36):12945–55. 66. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40(12):1461–5. 67. Krawczyk M, Stokes CS, Romeo S, et al. HCC and liver disease risks in homozygous PNPLA3 p.I148M carriers approach monogenic inheritance. J Hepatol 2015;62(4):980–1. 68. Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011;53(3): 1020–2. 69. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35(3):421–30. 70. Forner A, Reig M, Bruix J. Alpha-fetoprotein for hepatocellular carcinoma diagnosis: the demise of a brilliant star. Gastroenterology 2009;137(1):26–9. 71. Davila JA, Morgan RO, Richardson PA, et al. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology 2010;52(1):132–41. 72. Mittal S, Sada YH, El-Serag HB, et al. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol 2015;13(3):594–601.e1.
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73. Younossi ZM, Otgonsuren M, Henry L, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology 2015;62(6):1723–30. 74. Del Poggio P, Olmi S, Ciccarese F, et al. Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirhhosis. Clin Gastroenterol Hepatol 2014;12:1927e2–33e2. 75. Thompson Coon J, Rogers G, Hewson P, et al. Surveillance of cirrhosis for hepatocellular carcinoma: a cost-utility analysis. Br J Cancer 2008;98(7):1166–75. 76. Gopal P, Yopp AC, Waljee AK, et al. Factors that affect accuracy of alphafetoprotein test in detection of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2014;12(5):870–7. 77. Chen HP, Shieh JJ, Chang CC, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut 2013;62(4):606–15. 78. Zhang H, Gao C, Fang L, et al. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis. Scand J Gastroenterol 2013;48(1): 78–87. 79. Singh S, Singh PP, Singh AG, et al. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 2013;144(2):323–32.
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a
, Michael Charlton,
b, MD, FRCP *
KEYWORDS Nonalcoholic steatohepatitis Obesity Hepatocellular carcinoma Metabolic syndrome KEY POINTS The progressive increase in the prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis are likely to make nonalcoholic fatty liver disease/nonalcoholic steatohepatitis the most common predisposing factor of hepatocellular carcinoma in the upcoming decades. The frequency of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis –related hepatocellular carcinoma in the absence of cirrhosis is unclear. Screening and surveillance for hepatocellular carcinoma should, for now, be limited to patients thought to have cirrhosis. Obesity can make screening for hepatocellular carcinoma in patients with nonalcoholic steatohepatitis cirrhosis challenging, increasing the technical failure rate of ultrasound scan as a screening method. The delay in the diagnosis of hepatocellular carcinoma in the setting of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis and the presence of multiple comorbidities in this population negatively impacts prognosis.
INTRODUCTION
The incidence of hepatocellular carcinoma (HCC) in the United States has tripled over the last 3 decades. A recent study using the Surveillance, Epidemiology and End Result (SEER) database found an increase in the incidence rate of HCC from 1.6 per 100000 in 1975 to 4.9 per 100000 in 2000.1 HCC is the fastest growing cause of
The authors have nothing to disclose. a Division of Gastroenterology and Hepatology, University of Alabama, 1720 2nd Avenue South, BDB 380, Birmingham, AL 35233, USA; b Division of Gastroenterology and Hepatology, University of Chicago, Center for Liver Diseases, The University of Chicago Biological Sciences, 5841 South Maryland Avenue, Room M-454, Chicago, IL 60637, USA * Corresponding author. E-mail address: [email protected] Clin Liver Dis 22 (2018) 201–211 http://dx.doi.org/10.1016/j.cld.2017.08.014 1089-3261/18/ª 2017 Elsevier Inc. All rights reserved.
