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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Veterans Affairs Medical Center, Univ. California San Francisco
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    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
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Diabetes and Risk of Hepatocellular Carcinoma in Cirrhosis Patients with Nonalcoholic Fatty Liver Disease

Pai-Chi Teng1,2,3 , Daniel Q. Huang4,5 , Ting-Yi Lin6 , Mazen Noureddin7 , Ju Dong Yang3,7,8

1Division of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei, 2Department of Urology, National Taiwan University Hospital, Taipei, Taiwan, 3Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA, 4Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 5Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, 6Doctoral Degree Program of Translational Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan, 7Karsh Division of Gastroenterology and Hepatology, and 8Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Correspondence to: Ju Dong Yang
ORCID https://orcid.org/0000-0001-7834-9825
E-mail JuDong.Yang@cshs.org

Received: August 14, 2022; Revised: September 9, 2022; Accepted: September 19, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2023;17(1):24-33. https://doi.org/10.5009/gnl220357

Published online December 19, 2022, Published date January 15, 2023

Copyright © Gut and Liver.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. NAFLD is a hepatic manifestation of insulin resistance, the core pathophysiology of diabetes. Multiple clinical studies show that diabetes increases the risk of liver disease progression and cirrhosis development in patients with NAFLD. Diabetes has causal associations with many different cancers, including hepatocellular carcinoma (HCC). More recent studies demonstrate that diabetes increases the risk of HCC in patients with underlying NAFLD cirrhosis, confirming the direct hepatocarcinogenic effect of diabetes among cirrhosis patients. Diabetes promotes hepatocarcinogenesis via the activation of inflammatory cascades producing reactive oxygen species and proinflammatory cytokines, leading to genomic instability, cellular proliferation, and inhibition of apoptosis. Given the global increase in the burden of NAFLD and HCC, high-risk patients such as older diabetic individuals should be carefully monitored for HCC development. Future larger studies should explore whether the effect of diabetes on HCC risk in NAFLD cirrhosis is modifiable by the type of antidiabetic medication and the effectiveness of diabetes control.

Keywords: Cirrhosis, Diabetes mellitus, Hepatocellular carcinoma, Non-alcoholic fatty liver disease

Hepatocellular carcinoma (HCC) comprises approximately 80% of primary liver cancer cases1 and leads to the fourth most common cancer-related death worldwide.2 Although new advances in systemic therapy, such as targeted therapies3 and immune checkpoint inhibitors,4 have substantially improved the clinical outcomes of patients with advanced HCC, early diagnosis is still essential since patients with early-stage HCC can potentially undergo curative-intent treatment.5 As such, identifying risk factors of HCC and implementing surveillance among at-risk patients play a crucial role in early-stage cancer detection and improving the prognosis of patients with HCC. The main risk factors for HCC include chronic hepatitis B virus, hepatitis C virus infection, heavy alcohol consumption, nonalcoholic fatty liver disease (NAFLD), aflatoxin,6 smoking, and type 2 diabetes with variation in the proportion of each risk factor by regions.7,8 These risk factors can result in cirrhosis, the strongest risk factor for HCC development.9,10

NAFLD includes a spectrum of diseases, such as simple hepatic steatosis and nonalcoholic steatohepatitis (NASH).11 A meta-analysis by Le et al.12 including 245 studies of approximately 5.4 million individuals reported that the global prevalence of NAFLD was 29.8%, with South America and North America having the highest prevalence (35.7% and 35.3%, respectively). Risk factors for NAFLD-related HCC include diabetes, obesity, metabolic syndrome, smoking, gut microbiome and bile acids, ethnicity, and genetics.13,14 Of note, diabetes is associated with higher rates of advanced fibrosis in patients with NASH15,16 and is the most significant population-attributable fraction of risk factors for HCC in the United States.17

In this review, we will discuss the role of diabetes on the risk of HCC in patients with cirrhosis and NAFLD. We will also summarize risk stratification, prediction models, and potential preventive strategies for these patients.

NAFLD can account for up to 38% of the HCC burden in some regions and is the most rapidly growing cause of HCC worldwide.7,18 Karim et al.19 identified 5,098 HCC patients in the United States from the Surveillance, Epidemiology and End Results–Medicare database and reported that NAFLD was the leading cause of HCC (35.6%). The authors also found that NAFLD was associated with lower surveillance receipt (adjusted odds ratio [aOR], 0.31) and more unrecognized cirrhosis at HCC diagnosis (aOR, 4.42). Dyson et al.20 reported that the proportion of NAFLD-associated HCC increased from <10% in 2000 to 35% in 2010, and the proportion might be substantially higher because only patients with histologic or radiological evidence were considered to define NAFLD, while half the HCC patients with no known chronic liver disease had at least one metabolic risk factor. Estes et al.21 projected that the incidence of NAFLD-associated HCC in the United Kingdom would increase by 88% from 2016 to 2030, and the incidence would be the highest in Germany in 2030. Similarly, the incidence of NAFLD-related HCC by 2030 is projected to rise by 82%, 117%, and 122% from 2016 in China, France, and the United States, respectively.7 Rising rates of obesity may contribute to the increasing incidence of diabetes and NAFLD as well as NAFLD-related HCC. A United States-based study by Lee et al.22 demonstrated a moderate, positive correlation between the temporal trend of HCC incidence rates and obesity prevalence among different states. In addition, state-level physical activity was inversely associated with the trend of HCC incidence rates, which suggested that NAFLD may have a significant impact on the ongoing rise in HCC incidences in some states.

A meta-analysis including 18 studies with 470,404 patients showed that the incidence of HCC in patients with NAFLD was 0.03 per 100 person-years, compared to 3.78 per 100 person-years in those with cirrhosis.23 In contrast to viral hepatitis-related and alcohol-related HCC, which typically occurs in the setting of underlying cirrhosis, NAFLD-associated HCC can develop without cirrhosis.24 A recent U.S. population-based study showed that only 57.9% of patients with NAFLD-related HCC had confirmed cirrhosis,19 and a meta-analysis including 61 studies demonstrated that 38.5% of patients with NAFLD-related HCC did not have cirrhosis.25 Rates of NAFLD-related HCC were estimated at 0.01 to 0.08 per 100 person-years in patients with non-cirrhotic liver.13 The absence of cirrhosis often leads to late detection of HCC in NAFLD patients as cancers are often diagnosed when patients develop cancer-related symptoms in the absence of a surveillance program.

Multiple studies confirmed diabetes as a risk factor for HCC. El-Serag et al.26 published a prospective cohort study, including 173,643 diabetic patients and 650,620 non-diabetic patients, and reported that diabetes was significantly associated with NAFLD (hazard ratio [HR], 1.98) and HCC (HR, 2.16). They also found that diabetic patients with more than 10 years of follow-up carried the highest risk. Hassan et al.27 conducted a hospital-based case-control study comparing 420 HCC patients with 1,104 healthy controls and found that diabetes was more prevalent in HCC patients (aOR, 4.2). Compared to patients with a diabetes duration of 2 to 5 years, patients with a diabetes duration of 6 to 10 years and more than 10 years had an OR of 1.8 and 2.2 for HCC, respectively. This suggests that the duration of diabetes is associated with the risk of HCC development.

A systematic review by El-Serag et al.28 exhibited that type 2 diabetes was associated with an approximately 2.5-fold increase in the risk for HCC. In addition, the risk estimate from 13 case-control studies indicated a 2.5-fold increased odds of diabetes in patients with HCC compared to controls without diabetes. Kanwal et al.29 conducted a study of 271,906 NAFLD patients from 130 facilities in the Veterans Administration with a mean follow-up of 9 years. They observed a stepwise increase in the risk of developing cirrhosis or HCC with each additional metabolic trait (i.e., obesity, diabetes, hypertension, and dyslipidemia), and diabetes had an adjusted HR of 2.77 and 1.31 for developing HCC and cirrhosis, respectively.29 Moreover, NAFLD is associated with an approximately 2-fold risk of diabetes, independent of obesity and other metabolic traits. The risk of diabetes is also correlated with the severity of NAFLD.30

Studies showed that the prevalence of diabetes increased with liver disease progression and cirrhosis development.31,32 Diabetes also accelerates fibrosis progression in NASH patients.15 More recently, several studies investigated the association between diabetes and HCC in NASH cirrhosis patients to determine if diabetes has a direct carcinogenic effect independent of liver disease progression. In this study, diabetic patients had an increased risk of developing HCC in a Mayo Clinic Rochester cohort (n=354 patients with NASH cirrhosis; HR, 4.2) and a United Network for Organ Sharing cohort (n=6,630 NASH registrants; HR, 1.3) in multivariable analyses.33 Similar results were seen in a nationwide study involving 130 Veterans Administration facilities by Kanwal et al.34 suggesting a 1.5-fold increased risk of HCC among NAFLD cirrhosis patients with diabetes compared to those without diabetes.

Diabetes mellitus, type 2, is characterized by hyperglycemia, hyperinsulinemia, and insulin resistance, which can contribute to hepatocarcinogenesis (Fig. 1).35 Hyperglycemia initiates modification in cell vasculature and causes endothelial cell debilitation, resulting in increased growth factor production, upregulation of inflammatory genes, excessive generation of reactive oxygen species (ROS), increased oxidative stress, and enhanced cell permeability. Vascular endothelial growth factor in response to endothelial damage stimulates the proliferation of liver cells and the development of HCC.36 ROS can interact with lipids and amino acids and damage DNA.37 For example, ROS may induce mutations in TP53, which is a tumor suppressor gene.38 Hyperinsulinemia leads to de novo lipogenesis and consequently lipid accumulation within the liver.39 Adipocytes excrete adipokines and leptin that promote insulin resistance.40,41 Cytokines produced by the liver, infiltrating immune cells, and adipocytes, such as tumor necrosis factor α, interleukin 6, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), due to chronic lipid accumulation and lipotoxicity can also lead to insulin resistance, which further accelerates the defects in insulin signaling in pancreatic β cells.42,43 In addition, adipocytes produce adiponectin, a peptide hormone that enhances insulin reaction, decreases triglyceride synthesis, and stimulates β oxidation in favor of lipid clearance in skeletal muscle and liver.44 Clinically, the leptin to adiponectin ratio can be used to measure insulin resistance, with lower values associated with higher insulin sensitivity and lower cardiovascular risks.45 Hyperinsulinemia also involves upregulation of the insulin growth factor (IGF) pathway as the consequence of overexpressed IGF-1 and aberrantly expressed fetal IGF-2.46 IGF-1 then activates protein kinase B/mammalian target of rapamycin (AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways, which inhibit apoptosis and enhance cell proliferation.47 Activation of the IGF pathway has been observed in a subset of human HCC.46 Besides, the production of free fatty acids also activates c-Jun N-terminal kinase 1 (JNK1) that inhibits cell apoptosis.48

Figure 1.Brief illustration of hepatocarcinogenesis in diabetes. Diabetes enhances the production of FFA, insulin secretion, and IR. These lead to increased reactive oxygen species, inflammation, and oxidative stress in adipocytes and hepatocytes. Impaired PKC, NF-κB, STAT, leptin, and TNF-α cascades due to diabetes also accelerate fibrosis by stellate cells and contribute to hepatocarcinogenesis.
FFA, free fatty acid; IR, insulin resistance; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; ox-phosphorylation, oxidative phosphorylation; PKC, protein kinase C; STAT, signal transducer and activator of transcription protein; TNF-α, tumor necrosis factor α; HCC, hepatocellular carcinoma.

