• Users Online: 277
  • Print this page
  • Email this page

 Table of Contents  
Year : 2022  |  Volume : 7  |  Issue : 1  |  Page : 1-9

Nonalcoholic steatohepatitis-induced hepatocellular carcinoma

Department of Internal Medicine, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia

Date of Submission01-Jan-2022
Date of Decision28-Mar-2022
Date of Acceptance13-Apr-2022
Date of Web Publication27-Jul-2022

Correspondence Address:
Dr. Abdulrahman Mohammed Hakami
Department of Medicine, College of Medicine, Jazan University, Jazan
Saudi Arabia
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/KKUJHS.KKUJHS_1_22

Rights and Permissions

The incidence and prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)-related cirrhosis is globally increasing, especially among communities with sedentary lifestyles. NASH-related liver cirrhosis is an emerging etiology of liver cancer. Given the increasing rates of obesity and the other risk factors of NAFLD/NASH such as diabetes mellitus, dyslipidemia, hypertension, and metabolic syndrome, NASH-related liver cancer will remain a challenging disease in the coming decades. Recent reports have shown that NASH also can cause hepatocellular carcinoma (HCC) directly without causing liver cirrhosis, the so-called noncirrhotic liver cancer. Furthermore, the pathogenicity of noncirrhotic HCC caused by NASH is not well understood and needs more future research. In the present time, NASH-related HCC has become one of the leading indications of liver transplantation. However, as the major risk factors of NASH are controllable, NASH-related HCC is a potentially preventable condition.

Keywords: Hepatocellular carcinoma, liver cancer, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis

How to cite this article:
Hakami AM, Elmakki E. Nonalcoholic steatohepatitis-induced hepatocellular carcinoma. King Khalid Univ J Health Sci 2022;7:1-9

How to cite this URL:
Hakami AM, Elmakki E. Nonalcoholic steatohepatitis-induced hepatocellular carcinoma. King Khalid Univ J Health Sci [serial online] 2022 [cited 2022 Nov 28];7:1-9. Available from: https://www.kkujhs.org/text.asp?2022/7/1/1/352514

  Introduction Top

Nonalcoholic fatty liver disease (NAFLD) is the term given to describe the accumulation of fat in the liver (steatosis) due to metabolic disturbances. This term was first introduced in 1980 to differentiate it from alcoholic fatty liver disease. On the other hand, nonalcoholic steatohepatitis (NASH) is the term given to describe steatosis with the development of inflammation.[1],[2]

Currently, NAFLD/metabolic-associated fatty liver disease is recognized as a highly prevalent disease affecting one in four people globally and is the leading cause of chronic liver disease in developed countries.[2],[3],[4],[5]

A reasonable percentage of the population in the developed world are affected by NAFLD/NASH-related liver cancer and there is an increase in the global prevalence and incidence of this chronic disease to epidemic proportions.[6] NASH related or NAFLD, just like any other cirrhosis-caused liver disease, escalates the threat of developing liver cancer, an illness known to have limited choices of remedy and with poor therapeutic results. The world is also experiencing a rise in the incidences of both intrahepatic cholangiocarcinoma and hepatocellular carcinoma (HCC) with HCC being linked to most deaths related to obesity cancer among the USA's middle-aged males today.[6] This article reviews correlations between NASH-related HCC and the risk of developing liver cancer focusing on the epidemiology of NASH-related HCC, etiology and pathogenesis of NASH-related cirrhosis HCC, and clinical characteristics of NASH-related HCC. The article further explores diagnosis, treatment, prognosis, and prevention of NASH-related HCC.