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cancer death in the United States male population.2 The primary risk factor for HCC is cirrhosis, which is present in 70% to 90% of cases.2 The most common causes of cirrhosis are viral hepatitis (hepatitis B and hepatitis C), alcoholic hepatitis, and nonalcoholic steatohepatitis (NASH), the most common cause of liver disease in the West and globally.3–10 However, 15% to 50% of HCC cases occur in patients with cryptogenic cirrhosis without other known chronic liver disease.2 Further, there is a growing body of literature showing that HCC can develop from noncirrhotic NASH or even simple hepatic steatosis.11 In addition, obesity has been established as a risk factor for the development of a variety of malignancies, including liver cancer.12–14 This review discusses the association between HCC and NASH cirrhosis, noncirrhotic NASH/ nonalcoholic fatty liver disease (NAFLD), diabetes, obesity, and metabolic syndrome. This review also discusses the pathogenesis of HCC in cirrhosis and noncirrhosis and reviews the challenges of surveillance for HCC in NASH/NAFLD population. HEPATOCELLULAR CARCINOMA AND NONALCOHOLIC FATTY LIVER DISEASE/ NONALCOHOLIC STEATOHEPATITIS–RELATED CIRRHOSIS
The first report on HCC complicating NASH with cirrhosis was published in the 1990s. Further studies indicated that NASH is a risk factor for the development of cirrhosis and HCC.15 Although most cases of HCC occur in the setting of hepatitis C virus (HCV) or alcoholic cirrhosis, in 15% to 50% of cases, HCC occurs in the setting of cryptogenic cirrhosis.2,10 It is widely believed that cryptogenic cirrhosis represents “burnt out” NASH, bearing metabolic features of metabolic syndrome but no longer having the classic biopsy features of NASH, such as steatosis, which dissipates with more advanced liver disease.14,16 The risk of HCC in NASH-related cirrhosis seems to be lower than in viral or alcohol-related cirrhosis.17 In a large cohort study, HCC was significantly more common in HCV than in NAFLD (6.8% vs 2.4% overall, respectively).18 The perception that HCC is less common in NASH-related cirrhosis has, however, recently been challenged. In a report from England, the overall incidence of HCC increased 1.8fold from 2000 to 2010 with more than 10-fold increase in HCC associated with NAFLD, accounting for 34.8% of all the cases in 2010 and making it the single most common underlying etiology.19 The lower incidence of HCC with NASH cirrhosis may be outweighed by the progressive increase in NASH-related cirrhosis.17 Ascha and colleagues20 compared the incidence of HCV- and NASH-related cirrhosis. Among 510 patients with cirrhosis, 196 had underlying NASH, whereas 315 had cirrhosis secondary to HCV. Median follow-up of 3.2 years found an annual cumulative HCC incidence of 2.6% for NASH-related cirrhosis compared with 4% for HCV-related cirrhosis cases. Despite the estimated low HCC incidence rate of 2.6% in patients with NASH-related cirrhosis, the surge in the number of cases with NAFLD is projected to lead to an increase in the number of patients with NASH-related HCC.10 A recent study found a 4-fold increase in the prevalence of NASH-related HCC among liver transplant recipients since the implementation of the model for end-stage liver disease in 2002. In this large US population-based study, which used the United Network for Organ Sharing database from 2002 to 2012, Wong and colleagues21,22 reported 10,061 patients with HCC among 61,868 liver transplant recipients. To achieve a more accurate assessment of the true prevalence of NASH, the investigators created a modified NASH category, which included patients with a formal diagnosis of NASH and obese patients (body mass index [BMI] more than 30 kg/m2) with cryptogenic cirrhosis and obese patients with unknown etiology of HCC. The proportion of HCC patients undergoing liver transplantation increased from 3.3% in 2000 to 13.5% in 2012 (Table 1). Although HCV remained the leading
NAFLD/NASH and HCC
Table 1 The etiologies of liver disease among hepatocellular carcinoma–related liver transplant recipients after the implementation of MELD in 2002 Etiology of HCC
2002
2007
HCV (%)
43.4
46.3
2012 49.9
NASH (%)
0
4
6
Modified NASH (%)
8.3
10.3
13.5