Fujii et al.49 developed a murine model and proposed that NASH-based fibrosis might be a pivotal link to diabetes and HCC. They exposed neonatal mice to low-dose streptozotocin, and the mice developed liver steatosis with diabetes after 1 week of a high-fat diet. Liver biopsy displayed increased lobular inflammation and foam cell-like macrophages, consistent with NASH pathology. In parallel, fibroblasts accumulated to form chicken-wired fibrosis, and all of these mice developed HCC later. Interestingly, mice with diabetes alone but without NASH-based fibrosis never developed HCC.49 More biological studies are still necessary to comprehensively determine the pathophysiological role of diabetes in cirrhosis and NAFLD-associated HCC.

HCC risk stratification of non-cirrhotic NAFLD and early recognition of cirrhosis among patients with NAFLD will be critical to increase surveillance implementation and earlier detection of HCC eventually leading to utilization of curative-intent treatment and improved survival.19 Cirrhotic patients of any etiology are recommended to undergo semiannual HCC surveillance based on the American Association for the Study of Liver Diseases or the European Association for the Study of the Liver guideline. However, the risks are still heterogeneous across all cirrhotic and non-cirrhotic patients. Thus, several prediction models considering different etiologies were used for better risk stratification, especially for cirrhotic NAFLD patients (e.g., ADRESS-HCC,50 THRI score,51 and APAC score52). The ADRESS-HCC represented the first model derived from 34,932 cirrhotic patients, and the primary etiology of cirrhosis (NASH, hepatitis C virus, alcohol, hepatitis B virus, others) was associated with 1-year HCC risk. The ADRESS-HCC model could differentiate whether the cirrhotic patients would develop HCC with a C-index of around 0.7.50 The primary etiology of cirrhosis in the THRI score included steatohepatitis, viral hepatitis, primary biliary cirrhosis, and autoimmune hepatitis. The THRI model could predict 10-year cumulative HCC incidence, with 3%, 10%, and 32% for scores <120, 120 to 240, and >240, respectively.51 The APAC score was based on serum sPDGFRβ (soluble platelet-derived growth factor receptor β), age, serum alpha-fetoprotein (AFP), and creatinine and categorized the etiology of cirrhosis into NAFLD, viral hepatitis, and alcohol. The APAC score could predict HCC with an area under the curve (AUC) of 0.95. The AUC was also around 0.95 in a sub-analysis of NAFLD-associated cirrhosis.52 Most recently, a study reported prognostic liver signature (PLS)–NAFLD, which predicted incident HCC over up to 15 years of longitudinal observation.53 Four-protein secretome signature, PLSec-NAFLD, showed excellent risk stratification among NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6% and 0% in high- and low-risk patients, respectively).53

In non-cirrhotic NAFLD patients, HCC screening by ultrasonography and serum AFP levels could be considered in the presence of advanced fibrosis (F3).7 Besides, ethnicity and genetics may play an essential role on risk stratification in this population. For example, Hispanics have higher rates of NAFLD-associated HCC in the United States, possibly due to their higher rates of metabolic syndromes.34,54,55 The PNPLA3 single-nucleotide polymorphisms (SNPs) are strongly linked to HCC.7 Genome-wide association studies (GWAS) have also uncovered SNPs of many other genes that contribute to NAFLD-associated HCC, including TM6SF2, MBOAT7, GCKR, HSD17B13, etc.13 Therefore, researchers built polygenic risk score (PRS) models, which consider effects of different SNPs at different genes, combined with clinical features to predict risks on developing HCC.56-59 For example, Bianco et al.56 developed two PRS models considering four (PNPLA3, TM6SF2, MBOAT7, and GCKR) or five (adjusted for the rs72613567 HSD17B13) genetic variants in Italian and the U.K. cohorts. These two models could predict HCC in NAFLD patients with or without cirrhosis, with an AUC of around 0.65. Gellert-Kristensen et al.57 established a PRS model based on PNPLA3, TM6SF2, and HSD17B13 in United Kingdom and Danish cohorts. This model demonstrated up to a 12-fold and a 29-fold higher risk of cirrhosis and HCC, respectively. Pelusi et al.58 and Donati et al.59 also demonstrated PRS models with outstanding AUC (>0.9), but these require further careful validation. Despite these potential PRS models, risk stratification without genetic input is more likely feasible in the clinical setting since GWAS is currently not applicable to each individual. For instance, the GALAD score considers gender, age, AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy prothrombin and has been used in many studies.60 In a German cohort with 356 NAFLD patients, the GALAD score could identify HCC patients with an AUC of 0.96. Notably, the AUC for detecting HCC based on the GALAD score in NASH patients without cirrhosis was 0.98.60 Liver enzymes, platelets number, serum albumin levels, and presence of diabetes were also proposed as variables in some risk stratification models.61

Researchers have extensively developed liquid biopsy, including circulating tumor DNA,62 circulating tumor cells,63 and extracellular vesicles,64 for HCC biomarkers. For example, Kalinich et al.65 utilized digital polymerase chain reaction (dPCR) to quantify RNA expression of 10 HCC-relevant genes in purified circulating tumor cells and yield genetic scores that had values in screening high-risk patients. Sun et al.66 also detected the same 10-gene expression by dPCR in purified HCC extracellular vesicles that could aid with early diagnosis of HCC. The dPCR can quantify tiny amounts of DNA or RNA, as sensitive as one copy per cell, which is a huge advance in the early diagnosis of malignancy at a low cost. The combination of the cutting-edge dPCR system and liquid biopsy may allow these blood-based, noninvasive biomarkers to hold great potential for early diagnosis of HCC, particularly in patients with non-cirrhotic NAFLD.

Given the strong association of obesity with insulin resistance, diabetes, and HCC,67-69 encouraging physical activity to control weight and other major metabolic traits is a rational and cost-effective way to prevent the development of HCC. Smoking cessation should be encouraged for HCC prevention with the evidence from a meta-analysis demonstrating a pooled OR of 1.55 and 1.39 for HCC in current and former smokers, respectively.70

Although life modifications are cost-effective and the first step for diabetes management, most patients still require antihyperglycemic agents. Metformin, a biguanide, has long been the first-line medication for managing diabetes. In addition, metformin can inhibit mitochondrial respiration with decreased adenosine triphosphate (ATP) production. Reduced ATP production activates the adenosine monophosphate-activated protein kinase signaling pathway, resulting in mTOR pathway inactivation and subsequent inhibition of cancer cell proliferation (Fig. 2).71 Metformin also regulates the glucose metabolic intermediate to influence de novo lipid biosynthesis.72 Other anti-tumor mechanisms of metformin include epigenetic modification, immunoregulation via the NF-κB pathway, and regulation of autophagy.73 Clinically, metformin can help lose weight and increase insulin sensitivity.74

Figure 2.Possible mechanisms of protective effects against hepatocellular carcinoma by metformin. Metformin may inhibit cell proliferation via AMPK and PI3K pathways. Metformin is also an autophagy inducer that can prohibit carcinogenesis by inhibiting IL-6. Arrows denote facilitation and blunt arrows denote inhibition.
AMPK, adenosine monophosphate (AMP)-activated protein kinase; IL-6, interleukin 6; IRS1, insulin receptor substrate 1; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B (also known as PKB); JAK, Janus kinase; TSC, tuberous sclerosis complex; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; STAT, signal transducer and activator of transcription protein; Rheb, Ras homolog enriched in brain; mTOR, mammalian target of rapamycin.

Chen et al.75 conducted a nationwide case-control study, recruiting 97,430 HCC patients and 194,860 match controls, and found that each incremental year increase in metformin use led to a 7% reduction in the risk of HCC (aOR, 0.93), for diabetic patients, indicating a strong dose-dependent relation. A meta-analysis by Singh et al.76 including 10 studies of 22,650 HCC cases in 334,307 patients with type 2 diabetes showed that metformin use was associated with decreased risk of HCC with an OR of 0.50. Interestingly, sulfonylurea and insulin use was significantly associated with an increased HCC risk (OR of 1.62 and 2.61, respectively). Kramer et al.77 assembled a retrospective cohort of 85,936 patients with NAFLD and diabetes from 130 Veterans Administration facilities. They reported that, in landmark multivariate Cox proportional hazards models, metformin use was associated with an HR of 0.80 for developing HCC. The use of insulin alone or sulfonylureas alone was not significantly associated with the risk of HCC compared with no antihyperglycemic agent use.77 Still, insulin in combination with other oral antihyperglycemic agents was associated with a 1.6- to 1.7-fold higher risk of developing HCC. More importantly, patients with adequate glycemic control were associated with an HR of 0.69 for developing HCC.77 In a subgroup analysis of patients who received at least one diabetes medication, the use of insulin or sulfonylureas was associated with a 44% and 31% higher risk of HCC compared to metformin, respectively.77 Another systemic review by Cunha et al.78 showed an OR of 0.468 for the risk of HCC in metformin users. Tseng performed a propensity score-matched study pairing 21,900 ever-users and never-users of metformin. This case-control study reported an overall HR of 0.49 for developing HCC in metformin ever-users.79

In recent years, sodium-glucose linked transporter-2 (SGLT2) inhibitors have attracted attention not only for their efficacy in treating hyperglycemia but also for their outstanding effects on cardiovascular and renal protection.80,81 By inhibiting SGLT2 in the kidney, the inhibitors lead to glycosuria, resulting in decreased serum glucose, caloric deficit, and thus weight loss.82 Researchers have also observed the potential of SGLT2 inhibitors against HCC and other malignancies due to the established correlation between hyperglycemia and HCC. For example, Luo et al.83 reported that canagliflozin (an SGLT2 inhibitor) could decrease HIF-1α protein synthesis via the AKT/mTOR pathway, leading to reduced hypoxia-induced metastasis and angiogenesis in HCC. Many others also demonstrated consistent results of the effects of canagliflozin and other SGLT2 inhibitors on HCC cells.82 A meta-analysis of multiple randomized controlled trials by Benedetti et al.84 exhibited an overall reduced risk of cancer (not limited to HCC) in users of SGLT2 inhibitors, with a risk ratio of 0.35.