  Epidemiology of Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma Top

The prevalence of NAFLD is closely related to the increase in the prevalence of obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome and is increasing in both developed and developing nations, with approximately 30% of the world's population being affected.[7],[8],[9],[10]

The onset and progress of NAFLD/NASH-related HCC is an indicator of a patient's possibility of getting a HCC diagnosis. Studies show that the standard ratio of HCC prevalence in patients established to have NASH/NAFLD is 4.4%.[6] The research also indicates that there is a consistent growth in the global prevalence of NAFLD/NASH-related HCC. Surprisingly, the literature review in the western world shows different prevalence rates of HCC in patients with NASH/NAFLD ranging from 4% to 22%.[11] Another research on the epidemiology of NAFLD/NASH-related HCC indicates that about 59% of the HCC cases were related to NASH/NAFLD with a 6-year aggregate prevalence rate of 0.3%.[11] In a recent international annual meta-analysis, it was established that the frequency rate of NASH/NAFLD is approximately 5.3 for every 1000 person-years.[11] The death rates related to HCC range between 0.25% and 2.3% in the follow-up years, 8.3 and 13.7, respectively.[11] From these studies, it is evident that the leading contributor to obesity-related cancer mortality rates is NAFLD/NASH-related HCC. In Asia, however, the prevalence rates are lower compared to the United States because of the fact that there is a persistent endemic viral hepatitis in the Western countries leading to the highest cases of HCC.[12] NAFLD/NASH-related HCC cases are systematically ignored in other studies due to the fact that they link HCC occurrence to cryptogenic cirrhosis. For that, there is uncertainty regarding the precise cost of NAFLD/NASH-related HCC.[11] It appears, however, clear that both NASH and NAFLD are the potential common global underlying factors influencing the development of HCC in the future, outstanding alcohol and viral-related cirrhosis. Nonetheless, it is hard to separately evaluate etiological risk influences because by doing so, the level of threat of HCC in other liver illnesses can be affected. For instance, the risk for HCC in chronic hepatitis C virus (HCV) is higher by up to three fold in patients diagnosed with other related diseases such as NAFL/coincident steatosis hepatis compared to people without these diseases. The opposite is reported in cases of people suffering from chronic hepatitis B and their relationship with the risk of HCC and NAFL/steatosis hepatis. Therefore, it seems like the association between people with NAFLD and HCC risk is dependent on the extent of the causal liver disorder. HCC risk appears to be more prevalent in people suffering from NASH than in patients with mild NAFL/steatosis hepatic with the important factor being NASH. The risk for developing HCC is reported to increase by up to 25-fold with advanced fibrosis.[11] In conclusion, the risk for HCC in patients with cirrhosis and NASH/NAFLD is higher by up to 13% in a period of 3 years in relation to between 0% and 3% for about 1–2 decades in their NAFLD counterparts not diagnosed with cirrhosis.[11] From the analysis above, it becomes evident that the risk of getting HCC increases with cirrhosis but is not evidently a necessity for HCC to occur for the period of NAFLD.

The literature review shows that a larger percentage of the Western population is affected by NAFLD/NASH-related HCC and their prevalence and incidences are increasing to endemic levels globally.[13] Cirrhosis is regarded as the main influence to the NAFLD/NASH increasing the threat of people developing liver cancer.[11] Liver cancer is a disease associated with limited therapeutic choices and poor clinical outcomes. The prevalence and incidences of HCC are steadily increasing. While HCC is today believed to be the primary cause of cancer mortalities associated with obesity, NASH and NAFLD are projected to be the main causal etiological risk influences to liver transplantation and HCC in future.[14]

  Etiology and Pathogenesis of Nonalcoholic Steatohepatitis-Related Cirrhosis and Hepatocellular Carcinoma Top