etiology of HCC, NASH was found to be the second leading cause of HCC in patients undergoing liver transplantation. With the growing burden of obesity and diabetes mellitus (DM) in the developed countries leading to NAFLD and NASH, there is cumulative evidence suggesting that NASH may account for a large portion of idiopathic or cryptogenic cirrhosis.16,23 NASH-related HCC patients undergoing liver transplantation have significantly higher rates of DM and higher BMI.22 Similar to the NASH population, patients with cryptogenic cirrhosis have a high prevalence of obesity and DM. Additionally, a significant number of liver transplant recipients with cryptogenic cirrhosis go on to have NAFLD (25.4%) or NASH (15.7%) within 2 years after transplant surgery.24 This finding provides further support that patients with end-stage or burnt out NASH are potentially being misclassified with cryptogenic cirrhosis.25 HEPATOCELLULAR CARCINOMA AND NONCIRRHOTIC NONALCOHOLIC FATTY LIVER DISEASE/NONALCOHOLIC STEATOHEPATITIS
NAFLD, the most common liver disorder in the United States and other industrialized countries, affects between 25% and 45% of the US population. NASH affects 5% of the population.26–29 Although HCC almost always occurs in adults in the setting of cirrhosis, there is growing evidence that HCC can develop in the setting of noncirrhotic NAFLD.11 Since 2004, several reports have described the development of HCC in noncirrhotic NAFLD.14,30–43 The largest study was from Japan and included 87 patients who had HCC in the setting of NAFLD. Forty-three of these patients did not have cirrhosis.43 In 2008 Guzman and colleagues37 published a small case series of 3 patients with noncirrhotic HCC in the setting of NAFLD. All had at least 2 features of metabolic syndrome with a mean BMI of 33.5. More recently, Perumpail and colleagues26 published a case series of 9 patients who had HCC in the absence of cirrhosis. Of these, 1 patient had chronic hepatitis B virus (HBV), 1 had chronic HCV infection, and 1 had the fibrolamellar variant of HCC. Six patients (66.7%) had either NASH/NAFLD or at least 2 features of metabolic syndrome without underlying liver disease. The mean age of the 6 patients was 72 8 years. One patient had NASH, 2 had NAFLD, and 3 had no known liver disease. All 6 patients had at least 2 of the features of metabolic syndrome; all 6 had hypertension, and 5 had dyslipidemia. All 6 had either type II diabetes or evidence of insulin resistance. The mean BMI was 29.4, with 2 patients meeting criteria for severe obesity (BMI, 35–39.9), 1 for obesity (BMI, 30–34.9), 2 for overweight (BMI, 25–29.9), and 1 for normal weight. Patients with HCC in the setting of noncirrhotic NAFLD were older in age and mostly men.26 HCC was more likely to be well differentiated, and many developed in a preexisting liver cell adenoma.38 Although the growing body of evidence suggesting HCC can develop in the setting of NAFLD without cirrhosis deserves particular attention, current guidelines recommend HCC screening only in patients with cirrhosis, with the exception of patients with chronic HBV.14
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HEPATOCELLULAR CARCINOMA AND OBESITY, DIABETES, AND METABOLIC SYNDROME
The prevalence of obesity, type II diabetes, and metabolic syndrome has been increasing at alarming rates, both in the United States and worldwide. Obesity affects more than one-third of the population of the USA.44 Type II diabetes affects one in ten middle-aged adults.27,45 Metabolic syndrome, as defined by the presence of at least 3 of the following risk factors: central obesity, elevated triglycerides, hypertension, impaired fasting glucose, and reduced high-density lipoprotein cholesterol, affects up to 25% of the US population.46,47 In a prospectively studied population of more than 900,000 US adults, who were free from cancer at enrollment in 1982, Calle and colleagues13 identified 57,145 deaths from cancer during 16 years of follow-up. The investigators examined the relation in men and women between the BMI in 1982 and the risk of death from all cancers and from cancers at individual sites, while controlling for other risk factors in multivariate and proportional-hazards models. The study found that individuals with BMI of at least 40 had death rates from all cancers combined of 52% higher (for men) and 62% higher (for women) than the rates in men and women of normal weight. The relative risk of death was 1.52 for men and 1.62 for women. In both men and women, BMI was significantly associated with higher rates of death from cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney. On the basis of associations observed in this study, the authors estimated that current patterns of overweight and obesity in the United States could account for 14% of all deaths from cancer in men and 20% of those in women. Other studies confirmed the association between obesity and the increase in the risk of cancer. In a Swedish population-based cohort of 28,129 hospital patients, Wolk and colleagues48 reported a 33% increase in the incidence of cancer in obese persons compared with