Statins inhibit the conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate. The inhibition of this pathway by statins prevents the formation of both mevalonate and its downstream product, which have several pathophysiological functions potentially involved in carcinogenesis.85 Singh et al.86 conducted a meta-analysis including 10 studies with 4,298 HCC cases in 1,459,417 patients and showed that statin use was associated with a significantly lower risk of developing HCC (aOR, 0.63). A more recent meta-analysis by Zou et al.87 including 272,431 patients with NAFLD reported that statin users had a lower risk of developing HCC than nonusers (HR, 0.47). Statin initiation was still associated with a lower risk of HCC after adjusting for fibrosis-4 index score (HR, 0.49). They also showed that statin had a protective effect against HCC in patients with NAFLD in a dose-dependent manner.87 Aspirin, a cyclooxygenase (COX) inhibitor, was also proposed to have a protective effect against HCC because chronic inflammation could trigger the COX-2 signaling pathway, resulting in decreased apoptosis, increased cell proliferation, and angiogenesis.88,89 A pooled analysis of two prospective cohort studies in the United States involving 133,371 healthcare professionals reported that regular use of at least 650 mg of aspirin a week was associated with a 50% reduction in HCC risk (adjusted HR, 0.51).90 However, the chemopreventive effect of these medications has not been rigorously evaluated in the context of NASH and requires further evaluation in prospective studies.

Diabetes is an important risk factor for HCC development in patients with NAFLD. Diabetes also increases the risk of developing HCC in patients with NAFLD cirrhosis. Hepatocarcinogenic effects of diabetes include increased ROS production, endothelial damage, release of proinflammatory cytokines, and activation of the IGF pathway. Based on a murine model, NAFLD fibrosis may serve as a pivotal link between diabetes and HCC development. Several HCC risk stratification models were proposed, and it will be useful to determine surveillance strategies for the early detection of HCC in these patients. Since diabetes is a potentially modifiable risk factor, researchers have established preventive strategies focused on diabetes and relevant metabolic traits including physical activity (or exercise) and chemoprevention using metformin, SGLT2 inhibitors, statin, and aspirin. More biological studies are required to delineate the pathophysiological role of diabetes in patients with cirrhosis and refine risk stratification and prevention of NAFLD-associated HCC with new therapeutics.