Cirrhosis and chronic fibrosing liver disease are the primary risk factors that trigger the occurrence of HCC. The main cause of cirrhosis and chronic fibrosing liver disease is hepatitis virus infection.[15] Cirrhosis and chronic fibrosing liver disease is further influenced by several other nonviral factors. Clinical tests indicate that HCV and hepatitis B virus infections are the fundamental etiologic players in the development of HCC-related liver cirrhosis. HCV and hepatitis B virus infections do not, however, only play the role of pro-cirrhosis effect but also perform the function of oncogenic agents. The risk of HCC is also increased by another category of hepatic inflammatory disorders including NASH and its related metabolic conditions. HCC risk is further stimulated by different hepatotoxic factors such as iron, particularly hemochromatosis, alcohol like an alcoholic liver disease, and a wide range of toxic molecules.[15] Other hepatotoxic factors associated with an increase in HCC are pesticides and aflatoxin. Sex steroids, as well as their derivate, are some of the drugs increase the risk of liver cancer. Other than different types of hemochromatosis, research shows that increased HCC risk can also be caused by other inborn metabolic errors including tyrosinemia, glycogenosis, and Wilson's disease.[15]

HCC cases have drastically risen in the developed economies because of numerous critical risk factors. Studies show that about half of the new occurring HCC cases are influenced by HCV while between 15% and 50% of HCC cases caused by the etiology of cirrhosis is still unclear. Given the increased cost of DM and obesity in the Western countries resulting into NASH and NAFLD, studies increasingly indicate that NASH may be responsible for a bigger percentage of cryptogenic cirrhosis or idiopathic cases.[15] Patients with NASH-related HCC but also going through liver transplantation tend to have considerably higher proportions of BMI and advanced degrees of DM. People suffering from cryptogenic cirrhosis, just like their NASH counterparts have great pervasiveness of DM and obesity. Furthermore, a substantial number of cryptogenic cirrhosis recipients of liver transplant develop NASH at an estimated probability of 15.7% or NAFLD at an approximated chance of 25.4% within 2 years due to transplant surgery.[15] This study findings further prove that patients that have burned out NASH have the possibility of being incorrectly diagnosed with cryptogenic cirrhosis. Regardless of the causal aspect of the liver disorder, cirrhosis has been identified as the primary HCC risk factor.

  Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinomas Underlying Mechanisms Top

The pathogenesis of HCC caused by NASH is underlined by several distinctive mechanisms as depicted in [Figure 1].[16]
Figure 1: Pathogenesis of NAFLD/NASH-related HCC and risk factors for progression of NASH to HCC, adapted from Goh and McCullough.[16] NAFLD: Nonalcoholic fatty liver disease, NASH: Nonalcoholic steatohepatitis, HCC: Hepatocellular carcinoma

Click here to view

Several studies have shown that immune cells and cytokines play an important role in the pathogenesis of NASH-related HCC.[1],[17],[18]

NAFLD's associated insulin resistance influences the manufacture and release of free fatty acids. The insulin resistance also leads to the production of some pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α).[15] Pro-oncogenic pathways including c-Jun amino acid-terminal kinase (JNK) and nuclear factor κB are facilitated by TNF-α. Other TNF-α promoted pro-oncogenic channels are the mammalian target of rapamycin complex. Increased levels of IL-6 lead to obesity while the levels of IL-6 and TNF-α are reduced by weight loss resulting in a reduced potentially carcinogenic and inflammatory reaction.[15] Persistent uncontrolled STAT3 axis/IL-6 leads to an increased likelihood that malignant transformation of hepatocytes which has already attained oncogenic transfigurations due to contact with carcinogens will last. The production of insulin-like growth factor 1 (IGF-1), a growth factor-1which is insulin-like is up-regulated by insulin resistance. IGF-1 is known to facilitate development processes related to HCC including stimulating mitogen-activated protein kinases (MAPK) and manifestation of c-jun in vitro and proto-oncogenes c-fos. A MAPK-related JNK is downregulated by weight loss and stimulated by IR.[15] Histopathological exploration indicates that close to 70% of tissue specimens associated with HCC confidently color wash for phosphorylated JNK, illustrating the role of a MAPK in the advancement of the risk factor of having HCC.[15] Moreover, CD-8 T-cells have been recently shown to be incriminated in the pathogenicity of NASH-induced HCC.[19],[20],[21]

Overall, numerous factors contribute to the development of NASH-related HCC. The elucidated HCC underlying mechanisms create a foundation for novel therapeutic goals.