nonobese persons. In a Danish cohort of 43,965 obese persons, Moller and colleagues49 observed increased incidences of liver cancer (58 cases; relative risk, 1.9) compared with the general population. In a prospective study of 771 French patients with well-compensated alcoholic and hepatitis C–related cirrhosis, BMI was found to have a positive linear relationship with incidence of HCC over the follow-up period of up to 7 years. In this study, BMI between 25 and 30 kg/m2 was associated with a hazard ratio of 2, whereas BMI of 30 kg/m2 or greater was associated with a hazard ratio of 2.8.50 An association between HCC and diabetes has been reported as early as 1986.51,52 El-Serag and colleagues,53 in a study that included 823 patients, found an increase in the risk of HCC in diabetics. In a large prospective study, investigators found that patients with diabetes were more than twice as likely as controls to have chronic nonalcoholic liver disease or HCC.54 A large population-based study, which used the SEER database, showed a 2.87 odds ratio of HCC among older patients with DM without other risk factors for chronic liver disease.55 Diabetes was also found to be an independent risk factor for HCC in the setting of cryptogenic cirrhosis.16 The association between HCC and diabetes was confirmed in many other studies.14,16,56,57 A systematic review and meta analysis of the studies published between 1966 and 2005 also found a significant association of diabetes and HCC in 9 of 13 case-controlled studies (pooled odds ratio, 2.5) and 7 of 13 cohort studies (pooled odds ratio, 2.5).55 The association between HCC and metabolic syndrome is more difficult to assess because of the lack of uniform diagnostic criteria for the metabolic syndrome. The most widely used criteria for diagnosis are those set by the US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) (Table 2).58
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Table 2 National Cholesterol Education Program Adult Treatment Panel III definition for metabolic syndrome (2001) Three or More of the Following Risk Factors Fasting plasma glucose
5.6 mmol/L (100 mg/dL)
Blood pressure
130/85 mm Hg
Triglycerides
1.7 mmol/L (150 mg/dL)
High-density lipoprotein cholesterol
Men: <1.03 mmol/L (40 mg/dL) Women: <1.29 mmol/L (50 mg/dL)
Obesity
Men: waist circumference >102 cm Women: waist circumference >88 cm
Data from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Treatment of high blood cholesterol in, executive summary of the third report of The National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001:285(19);2486–97.
In a population-based study, using the SEER-Medicare database, Welzel and colleagues59 identified 3649 HCC cases. Metabolic syndrome, defined by the NCEP ATP III, was significantly more common among persons who had HCC (37.1%) than the comparison group (17.1%; P<.0001). In an adjusted multiple logistic regression analysis, metabolic syndrome remained significantly associated with increased risk of HCC (odds ratio, 2.13; confidence interval, 1.96–2.31; P<.0001).59 More recently, Perumpail and colleagues26 published a case series of 6 patients who had HCC in the absence of cirrhosis, HBV, or HCV infection. All 6 patients had at least 2 or more features of metabolic syndrome; all 6 had hypertension, all 6 had either type 2 diabetes or evidence of insulin resistance, and 5 had dyslipidemia. MECHANISM OF HEPATOCELLULAR CARCINOMA IN THE SETTING OF NONALCOHOLIC FATTY LIVER DISEASE/NONALCOHOLIC STEATOHEPATITIS
The mechanism of HCC arising in the setting of cirrhosis has been extensively studied. It is generally characterized by cycles of hepatocellular death and compensatory regeneration, accompanied by constant cell growth and proliferation that favor tumor development.16 The mechanisms of HCC in the setting of NAFLD, in the absence of cirrhosis, are less well understood. These mechanisms involve 3 groups of factors: proinflammatory cytokines, diet and gut microbiomes, and genetic factors. Proinflammatory Cytokines
Insulin resistance, in the setting of obesity, is characterized by low-grade inflammation that is associated with macrophage activation with release of proinflammatory cytokines including tumor necrosis factor alpha (TNF-a) and interleukin 6 (IL-6).60 TNF-a interacts with the nuclear factor kappa-B kinase beta subunit (NF-kB) to promote apoptosis, inflammation, proliferation, and angiogenesis.61 IL-6 activates the signal transducer and activator of transcription 3 (STAT3), which promotes cell growth and differentiation. STAT3 is also involved in other tumor pathogenesis.62 Diet and Gut Microbiome