  1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-249.
    Pubmed CrossRef
  2. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019;16:589-604.
    Pubmed KoreaMed CrossRef
  3. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.
    Pubmed CrossRef
  4. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894-1905.
    Pubmed CrossRef
  5. Yang JD, Heimbach JK. New advances in the diagnosis and management of hepatocellular carcinoma. BMJ 2020;371:m3544.
    Pubmed CrossRef
  6. Kew MC. Aflatoxins as a cause of hepatocellular carcinoma. J Gastrointestin Liver Dis 2013;22:305-310.
    Pubmed
  7. Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2021;18:223-238.
    Pubmed KoreaMed CrossRef
  8. Teng PC, Agopian VG, Lin TY, et al. Circulating tumor cells: a step toward precision medicine in hepatocellular carcinoma. J Gastroenterol Hepatol 2022;37:1179-1190.
    Pubmed KoreaMed CrossRef
  9. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127(5 Suppl 1):S35-S50.
    Pubmed CrossRef
  10. Singal AG, Zhang E, Narasimman M, et al. HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: a meta-analysis. J Hepatol 2022;77:128-139.
    Pubmed KoreaMed CrossRef
  11. Noureddin M, Sanyal AJ. Pathogenesis of NASH: the impact of multiple pathways. Curr Hepatol Rep 2018;17:350-360.
    Pubmed KoreaMed CrossRef
  12. Le MH, Yeo YH, Li X, et al. 2019 Global NAFLD prevalence: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2022;20:2809-2817.e28.
    Pubmed CrossRef
  13. Shah PA, Patil R, Harrison SA. NAFLD-related hepatocellular carcinoma: the growing challenge. Hepatology. Epub 2022 Apr 28. https://doi.org/10.1002/hep.32542.
    Pubmed CrossRef
  14. Noureddin M, Rinella ME. Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis 2015;19:361-379.
    Pubmed KoreaMed CrossRef
  15. Pelusi S, Petta S, Rosso C, et al. Renin-angiotensin system inhibitors, type 2 diabetes and fibrosis progression: an observational study in patients with nonalcoholic fatty liver disease. PLoS One 2016;11:e0163069.
    Pubmed KoreaMed CrossRef
  16. Noureddin M, Ntanios F, Malhotra D, et al. Predicting NAFLD prevalence in the United States using National Health and Nutrition Examination Survey 2017-2018 transient elastography data and application of machine learning. Hepatol Commun 2022;6:1537-1548.
    Pubmed KoreaMed CrossRef
  17. Welzel TM, Graubard BI, Quraishi S, et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am J Gastroenterol 2013;108:1314-1321.
    Pubmed KoreaMed CrossRef
  18. Huang DQ, Singal AG, Kono Y, Tan DJ, El-Serag HB, Loomba R. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab 2022;34:969-977.
    Pubmed CrossRef
  19. Karim MA, Singal AG, Kum HC, et al. Clinical characteristics and outcomes of nonalcoholic fatty liver disease-associated hepatocellular carcinoma in the United States. Clin Gastroenterol Hepatol. Epub 2022 Mar 17. https://doi.org/10.1016/j.cgh.2022.03.010.
    Pubmed KoreaMed CrossRef
  20. Dyson J, Jaques B, Chattopadyhay D, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 2014;60:110-117.
    Pubmed CrossRef
  21. Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol 2018;69:896-904.
    Pubmed CrossRef
  22. Lee YT, Wang JJ, Luu M, et al. State-level HCC incidence and association with obesity and physical activity in the United States. Hepatology 2021;74:1384-1394.
    Pubmed CrossRef
  23. Orci LA, Sanduzzi-Zamparelli M, Caballol B, et al. Incidence of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression. Clin Gastroenterol Hepatol 2022;20:283-292.
    Pubmed CrossRef
  24. Stine JG, Wentworth BJ, Zimmet A, et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment Pharmacol Ther 2018;48:696-703.
    Pubmed KoreaMed CrossRef
  25. Tan DJH, Ng CH, Lin SY, et al. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis. Lancet Oncol 2022;23:521-530.
    Pubmed KoreaMed CrossRef
  26. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126:460-468.
    Pubmed CrossRef
  27. Hassan MM, Curley SA, Li D, et al. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer 2010;116:1938-1946.
    Pubmed KoreaMed CrossRef
  28. El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006;4:369-380.
    Pubmed CrossRef
  29. Kanwal F, Kramer JR, Li L, et al. Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in nonalcoholic fatty liver disease. Hepatology 2020;71:808-819.
    Pubmed CrossRef
  30. Targher G, Corey KE, Byrne CD, Roden M. The complex link between NAFLD and type 2 diabetes mellitus: mechanisms and treatments. Nat Rev Gastroenterol Hepatol 2021;18:599-612.
    Pubmed CrossRef
  31. Veldt BJ, Chen W, Heathcote EJ, et al. Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 2008;47:1856-1862.
    Pubmed CrossRef
  32. Gentile S, Loguercio C, Marmo R, Carbone L, Del Vecchio Blanco C. Incidence of altered glucose tolerance in liver cirrhosis. Diabetes Res Clin Pract 1993;22:37-44.
    Pubmed CrossRef
  33. Yang JD, Ahmed F, Mara KC, et al. Diabetes is associated with increased risk of hepatocellular carcinoma in patients with cirrhosis from nonalcoholic fatty liver disease. Hepatology 2020;71:907-916.
    Pubmed KoreaMed CrossRef
  34. Kanwal F, Kramer JR, Mapakshi S, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 2018;155:1828-1837.
    Pubmed KoreaMed CrossRef
  35. Singh MK, Das BK, Choudhary S, Gupta D, Patil UK. Diabetes and hepatocellular carcinoma: a pathophysiological link and pharmacological management. Biomed Pharmacother 2018;106:991-1002.
    Pubmed CrossRef
  36. Moon WS, Rhyu KH, Kang MJ, et al. Overexpression of VEGF and angiopoietin 2: a key to high vascularity of hepatocellular carcinoma? Mod Pathol 2003;16:552-557.
    Pubmed CrossRef
  37. Popova EA, Mironova RS, Odjakova MK. Non-enzymatic glycosylation and deglycating enzymes. Biotechnol Biotechnol Equip 2014;24:1928-1935.
    CrossRef
  38. Assi M. The differential role of reactive oxygen species in early and late stages of cancer. Am J Physiol Regul Integr Comp Physiol 2017;313:R646-R653.
    Pubmed CrossRef
  39. Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci 2014;15:8591-8638.
    Pubmed KoreaMed CrossRef
  40. Wang TN, Chang WT, Chiu YW, et al. Relationships between changes in leptin and insulin resistance levels in obese individuals following weight loss. Kaohsiung J Med Sci 2013;29:436-443.
    Pubmed CrossRef
  41. Coppack SW. Adipose tissue changes in obesity. Biochem Soc Trans 2005;33(Pt 5):1049-1052.
    Pubmed CrossRef
  42. Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol (Lausanne) 2013;4:37.
    Pubmed KoreaMed CrossRef
  43. Allaire M, Nault JC. Type 2 diabetes-associated hepatocellular carcinoma: a molecular profile. Clin Liver Dis (Hoboken) 2016;8:53-58.
    Pubmed KoreaMed CrossRef
  44. Yadav A, Jyoti P, Jain SK, Bhattacharjee J. Correlation of adiponectin and leptin with insulin resistance: a pilot study in healthy north Indian population. Indian J Clin Biochem 2011;26:193-196.
    Pubmed KoreaMed CrossRef
  45. Finucane FM, Luan J, Wareham NJ, et al. Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals. Diabetologia 2009;52:2345-2349.
    Pubmed KoreaMed CrossRef
  46. Tovar V, Alsinet C, Villanueva A, et al. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol 2010;52:550-559.
    Pubmed KoreaMed CrossRef
  47. Chettouh H, Lequoy M, Fartoux L, Vigouroux C, Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int 2015;35:2203-2217.
    Pubmed CrossRef
  48. Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol 2013;10:656-665.
    Pubmed CrossRef
  49. Fujii M, Shibazaki Y, Wakamatsu K, et al. A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma. Med Mol Morphol 2013;46:141-152.
    Pubmed CrossRef
  50. Flemming JA, Yang JD, Vittinghoff E, Kim WR, Terrault NA. Risk prediction of hepatocellular carcinoma in patients with cirrhosis: the ADRESS-HCC risk model. Cancer 2014;120:3485-3493.
    Pubmed KoreaMed CrossRef
  51. Sharma SA, Kowgier M, Hansen BE, et al. Toronto HCC risk index: a validated scoring system to predict 10-year risk of HCC in patients with cirrhosis. J Hepatol 2018;68:P92-P99.
    Pubmed CrossRef
  52. Lambrecht J, Porsch-Özçürümez M, Best J, et al. The APAC score: a novel and highly performant serological tool for early diagnosis of hepatocellular carcinoma in patients with liver cirrhosis. J Clin Med 2021;10:3392.
    Pubmed KoreaMed CrossRef
  53. Fujiwara N, Kubota N, Crouchet E, et al. Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease. Sci Transl Med 2022;14:eabo4474.
    Pubmed KoreaMed CrossRef
  54. Weston SR, Leyden W, Murphy R, et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology 2005;41:372-379.
    Pubmed CrossRef
  55. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356-359.
    Pubmed CrossRef
  56. Bianco C, Jamialahmadi O, Pelusi S, et al. Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores. J Hepatol 2021;74:775-782.
    Pubmed KoreaMed CrossRef
  57. Gellert-Kristensen H, Richardson TG, Davey Smith G, Nordestgaard BG, Tybjaerg-Hansen A, Stender S. Combined effect of PNPLA3, TM6SF2, and HSD17B13 variants on risk of cirrhosis and hepatocellular carcinoma in the general population. Hepatology 2020;72:845-856.
    Pubmed CrossRef
  58. Pelusi S, Baselli G, Pietrelli A, et al. Rare pathogenic variants predispose to hepatocellular carcinoma in nonalcoholic fatty liver disease. Sci Rep 2019;9:3682.
    Pubmed KoreaMed CrossRef
  59. Donati B, Dongiovanni P, Romeo S, et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep 2017;7:4492.
    Pubmed KoreaMed CrossRef
  60. Yang JD, Addissie BD, Mara KC, et al. GALAD score for hepatocellular carcinoma detection in comparison with liver ultrasound and proposal of GALADUS score. Cancer Epidemiol Biomarkers Prev 2019;28:531-538.
    Pubmed KoreaMed CrossRef
  61. Younes R, Caviglia GP, Govaere O, et al. Long-term outcomes and predictive ability of non-invasive scoring systems in patients with non-alcoholic fatty liver disease. J Hepatol 2021;75:786-794.
    Pubmed CrossRef
  62. Wu X, Li J, Gassa A, et al. Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma. Int J Biol Sci 2020;16:1551-1562.
    Pubmed KoreaMed CrossRef
  63. Ahn JC, Teng PC, Chen PJ, et al. Detection of circulating tumor cells and their implications as a biomarker for diagnosis, prognostication, and therapeutic monitoring in hepatocellular carcinoma. Hepatology 2021;73:422-436.
    Pubmed KoreaMed CrossRef
  64. Lee YT, Tran BV, Wang JJ, et al. The role of extracellular vesicles in disease progression and detection of hepatocellular carcinoma. Cancers (Basel) 2021;13:3076.
    Pubmed KoreaMed CrossRef
  65. Kalinich M, Bhan I, Kwan TT, et al. An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma. Proc Natl Acad Sci U S A 2017;114:1123-1128.
    Pubmed KoreaMed CrossRef
  66. Sun N, Lee YT, Zhang RY, et al. Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring. Nat Commun 2020;11:4489.
    Pubmed KoreaMed CrossRef
  67. Polesel J, Zucchetto A, Montella M, et al. The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma. Ann Oncol 2009;20:353-357.
    Pubmed CrossRef
  68. Regimbeau JM, Colombat M, Mognol P, et al. Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl 2004;10(2 Suppl 1):S69-S73.
    Pubmed CrossRef
  69. Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM. Obesity and hepatocellular carcinoma. Gastroenterology 2004;127(5 Suppl 1):S97-S103.
    Pubmed CrossRef
  70. Abdel-Rahman O, Helbling D, Schöb O, et al. Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: an updated systematic review of 81 epidemiological studies. J Evid Based Med 2017;10:245-254.
    Pubmed CrossRef
  71. Amable G, Martínez-León E, Picco ME, et al. Metformin inhibits β-catenin phosphorylation on Ser-552 through an AMPK/PI3K/Akt pathway in colorectal cancer cells. Int J Biochem Cell Biol 2019;112:88-94.
    Pubmed CrossRef
  72. Loubière C, Goiran T, Laurent K, Djabari Z, Tanti JF, Bost F. Metformin-induced energy deficiency leads to the inhibition of lipogenesis in prostate cancer cells. Oncotarget 2015;6:15652-15661.
    Pubmed KoreaMed CrossRef
  73. Zhao B, Luo J, Yu T, Zhou L, Lv H, Shang P. Anticancer mechanisms of metformin: a review of the current evidence. Life Sci 2020;254:117717.
    Pubmed CrossRef
  74. Golay A. Metformin and body weight. Int J Obes (Lond) 2008;32:61-72.
    Pubmed CrossRef
  75. 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;62:606-615.
    Pubmed CrossRef
  76. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol 2013;108:881-891.
    Pubmed CrossRef
  77. Kramer JR, Natarajan Y, Dai J, et al. Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease. Hepatology 2022;75:1420-1428.
    Pubmed KoreaMed CrossRef
  78. Cunha V, Cotrim HP, Rocha R, Carvalho K, Lins-Kusterer L. Metformin in the prevention of hepatocellular carcinoma in diabetic patients: a systematic review. Ann Hepatol 2020;19:232-237.
    Pubmed CrossRef
  79. Tseng CH. Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes. Liver Int 2018;38:2018-2027.
    Pubmed CrossRef
  80. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol 2021;6:148-158.
    Pubmed KoreaMed CrossRef
  81. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31-39.
    Pubmed CrossRef
  82. Arvanitakis K, Koufakis T, Kotsa K, Germanidis G. The effects of sodium-glucose cotransporter 2 inhibitors on hepatocellular carcinoma: from molecular mechanisms to potential clinical implications. Pharmacol Res 2022;181:106261.
    Pubmed CrossRef
  83. Luo J, Sun P, Zhang X, et al. Canagliflozin modulates hypoxia-induced metastasis, angiogenesis and glycolysis by decreasing HIF-1α protein synthesis via AKT/mTOR pathway. Int J Mol Sci 2021;22:13336.
    Pubmed KoreaMed CrossRef
  84. Benedetti R, Benincasa G, Glass K, et al. Effects of novel SGLT2 inhibitors on cancer incidence in hyperglycemic patients: a meta-analysis of randomized clinical trials. Pharmacol Res 2022;175:106039.
    Pubmed CrossRef
  85. El-Serag HB, Johnson ML, Hachem C, Morgana RO. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 2009;136:1601-1608.
    Pubmed KoreaMed CrossRef
  86. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 2013;144:323-332.
    Pubmed CrossRef
  87. Zou B, Odden MC, Nguyen MH. Statin use and reduced hepatocellular carcinoma risk in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. Epub 2022 Feb 11. https://doi.org/10.1016/j.cgh.2022.01.057.
    Pubmed CrossRef
  88. Chen H, Cai W, Chu ES, et al. Hepatic cyclooxygenase-2 overexpression induced spontaneous hepatocellular carcinoma formation in mice. Oncogene 2017;36:4415-4426.
    Pubmed KoreaMed CrossRef
  89. Kern MA, Schubert D, Sahi D, et al. Proapoptotic and antiproliferative potential of selective cyclooxygenase-2 inhibitors in human liver tumor cells. Hepatology 2002;36(4 Pt 1):885-894.
    Pubmed CrossRef
  90. Simon TG, Ma Y, Ludvigsson JF, et al. Association between aspirin use and risk of hepatocellular carcinoma. JAMA Oncol 2018;4:1683-1690.
    Pubmed KoreaMed CrossRef

Article

Review Article

Gut and Liver 2023; 17(1): 24-33

Published online January 15, 2023 https://doi.org/10.5009/gnl220357

Copyright © Gut and Liver.

Diabetes and Risk of Hepatocellular Carcinoma in Cirrhosis Patients with Nonalcoholic Fatty Liver Disease

Pai-Chi Teng1,2,3 , Daniel Q. Huang4,5 , Ting-Yi Lin6 , Mazen Noureddin7 , Ju Dong Yang3,7,8

1Division of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei, 2Department of Urology, National Taiwan University Hospital, Taipei, Taiwan, 3Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA, 4Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 5Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, 6Doctoral Degree Program of Translational Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan, 7Karsh Division of Gastroenterology and Hepatology, and 8Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Correspondence to:Ju Dong Yang
ORCID https://orcid.org/0000-0001-7834-9825
E-mail JuDong.Yang@cshs.org

Received: August 14, 2022; Revised: September 9, 2022; Accepted: September 19, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. NAFLD is a hepatic manifestation of insulin resistance, the core pathophysiology of diabetes. Multiple clinical studies show that diabetes increases the risk of liver disease progression and cirrhosis development in patients with NAFLD. Diabetes has causal associations with many different cancers, including hepatocellular carcinoma (HCC). More recent studies demonstrate that diabetes increases the risk of HCC in patients with underlying NAFLD cirrhosis, confirming the direct hepatocarcinogenic effect of diabetes among cirrhosis patients. Diabetes promotes hepatocarcinogenesis via the activation of inflammatory cascades producing reactive oxygen species and proinflammatory cytokines, leading to genomic instability, cellular proliferation, and inhibition of apoptosis. Given the global increase in the burden of NAFLD and HCC, high-risk patients such as older diabetic individuals should be carefully monitored for HCC development. Future larger studies should explore whether the effect of diabetes on HCC risk in NAFLD cirrhosis is modifiable by the type of antidiabetic medication and the effectiveness of diabetes control.

Keywords: Cirrhosis, Diabetes mellitus, Hepatocellular carcinoma, Non-alcoholic fatty liver disease

INTRODUCTION

Hepatocellular carcinoma (HCC) comprises approximately 80% of primary liver cancer cases1 and leads to the fourth most common cancer-related death worldwide.2 Although new advances in systemic therapy, such as targeted therapies3 and immune checkpoint inhibitors,4 have substantially improved the clinical outcomes of patients with advanced HCC, early diagnosis is still essential since patients with early-stage HCC can potentially undergo curative-intent treatment.5 As such, identifying risk factors of HCC and implementing surveillance among at-risk patients play a crucial role in early-stage cancer detection and improving the prognosis of patients with HCC. The main risk factors for HCC include chronic hepatitis B virus, hepatitis C virus infection, heavy alcohol consumption, nonalcoholic fatty liver disease (NAFLD), aflatoxin,6 smoking, and type 2 diabetes with variation in the proportion of each risk factor by regions.7,8 These risk factors can result in cirrhosis, the strongest risk factor for HCC development.9,10

NAFLD includes a spectrum of diseases, such as simple hepatic steatosis and nonalcoholic steatohepatitis (NASH).11 A meta-analysis by Le et al.12 including 245 studies of approximately 5.4 million individuals reported that the global prevalence of NAFLD was 29.8%, with South America and North America having the highest prevalence (35.7% and 35.3%, respectively). Risk factors for NAFLD-related HCC include diabetes, obesity, metabolic syndrome, smoking, gut microbiome and bile acids, ethnicity, and genetics.13,14 Of note, diabetes is associated with higher rates of advanced fibrosis in patients with NASH15,16 and is the most significant population-attributable fraction of risk factors for HCC in the United States.17

In this review, we will discuss the role of diabetes on the risk of HCC in patients with cirrhosis and NAFLD. We will also summarize risk stratification, prediction models, and potential preventive strategies for these patients.

EPIDEMIOLOGY OF NAFLD-ASSOCIATED HCC

NAFLD can account for up to 38% of the HCC burden in some regions and is the most rapidly growing cause of HCC worldwide.7,18 Karim et al.19 identified 5,098 HCC patients in the United States from the Surveillance, Epidemiology and End Results–Medicare database and reported that NAFLD was the leading cause of HCC (35.6%). The authors also found that NAFLD was associated with lower surveillance receipt (adjusted odds ratio [aOR], 0.31) and more unrecognized cirrhosis at HCC diagnosis (aOR, 4.42). Dyson et al.20 reported that the proportion of NAFLD-associated HCC increased from <10% in 2000 to 35% in 2010, and the proportion might be substantially higher because only patients with histologic or radiological evidence were considered to define NAFLD, while half the HCC patients with no known chronic liver disease had at least one metabolic risk factor. Estes et al.21 projected that the incidence of NAFLD-associated HCC in the United Kingdom would increase by 88% from 2016 to 2030, and the incidence would be the highest in Germany in 2030. Similarly, the incidence of NAFLD-related HCC by 2030 is projected to rise by 82%, 117%, and 122% from 2016 in China, France, and the United States, respectively.7 Rising rates of obesity may contribute to the increasing incidence of diabetes and NAFLD as well as NAFLD-related HCC. A United States-based study by Lee et al.22 demonstrated a moderate, positive correlation between the temporal trend of HCC incidence rates and obesity prevalence among different states. In addition, state-level physical activity was inversely associated with the trend of HCC incidence rates, which suggested that NAFLD may have a significant impact on the ongoing rise in HCC incidences in some states.

A meta-analysis including 18 studies with 470,404 patients showed that the incidence of HCC in patients with NAFLD was 0.03 per 100 person-years, compared to 3.78 per 100 person-years in those with cirrhosis.23 In contrast to viral hepatitis-related and alcohol-related HCC, which typically occurs in the setting of underlying cirrhosis, NAFLD-associated HCC can develop without cirrhosis.24 A recent U.S. population-based study showed that only 57.9% of patients with NAFLD-related HCC had confirmed cirrhosis,19 and a meta-analysis including 61 studies demonstrated that 38.5% of patients with NAFLD-related HCC did not have cirrhosis.25 Rates of NAFLD-related HCC were estimated at 0.01 to 0.08 per 100 person-years in patients with non-cirrhotic liver.13 The absence of cirrhosis often leads to late detection of HCC in NAFLD patients as cancers are often diagnosed when patients develop cancer-related symptoms in the absence of a surveillance program.

DIABETES AS A RISK FACTOR FOR HCC

Multiple studies confirmed diabetes as a risk factor for HCC. El-Serag et al.26 published a prospective cohort study, including 173,643 diabetic patients and 650,620 non-diabetic patients, and reported that diabetes was significantly associated with NAFLD (hazard ratio [HR], 1.98) and HCC (HR, 2.16). They also found that diabetic patients with more than 10 years of follow-up carried the highest risk. Hassan et al.27 conducted a hospital-based case-control study comparing 420 HCC patients with 1,104 healthy controls and found that diabetes was more prevalent in HCC patients (aOR, 4.2). Compared to patients with a diabetes duration of 2 to 5 years, patients with a diabetes duration of 6 to 10 years and more than 10 years had an OR of 1.8 and 2.2 for HCC, respectively. This suggests that the duration of diabetes is associated with the risk of HCC development.

A systematic review by El-Serag et al.28 exhibited that type 2 diabetes was associated with an approximately 2.5-fold increase in the risk for HCC. In addition, the risk estimate from 13 case-control studies indicated a 2.5-fold increased odds of diabetes in patients with HCC compared to controls without diabetes. Kanwal et al.29 conducted a study of 271,906 NAFLD patients from 130 facilities in the Veterans Administration with a mean follow-up of 9 years. They observed a stepwise increase in the risk of developing cirrhosis or HCC with each additional metabolic trait (i.e., obesity, diabetes, hypertension, and dyslipidemia), and diabetes had an adjusted HR of 2.77 and 1.31 for developing HCC and cirrhosis, respectively.29 Moreover, NAFLD is associated with an approximately 2-fold risk of diabetes, independent of obesity and other metabolic traits. The risk of diabetes is also correlated with the severity of NAFLD.30

Studies showed that the prevalence of diabetes increased with liver disease progression and cirrhosis development.31,32 Diabetes also accelerates fibrosis progression in NASH patients.15 More recently, several studies investigated the association between diabetes and HCC in NASH cirrhosis patients to determine if diabetes has a direct carcinogenic effect independent of liver disease progression. In this study, diabetic patients had an increased risk of developing HCC in a Mayo Clinic Rochester cohort (n=354 patients with NASH cirrhosis; HR, 4.2) and a United Network for Organ Sharing cohort (n=6,630 NASH registrants; HR, 1.3) in multivariable analyses.33 Similar results were seen in a nationwide study involving 130 Veterans Administration facilities by Kanwal et al.34 suggesting a 1.5-fold increased risk of HCC among NAFLD cirrhosis patients with diabetes compared to those without diabetes.

DIABETES AND HEPATOCARCINOGENESIS

Diabetes mellitus, type 2, is characterized by hyperglycemia, hyperinsulinemia, and insulin resistance, which can contribute to hepatocarcinogenesis (Fig. 1).35 Hyperglycemia initiates modification in cell vasculature and causes endothelial cell debilitation, resulting in increased growth factor production, upregulation of inflammatory genes, excessive generation of reactive oxygen species (ROS), increased oxidative stress, and enhanced cell permeability. Vascular endothelial growth factor in response to endothelial damage stimulates the proliferation of liver cells and the development of HCC.36 ROS can interact with lipids and amino acids and damage DNA.37 For example, ROS may induce mutations in TP53, which is a tumor suppressor gene.38 Hyperinsulinemia leads to de novo lipogenesis and consequently lipid accumulation within the liver.39 Adipocytes excrete adipokines and leptin that promote insulin resistance.40,41 Cytokines produced by the liver, infiltrating immune cells, and adipocytes, such as tumor necrosis factor α, interleukin 6, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), due to chronic lipid accumulation and lipotoxicity can also lead to insulin resistance, which further accelerates the defects in insulin signaling in pancreatic β cells.42,43 In addition, adipocytes produce adiponectin, a peptide hormone that enhances insulin reaction, decreases triglyceride synthesis, and stimulates β oxidation in favor of lipid clearance in skeletal muscle and liver.44 Clinically, the leptin to adiponectin ratio can be used to measure insulin resistance, with lower values associated with higher insulin sensitivity and lower cardiovascular risks.45 Hyperinsulinemia also involves upregulation of the insulin growth factor (IGF) pathway as the consequence of overexpressed IGF-1 and aberrantly expressed fetal IGF-2.46 IGF-1 then activates protein kinase B/mammalian target of rapamycin (AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways, which inhibit apoptosis and enhance cell proliferation.47 Activation of the IGF pathway has been observed in a subset of human HCC.46 Besides, the production of free fatty acids also activates c-Jun N-terminal kinase 1 (JNK1) that inhibits cell apoptosis.48

Figure 1. Brief illustration of hepatocarcinogenesis in diabetes. Diabetes enhances the production of FFA, insulin secretion, and IR. These lead to increased reactive oxygen species, inflammation, and oxidative stress in adipocytes and hepatocytes. Impaired PKC, NF-κB, STAT, leptin, and TNF-α cascades due to diabetes also accelerate fibrosis by stellate cells and contribute to hepatocarcinogenesis.
FFA, free fatty acid; IR, insulin resistance; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; ox-phosphorylation, oxidative phosphorylation; PKC, protein kinase C; STAT, signal transducer and activator of transcription protein; TNF-α, tumor necrosis factor α; HCC, hepatocellular carcinoma.