A diet with high fat content increases the expression of TNF-a and IL-6 and activates NF-kB. All are involved in angiogenesis and cell differentiation.63 Fructose stimulates hepatic lipogenesis, which amplifies lipotoxic injury. Lipogenesis downregulates the expression of sirtuin-1, which is involved in the regulation of cellular survival.64 Obesity
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is associated with changes in composition of the gut microbiota, which produces reactive oxygen species leading to DNA damage and release of senescenceassociated secretory phenotype from hepatic stellate cells.65 Genetic Factors
Romeo and colleagues66 described a single-nucleotide polymorphism in the patatinlike phospholipase domain–containing 3 (PNPLA3) gene, which encodes the triglycerides lipase adiponutrin. The PNPLA3 rs738409 [G] risk allele increases the risk of HCC development by 12-fold. Further, GG homozygosity is associated with the development of HCC in younger age, and more diffuse nature at the diagnosis.67 SURVEILLANCE FOR HEPATOCELLULAR CARCINOMA IN THE SETTING OF NONALCOHOLIC FATTY LIVER DISEASE/NONALCOHOLIC STEATOHEPATITIS
US and European societies recommend regular surveillance for HCC in patients with cirrhosis every 6 months.68,69 Ultrasound scan is the recommended method of surveillance.68–70 There are data suggesting that HCC surveillance in cirrhotic patients in general is inadequate71 but much less used in patients with cirrhosis secondary to NASH.72 A retrospective analysis of a cohort with 1500 HCC patients from Veterans Administration hospitals found that patients with NAFLD HCC underwent less frequent surveillance (43.3%) in the 3 years before HCC diagnosis than patients with alcohol(59.8%) or HCV-induced (86.7%) HCC.73 The basis for the lower frequency of screening among patients with NAFLD cirrhosis is not clear. The lower US screening rate is compounded by the higher technical failure rate of US examinations of the liver in patients with BMI greater than 25 kg/m2. The fact that HCC can develop in the absence of cirrhosis adds uncertainty to who should undergo surveillance. Another challenge of surveillance in patients with NASH is that obesity can reduce the sensitivity of ultrasound examination. An Italian study found that a BMI greater than 25 was significantly associated with ultrasound surveillance failure.74 Computed tomography scans or MRIs are more accurate in this setting, but they may not be cost effective or appropriate for initial surveillance.75 A recent study suggested that alpha-fetoprotein has a better sensitivity and specificity in NAFLD cirrhosis patients than in HCV cirrhosis patients with a sensitivity of 89.7% and a specificity of 85.1% at a cutoff value of 20 ng/mL in NAFLD patients.76 Whether noncirrhotic NAFLD/ NASH patients should be screened for HCC and the best method for screening are still to be determined. PREVENTION
Metformin may have antineoplastic effects through both insulin-dependent and insulin-independent mechanisms.77 A meta-analysis including 22,650 cases of HCC in 334,307 patients with type 2 diabetes concluded that incidence of HCC was reduced by 50% with metformin use, increased with sulfonylurea or insulin, and unchanged with glitazones.78 Statins may also decrease the risk of cancers through antiproliferative, proapoptotic, anti-angiogenic, and immunomodulatory effects.17 A systematic meta-analysis of 26 randomized controlled trials, including almost 1.5 million patients and 4298 cases of HCC, found that the use of statins was associated with a 37% reduction in HCC incidence after adjusting for potential confounders.79 It is conceivable that controlling risk factors for metabolic syndrome would decrease the risk of HCC. The role of bariatric surgery in reducing the risk of HCC is to be determined.
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SUMMARY
The progressive increase in the prevalence of NAFLD and NASH are likely to make NAFLD/NASH the most common predisposing factor of HCC in the upcoming decades. The frequency of NAFLD/NASH-related HCC in the absence of cirrhosis is unclear. Screening and surveillance for HCC should, for now, be limited to patients thought to have cirrhosis. Obesity can make screening for HCC in patients with NASH cirrhosis challenging, increasing the technical failure rate of ultrasound scan as a screening method. The delay in the diagnosis of HCC in the setting of NAFLD/NASH and the presence of multiple comorbidities in this population negatively impacts prognosis. A better understanding of the mechanisms involved in the development of NAFLD/NASH-related HCC will allow the discovery of new targets for therapeutic and preventive intervention. REFERENCES
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