Fujii et al.49 developed a murine model and proposed that NASH-based fibrosis might be a pivotal link to diabetes and HCC. They exposed neonatal mice to low-dose streptozotocin, and the mice developed liver steatosis with diabetes after 1 week of a high-fat diet. Liver biopsy displayed increased lobular inflammation and foam cell-like macrophages, consistent with NASH pathology. In parallel, fibroblasts accumulated to form chicken-wired fibrosis, and all of these mice developed HCC later. Interestingly, mice with diabetes alone but without NASH-based fibrosis never developed HCC.49 More biological studies are still necessary to comprehensively determine the pathophysiological role of diabetes in cirrhosis and NAFLD-associated HCC.

RISK STRATIFICATION, PREDICTION MODELS, AND GENETIC RISK SCORES

HCC risk stratification of non-cirrhotic NAFLD and early recognition of cirrhosis among patients with NAFLD will be critical to increase surveillance implementation and earlier detection of HCC eventually leading to utilization of curative-intent treatment and improved survival.19 Cirrhotic patients of any etiology are recommended to undergo semiannual HCC surveillance based on the American Association for the Study of Liver Diseases or the European Association for the Study of the Liver guideline. However, the risks are still heterogeneous across all cirrhotic and non-cirrhotic patients. Thus, several prediction models considering different etiologies were used for better risk stratification, especially for cirrhotic NAFLD patients (e.g., ADRESS-HCC,50 THRI score,51 and APAC score52). The ADRESS-HCC represented the first model derived from 34,932 cirrhotic patients, and the primary etiology of cirrhosis (NASH, hepatitis C virus, alcohol, hepatitis B virus, others) was associated with 1-year HCC risk. The ADRESS-HCC model could differentiate whether the cirrhotic patients would develop HCC with a C-index of around 0.7.50 The primary etiology of cirrhosis in the THRI score included steatohepatitis, viral hepatitis, primary biliary cirrhosis, and autoimmune hepatitis. The THRI model could predict 10-year cumulative HCC incidence, with 3%, 10%, and 32% for scores <120, 120 to 240, and >240, respectively.51 The APAC score was based on serum sPDGFRβ (soluble platelet-derived growth factor receptor β), age, serum alpha-fetoprotein (AFP), and creatinine and categorized the etiology of cirrhosis into NAFLD, viral hepatitis, and alcohol. The APAC score could predict HCC with an area under the curve (AUC) of 0.95. The AUC was also around 0.95 in a sub-analysis of NAFLD-associated cirrhosis.52 Most recently, a study reported prognostic liver signature (PLS)–NAFLD, which predicted incident HCC over up to 15 years of longitudinal observation.53 Four-protein secretome signature, PLSec-NAFLD, showed excellent risk stratification among NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6% and 0% in high- and low-risk patients, respectively).53

In non-cirrhotic NAFLD patients, HCC screening by ultrasonography and serum AFP levels could be considered in the presence of advanced fibrosis (F3).7 Besides, ethnicity and genetics may play an essential role on risk stratification in this population. For example, Hispanics have higher rates of NAFLD-associated HCC in the United States, possibly due to their higher rates of metabolic syndromes.34,54,55 The PNPLA3 single-nucleotide polymorphisms (SNPs) are strongly linked to HCC.7 Genome-wide association studies (GWAS) have also uncovered SNPs of many other genes that contribute to NAFLD-associated HCC, including TM6SF2, MBOAT7, GCKR, HSD17B13, etc.13 Therefore, researchers built polygenic risk score (PRS) models, which consider effects of different SNPs at different genes, combined with clinical features to predict risks on developing HCC.56-59 For example, Bianco et al.56 developed two PRS models considering four (PNPLA3, TM6SF2, MBOAT7, and GCKR) or five (adjusted for the rs72613567 HSD17B13) genetic variants in Italian and the U.K. cohorts. These two models could predict HCC in NAFLD patients with or without cirrhosis, with an AUC of around 0.65. Gellert-Kristensen et al.57 established a PRS model based on PNPLA3, TM6SF2, and HSD17B13 in United Kingdom and Danish cohorts. This model demonstrated up to a 12-fold and a 29-fold higher risk of cirrhosis and HCC, respectively. Pelusi et al.58 and Donati et al.59 also demonstrated PRS models with outstanding AUC (>0.9), but these require further careful validation. Despite these potential PRS models, risk stratification without genetic input is more likely feasible in the clinical setting since GWAS is currently not applicable to each individual. For instance, the GALAD score considers gender, age, AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy prothrombin and has been used in many studies.60 In a German cohort with 356 NAFLD patients, the GALAD score could identify HCC patients with an AUC of 0.96. Notably, the AUC for detecting HCC based on the GALAD score in NASH patients without cirrhosis was 0.98.60 Liver enzymes, platelets number, serum albumin levels, and presence of diabetes were also proposed as variables in some risk stratification models.61

Researchers have extensively developed liquid biopsy, including circulating tumor DNA,62 circulating tumor cells,63 and extracellular vesicles,64 for HCC biomarkers. For example, Kalinich et al.65 utilized digital polymerase chain reaction (dPCR) to quantify RNA expression of 10 HCC-relevant genes in purified circulating tumor cells and yield genetic scores that had values in screening high-risk patients. Sun et al.66 also detected the same 10-gene expression by dPCR in purified HCC extracellular vesicles that could aid with early diagnosis of HCC. The dPCR can quantify tiny amounts of DNA or RNA, as sensitive as one copy per cell, which is a huge advance in the early diagnosis of malignancy at a low cost. The combination of the cutting-edge dPCR system and liquid biopsy may allow these blood-based, noninvasive biomarkers to hold great potential for early diagnosis of HCC, particularly in patients with non-cirrhotic NAFLD.

POTENTIAL PREVENTIVE STRATEGIES

Given the strong association of obesity with insulin resistance, diabetes, and HCC,67-69 encouraging physical activity to control weight and other major metabolic traits is a rational and cost-effective way to prevent the development of HCC. Smoking cessation should be encouraged for HCC prevention with the evidence from a meta-analysis demonstrating a pooled OR of 1.55 and 1.39 for HCC in current and former smokers, respectively.70

Although life modifications are cost-effective and the first step for diabetes management, most patients still require antihyperglycemic agents. Metformin, a biguanide, has long been the first-line medication for managing diabetes. In addition, metformin can inhibit mitochondrial respiration with decreased adenosine triphosphate (ATP) production. Reduced ATP production activates the adenosine monophosphate-activated protein kinase signaling pathway, resulting in mTOR pathway inactivation and subsequent inhibition of cancer cell proliferation (Fig. 2).71 Metformin also regulates the glucose metabolic intermediate to influence de novo lipid biosynthesis.72 Other anti-tumor mechanisms of metformin include epigenetic modification, immunoregulation via the NF-κB pathway, and regulation of autophagy.73 Clinically, metformin can help lose weight and increase insulin sensitivity.74

Figure 2. Possible mechanisms of protective effects against hepatocellular carcinoma by metformin. Metformin may inhibit cell proliferation via AMPK and PI3K pathways. Metformin is also an autophagy inducer that can prohibit carcinogenesis by inhibiting IL-6. Arrows denote facilitation and blunt arrows denote inhibition.
AMPK, adenosine monophosphate (AMP)-activated protein kinase; IL-6, interleukin 6; IRS1, insulin receptor substrate 1; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B (also known as PKB); JAK, Janus kinase; TSC, tuberous sclerosis complex; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; STAT, signal transducer and activator of transcription protein; Rheb, Ras homolog enriched in brain; mTOR, mammalian target of rapamycin.

Chen et al.75 conducted a nationwide case-control study, recruiting 97,430 HCC patients and 194,860 match controls, and found that each incremental year increase in metformin use led to a 7% reduction in the risk of HCC (aOR, 0.93), for diabetic patients, indicating a strong dose-dependent relation. A meta-analysis by Singh et al.76 including 10 studies of 22,650 HCC cases in 334,307 patients with type 2 diabetes showed that metformin use was associated with decreased risk of HCC with an OR of 0.50. Interestingly, sulfonylurea and insulin use was significantly associated with an increased HCC risk (OR of 1.62 and 2.61, respectively). Kramer et al.77 assembled a retrospective cohort of 85,936 patients with NAFLD and diabetes from 130 Veterans Administration facilities. They reported that, in landmark multivariate Cox proportional hazards models, metformin use was associated with an HR of 0.80 for developing HCC. The use of insulin alone or sulfonylureas alone was not significantly associated with the risk of HCC compared with no antihyperglycemic agent use.77 Still, insulin in combination with other oral antihyperglycemic agents was associated with a 1.6- to 1.7-fold higher risk of developing HCC. More importantly, patients with adequate glycemic control were associated with an HR of 0.69 for developing HCC.77 In a subgroup analysis of patients who received at least one diabetes medication, the use of insulin or sulfonylureas was associated with a 44% and 31% higher risk of HCC compared to metformin, respectively.77 Another systemic review by Cunha et al.78 showed an OR of 0.468 for the risk of HCC in metformin users. Tseng performed a propensity score-matched study pairing 21,900 ever-users and never-users of metformin. This case-control study reported an overall HR of 0.49 for developing HCC in metformin ever-users.79

In recent years, sodium-glucose linked transporter-2 (SGLT2) inhibitors have attracted attention not only for their efficacy in treating hyperglycemia but also for their outstanding effects on cardiovascular and renal protection.80,81 By inhibiting SGLT2 in the kidney, the inhibitors lead to glycosuria, resulting in decreased serum glucose, caloric deficit, and thus weight loss.82 Researchers have also observed the potential of SGLT2 inhibitors against HCC and other malignancies due to the established correlation between hyperglycemia and HCC. For example, Luo et al.83 reported that canagliflozin (an SGLT2 inhibitor) could decrease HIF-1α protein synthesis via the AKT/mTOR pathway, leading to reduced hypoxia-induced metastasis and angiogenesis in HCC. Many others also demonstrated consistent results of the effects of canagliflozin and other SGLT2 inhibitors on HCC cells.82 A meta-analysis of multiple randomized controlled trials by Benedetti et al.84 exhibited an overall reduced risk of cancer (not limited to HCC) in users of SGLT2 inhibitors, with a risk ratio of 0.35.

Statins inhibit the conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate. The inhibition of this pathway by statins prevents the formation of both mevalonate and its downstream product, which have several pathophysiological functions potentially involved in carcinogenesis.85 Singh et al.86 conducted a meta-analysis including 10 studies with 4,298 HCC cases in 1,459,417 patients and showed that statin use was associated with a significantly lower risk of developing HCC (aOR, 0.63). A more recent meta-analysis by Zou et al.87 including 272,431 patients with NAFLD reported that statin users had a lower risk of developing HCC than nonusers (HR, 0.47). Statin initiation was still associated with a lower risk of HCC after adjusting for fibrosis-4 index score (HR, 0.49). They also showed that statin had a protective effect against HCC in patients with NAFLD in a dose-dependent manner.87 Aspirin, a cyclooxygenase (COX) inhibitor, was also proposed to have a protective effect against HCC because chronic inflammation could trigger the COX-2 signaling pathway, resulting in decreased apoptosis, increased cell proliferation, and angiogenesis.88,89 A pooled analysis of two prospective cohort studies in the United States involving 133,371 healthcare professionals reported that regular use of at least 650 mg of aspirin a week was associated with a 50% reduction in HCC risk (adjusted HR, 0.51).90 However, the chemopreventive effect of these medications has not been rigorously evaluated in the context of NASH and requires further evaluation in prospective studies.

CONCLUSIONS

Diabetes is an important risk factor for HCC development in patients with NAFLD. Diabetes also increases the risk of developing HCC in patients with NAFLD cirrhosis. Hepatocarcinogenic effects of diabetes include increased ROS production, endothelial damage, release of proinflammatory cytokines, and activation of the IGF pathway. Based on a murine model, NAFLD fibrosis may serve as a pivotal link between diabetes and HCC development. Several HCC risk stratification models were proposed, and it will be useful to determine surveillance strategies for the early detection of HCC in these patients. Since diabetes is a potentially modifiable risk factor, researchers have established preventive strategies focused on diabetes and relevant metabolic traits including physical activity (or exercise) and chemoprevention using metformin, SGLT2 inhibitors, statin, and aspirin. More biological studies are required to delineate the pathophysiological role of diabetes in patients with cirrhosis and refine risk stratification and prevention of NAFLD-associated HCC with new therapeutics.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Fig 1.

Figure 1.Brief illustration of hepatocarcinogenesis in diabetes. Diabetes enhances the production of FFA, insulin secretion, and IR. These lead to increased reactive oxygen species, inflammation, and oxidative stress in adipocytes and hepatocytes. Impaired PKC, NF-κB, STAT, leptin, and TNF-α cascades due to diabetes also accelerate fibrosis by stellate cells and contribute to hepatocarcinogenesis.
FFA, free fatty acid; IR, insulin resistance; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; ox-phosphorylation, oxidative phosphorylation; PKC, protein kinase C; STAT, signal transducer and activator of transcription protein; TNF-α, tumor necrosis factor α; HCC, hepatocellular carcinoma.
Gut and Liver 2023; 17: 24-33https://doi.org/10.5009/gnl220357

Fig 2.

Figure 2.Possible mechanisms of protective effects against hepatocellular carcinoma by metformin. Metformin may inhibit cell proliferation via AMPK and PI3K pathways. Metformin is also an autophagy inducer that can prohibit carcinogenesis by inhibiting IL-6. Arrows denote facilitation and blunt arrows denote inhibition.
AMPK, adenosine monophosphate (AMP)-activated protein kinase; IL-6, interleukin 6; IRS1, insulin receptor substrate 1; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B (also known as PKB); JAK, Janus kinase; TSC, tuberous sclerosis complex; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; STAT, signal transducer and activator of transcription protein; Rheb, Ras homolog enriched in brain; mTOR, mammalian target of rapamycin.
Gut and Liver 2023; 17: 24-33https://doi.org/10.5009/gnl220357

References

  1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-249.
    Pubmed CrossRef
  2. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019;16:589-604.
    Pubmed KoreaMed CrossRef
  3. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.
    Pubmed CrossRef
  4. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894-1905.
    Pubmed CrossRef
  5. Yang JD, Heimbach JK. New advances in the diagnosis and management of hepatocellular carcinoma. BMJ 2020;371:m3544.
    Pubmed CrossRef
  6. Kew MC. Aflatoxins as a cause of hepatocellular carcinoma. J Gastrointestin Liver Dis 2013;22:305-310.
    Pubmed
  7. Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2021;18:223-238.
    Pubmed KoreaMed CrossRef
  8. Teng PC, Agopian VG, Lin TY, et al. Circulating tumor cells: a step toward precision medicine in hepatocellular carcinoma. J Gastroenterol Hepatol 2022;37:1179-1190.
    Pubmed KoreaMed CrossRef
  9. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127(5 Suppl 1):S35-S50.
    Pubmed CrossRef
  10. Singal AG, Zhang E, Narasimman M, et al. HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: a meta-analysis. J Hepatol 2022;77:128-139.
    Pubmed KoreaMed CrossRef
  11. Noureddin M, Sanyal AJ. Pathogenesis of NASH: the impact of multiple pathways. Curr Hepatol Rep 2018;17:350-360.
    Pubmed KoreaMed CrossRef
  12. Le MH, Yeo YH, Li X, et al. 2019 Global NAFLD prevalence: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2022;20:2809-2817.e28.
    Pubmed CrossRef
  13. Shah PA, Patil R, Harrison SA. NAFLD-related hepatocellular carcinoma: the growing challenge. Hepatology. Epub 2022 Apr 28. https://doi.org/10.1002/hep.32542.
    Pubmed CrossRef
  14. Noureddin M, Rinella ME. Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis 2015;19:361-379.
    Pubmed KoreaMed CrossRef
  15. Pelusi S, Petta S, Rosso C, et al. Renin-angiotensin system inhibitors, type 2 diabetes and fibrosis progression: an observational study in patients with nonalcoholic fatty liver disease. PLoS One 2016;11:e0163069.
    Pubmed KoreaMed CrossRef
  16. Noureddin M, Ntanios F, Malhotra D, et al. Predicting NAFLD prevalence in the United States using National Health and Nutrition Examination Survey 2017-2018 transient elastography data and application of machine learning. Hepatol Commun 2022;6:1537-1548.
    Pubmed KoreaMed CrossRef
  17. Welzel TM, Graubard BI, Quraishi S, et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am J Gastroenterol 2013;108:1314-1321.
    Pubmed KoreaMed CrossRef
  18. Huang DQ, Singal AG, Kono Y, Tan DJ, El-Serag HB, Loomba R. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab 2022;34:969-977.
    Pubmed CrossRef
  19. Karim MA, Singal AG, Kum HC, et al. Clinical characteristics and outcomes of nonalcoholic fatty liver disease-associated hepatocellular carcinoma in the United States. Clin Gastroenterol Hepatol. Epub 2022 Mar 17. https://doi.org/10.1016/j.cgh.2022.03.010.
    Pubmed KoreaMed CrossRef
  20. Dyson J, Jaques B, Chattopadyhay D, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 2014;60:110-117.
    Pubmed CrossRef
  21. Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol 2018;69:896-904.
    Pubmed CrossRef
  22. Lee YT, Wang JJ, Luu M, et al. State-level HCC incidence and association with obesity and physical activity in the United States. Hepatology 2021;74:1384-1394.
    Pubmed CrossRef
  23. Orci LA, Sanduzzi-Zamparelli M, Caballol B, et al. Incidence of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression. Clin Gastroenterol Hepatol 2022;20:283-292.
    Pubmed CrossRef
  24. Stine JG, Wentworth BJ, Zimmet A, et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment Pharmacol Ther 2018;48:696-703.
    Pubmed KoreaMed CrossRef
  25. Tan DJH, Ng CH, Lin SY, et al. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis. Lancet Oncol 2022;23:521-530.
    Pubmed KoreaMed CrossRef
  26. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126:460-468.
    Pubmed CrossRef
  27. Hassan MM, Curley SA, Li D, et al. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer 2010;116:1938-1946.
    Pubmed KoreaMed CrossRef
  28. El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006;4:369-380.
    Pubmed CrossRef
  29. Kanwal F, Kramer JR, Li L, et al. Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in nonalcoholic fatty liver disease. Hepatology 2020;71:808-819.
    Pubmed CrossRef
  30. Targher G, Corey KE, Byrne CD, Roden M. The complex link between NAFLD and type 2 diabetes mellitus: mechanisms and treatments. Nat Rev Gastroenterol Hepatol 2021;18:599-612.
    Pubmed CrossRef
  31. Veldt BJ, Chen W, Heathcote EJ, et al. Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 2008;47:1856-1862.
    Pubmed CrossRef
  32. Gentile S, Loguercio C, Marmo R, Carbone L, Del Vecchio Blanco C. Incidence of altered glucose tolerance in liver cirrhosis. Diabetes Res Clin Pract 1993;22:37-44.
    Pubmed CrossRef
  33. Yang JD, Ahmed F, Mara KC, et al. Diabetes is associated with increased risk of hepatocellular carcinoma in patients with cirrhosis from nonalcoholic fatty liver disease. Hepatology 2020;71:907-916.
    Pubmed KoreaMed CrossRef
  34. Kanwal F, Kramer JR, Mapakshi S, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 2018;155:1828-1837.
    Pubmed KoreaMed CrossRef
  35. Singh MK, Das BK, Choudhary S, Gupta D, Patil UK. Diabetes and hepatocellular carcinoma: a pathophysiological link and pharmacological management. Biomed Pharmacother 2018;106:991-1002.
    Pubmed CrossRef
  36. Moon WS, Rhyu KH, Kang MJ, et al. Overexpression of VEGF and angiopoietin 2: a key to high vascularity of hepatocellular carcinoma? Mod Pathol 2003;16:552-557.
    Pubmed CrossRef
  37. Popova EA, Mironova RS, Odjakova MK. Non-enzymatic glycosylation and deglycating enzymes. Biotechnol Biotechnol Equip 2014;24:1928-1935.
    CrossRef
  38. Assi M. The differential role of reactive oxygen species in early and late stages of cancer. Am J Physiol Regul Integr Comp Physiol 2017;313:R646-R653.
    Pubmed CrossRef
  39. Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci 2014;15:8591-8638.
    Pubmed KoreaMed CrossRef
  40. Wang TN, Chang WT, Chiu YW, et al. Relationships between changes in leptin and insulin resistance levels in obese individuals following weight loss. Kaohsiung J Med Sci 2013;29:436-443.
    Pubmed CrossRef
  41. Coppack SW. Adipose tissue changes in obesity. Biochem Soc Trans 2005;33(Pt 5):1049-1052.
    Pubmed CrossRef
  42. Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol (Lausanne) 2013;4:37.
    Pubmed KoreaMed CrossRef
  43. Allaire M, Nault JC. Type 2 diabetes-associated hepatocellular carcinoma: a molecular profile. Clin Liver Dis (Hoboken) 2016;8:53-58.
    Pubmed KoreaMed CrossRef
  44. Yadav A, Jyoti P, Jain SK, Bhattacharjee J. Correlation of adiponectin and leptin with insulin resistance: a pilot study in healthy north Indian population. Indian J Clin Biochem 2011;26:193-196.
    Pubmed KoreaMed CrossRef
  45. Finucane FM, Luan J, Wareham NJ, et al. Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals. Diabetologia 2009;52:2345-2349.
    Pubmed KoreaMed CrossRef
  46. Tovar V, Alsinet C, Villanueva A, et al. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol 2010;52:550-559.
    Pubmed KoreaMed CrossRef
  47. Chettouh H, Lequoy M, Fartoux L, Vigouroux C, Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int 2015;35:2203-2217.
    Pubmed CrossRef
  48. Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol 2013;10:656-665.
    Pubmed CrossRef
  49. Fujii M, Shibazaki Y, Wakamatsu K, et al. A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma. Med Mol Morphol 2013;46:141-152.
    Pubmed CrossRef
  50. Flemming JA, Yang JD, Vittinghoff E, Kim WR, Terrault NA. Risk prediction of hepatocellular carcinoma in patients with cirrhosis: the ADRESS-HCC risk model. Cancer 2014;120:3485-3493.
    Pubmed KoreaMed CrossRef
  51. Sharma SA, Kowgier M, Hansen BE, et al. Toronto HCC risk index: a validated scoring system to predict 10-year risk of HCC in patients with cirrhosis. J Hepatol 2018;68:P92-P99.
    Pubmed CrossRef
  52. Lambrecht J, Porsch-Özçürümez M, Best J, et al. The APAC score: a novel and highly performant serological tool for early diagnosis of hepatocellular carcinoma in patients with liver cirrhosis. J Clin Med 2021;10:3392.
    Pubmed KoreaMed CrossRef
  53. Fujiwara N, Kubota N, Crouchet E, et al. Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease. Sci Transl Med 2022;14:eabo4474.
    Pubmed KoreaMed CrossRef
  54. Weston SR, Leyden W, Murphy R, et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology 2005;41:372-379.
    Pubmed CrossRef
  55. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356-359.
    Pubmed CrossRef
  56. Bianco C, Jamialahmadi O, Pelusi S, et al. Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores. J Hepatol 2021;74:775-782.
    Pubmed KoreaMed CrossRef
  57. Gellert-Kristensen H, Richardson TG, Davey Smith G, Nordestgaard BG, Tybjaerg-Hansen A, Stender S. Combined effect of PNPLA3, TM6SF2, and HSD17B13 variants on risk of cirrhosis and hepatocellular carcinoma in the general population. Hepatology 2020;72:845-856.
    Pubmed CrossRef
  58. Pelusi S, Baselli G, Pietrelli A, et al. Rare pathogenic variants predispose to hepatocellular carcinoma in nonalcoholic fatty liver disease. Sci Rep 2019;9:3682.
    Pubmed KoreaMed CrossRef
  59. Donati B, Dongiovanni P, Romeo S, et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep 2017;7:4492.
    Pubmed KoreaMed CrossRef
  60. Yang JD, Addissie BD, Mara KC, et al. GALAD score for hepatocellular carcinoma detection in comparison with liver ultrasound and proposal of GALADUS score. Cancer Epidemiol Biomarkers Prev 2019;28:531-538.
    Pubmed KoreaMed CrossRef
  61. Younes R, Caviglia GP, Govaere O, et al. Long-term outcomes and predictive ability of non-invasive scoring systems in patients with non-alcoholic fatty liver disease. J Hepatol 2021;75:786-794.
    Pubmed CrossRef
  62. Wu X, Li J, Gassa A, et al. Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma. Int J Biol Sci 2020;16:1551-1562.
    Pubmed KoreaMed CrossRef
  63. Ahn JC, Teng PC, Chen PJ, et al. Detection of circulating tumor cells and their implications as a biomarker for diagnosis, prognostication, and therapeutic monitoring in hepatocellular carcinoma. Hepatology 2021;73:422-436.
    Pubmed KoreaMed CrossRef
  64. Lee YT, Tran BV, Wang JJ, et al. The role of extracellular vesicles in disease progression and detection of hepatocellular carcinoma. Cancers (Basel) 2021;13:3076.
    Pubmed KoreaMed CrossRef
  65. Kalinich M, Bhan I, Kwan TT, et al. An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma. Proc Natl Acad Sci U S A 2017;114:1123-1128.
    Pubmed KoreaMed CrossRef
  66. Sun N, Lee YT, Zhang RY, et al. Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring. Nat Commun 2020;11:4489.
    Pubmed KoreaMed CrossRef
  67. Polesel J, Zucchetto A, Montella M, et al. The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma. Ann Oncol 2009;20:353-357.
    Pubmed CrossRef
  68. Regimbeau JM, Colombat M, Mognol P, et al. Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl 2004;10(2 Suppl 1):S69-S73.
    Pubmed CrossRef
  69. Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM. Obesity and hepatocellular carcinoma. Gastroenterology 2004;127(5 Suppl 1):S97-S103.
    Pubmed CrossRef
  70. Abdel-Rahman O, Helbling D, Schöb O, et al. Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: an updated systematic review of 81 epidemiological studies. J Evid Based Med 2017;10:245-254.
    Pubmed CrossRef
  71. Amable G, Martínez-León E, Picco ME, et al. Metformin inhibits β-catenin phosphorylation on Ser-552 through an AMPK/PI3K/Akt pathway in colorectal cancer cells. Int J Biochem Cell Biol 2019;112:88-94.
    Pubmed CrossRef
  72. Loubière C, Goiran T, Laurent K, Djabari Z, Tanti JF, Bost F. Metformin-induced energy deficiency leads to the inhibition of lipogenesis in prostate cancer cells. Oncotarget 2015;6:15652-15661.
    Pubmed KoreaMed CrossRef
  73. Zhao B, Luo J, Yu T, Zhou L, Lv H, Shang P. Anticancer mechanisms of metformin: a review of the current evidence. Life Sci 2020;254:117717.
    Pubmed CrossRef
  74. Golay A. Metformin and body weight. Int J Obes (Lond) 2008;32:61-72.
    Pubmed CrossRef
  75. 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;62:606-615.
    Pubmed CrossRef
  76. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol 2013;108:881-891.
    Pubmed CrossRef
  77. Kramer JR, Natarajan Y, Dai J, et al. Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease. Hepatology 2022;75:1420-1428.
    Pubmed KoreaMed CrossRef
  78. Cunha V, Cotrim HP, Rocha R, Carvalho K, Lins-Kusterer L. Metformin in the prevention of hepatocellular carcinoma in diabetic patients: a systematic review. Ann Hepatol 2020;19:232-237.
    Pubmed CrossRef
  79. Tseng CH. Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes. Liver Int 2018;38:2018-2027.
    Pubmed CrossRef
  80. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol 2021;6:148-158.
    Pubmed KoreaMed CrossRef
  81. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31-39.
    Pubmed CrossRef
  82. Arvanitakis K, Koufakis T, Kotsa K, Germanidis G. The effects of sodium-glucose cotransporter 2 inhibitors on hepatocellular carcinoma: from molecular mechanisms to potential clinical implications. Pharmacol Res 2022;181:106261.
    Pubmed CrossRef
  83. Luo J, Sun P, Zhang X, et al. Canagliflozin modulates hypoxia-induced metastasis, angiogenesis and glycolysis by decreasing HIF-1α protein synthesis via AKT/mTOR pathway. Int J Mol Sci 2021;22:13336.
    Pubmed KoreaMed CrossRef
  84. Benedetti R, Benincasa G, Glass K, et al. Effects of novel SGLT2 inhibitors on cancer incidence in hyperglycemic patients: a meta-analysis of randomized clinical trials. Pharmacol Res 2022;175:106039.
    Pubmed CrossRef
  85. El-Serag HB, Johnson ML, Hachem C, Morgana RO. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 2009;136:1601-1608.
    Pubmed KoreaMed CrossRef
  86. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 2013;144:323-332.
    Pubmed CrossRef
  87. Zou B, Odden MC, Nguyen MH. Statin use and reduced hepatocellular carcinoma risk in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. Epub 2022 Feb 11. https://doi.org/10.1016/j.cgh.2022.01.057.
    Pubmed CrossRef
  88. Chen H, Cai W, Chu ES, et al. Hepatic cyclooxygenase-2 overexpression induced spontaneous hepatocellular carcinoma formation in mice. Oncogene 2017;36:4415-4426.
    Pubmed KoreaMed CrossRef
  89. Kern MA, Schubert D, Sahi D, et al. Proapoptotic and antiproliferative potential of selective cyclooxygenase-2 inhibitors in human liver tumor cells. Hepatology 2002;36(4 Pt 1):885-894.
    Pubmed CrossRef
  90. Simon TG, Ma Y, Ludvigsson JF, et al. Association between aspirin use and risk of hepatocellular carcinoma. JAMA Oncol 2018;4:1683-1690.
    Pubmed KoreaMed CrossRef
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January, 2023

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