  Clinical Features and Characteristics of Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma Top

In the medical literature, the data on clinical features and survival outcomes of NASH related HCC are so scarce[22] Interestingly, 50% of NASH-HCC presents without liver cirrhosis.[23],[24]

Most patients with NASH-related HCC are asymptomatic throughout most of the clinical course, but HCC may be incidentally detected on ultrasound or other imaging techniques.[25],[26],[27] Some patients may present with nonspecific symptoms or signs related to advanced liver disease, consisting of jaundice, anorexia, weight loss, malaise, upper abdominal pain, enlarged liver, ascites, encephalopathy, splenomegaly, bleeding, signs of paraneoplastic syndromes, such as hypercholesterolemia, erythrocytosis, hyperkalcemia, and hypoglycemia. In addition, the patients may present with comorbidities or risk factors associated with NASH-HCC.[25] Furthermore, the patients with NASH-related HCC are older in comparison with those patients who their HCC is due to other etiologies, have a higher mortality rate, have more comorbidities such as ischemic heart diseases and DM.[28],[29]

Some of the common clinical characteristics of NASH-related HCC are having a reduction in platelets count, elevation of some tumor markers, and iron deposition. On the other hand, NASH severity cannot be reflected based on the levels of γ-glutamyl transpeptidase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST).[30],[31]

Tumor markers

A study on patients with NASH-related HCC established that about 47% and 53% of the participants involved in the clinical test were positively diagnosed with some levels of tumor markers such as des-γ-carboxyprothrombin, protein prompted by antagonists (PIVKA)-II or Vitamin K absence and α-fetoprotein (AFP) in the proportions of >40 mAU/mL and >10 ng/mL, respectively.[32] The research findings suggest that patients with NASH-related HCC have low positive rates of tumor makers. Furthermore, there was no importance in the before and after HCC developments intensification in the average AFP from 6.0 to 10.5 ng/mL, but the significance was in the rise of PIVKA-II from the level of 18 to 34 mAU/mL.[32] The study results indicate that NASH-related HCC can easily be detected by an increase in the level of PIVKA-II.[24],[31] However, the use of tumor makers alone in the diagnosis of NASH-related HCC is not enough.

Platelet count

The diagnosis of the phase of NAFLD's hepatic fibrosis largely depends on the platelet count index. The platelet counts for NASH patients, when likened to NAFL patients is lower and NASH's development can be expected in patients exhibiting a reduction in the level of platelet count within a given time frame. Nevertheless, this process of assessment needs a cautious validation since most people suffering from NAFLD/NASH-related HCC tend to have a minor reduction in the level of platelet count as opposed to individuals diagnosed with viral hepatitis including patients with chronic hepatitis C.[33] For example, if the test results show 150,000/μL in platelet count, it indicates that chronic hepatitis C patients have stage E2 of hepatic fibrosis, whereas a range of 153,000 to 192,000 per μL in platelet counts show that NAFLD patients have stage F3 of hepatic fibrosis.[33] The test results of ≤150,000/μL in platelet count in patients with NAFLD/NASH-related HCC demonstrate the development of a risk factor of HR 7.19 for HCC.[34] The scale of ≤150,000/μL in a clinical test on platelet count of patients with NAFLD/NASH may indicate that person is at advanced risk of HCC because they have liver cirrhosis.[35],[36]

Iron deposition

In comparison with NAFLD iron deposition in liver tissues in NASH is higher. Moreover, iron deposition in NASH-HCC is higher as compared to NASH without HCC. Hence, excess iron is a marker of hepatic fibrosis and NASH oncogenicity.[31]

  Diagnosis of Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma Top

Different methods are used in the diagnosis of NASH-related HCC including undertaking imaging tests. Other medically recommended diagnosis approaches today are blood biomarkers and scoring systems of hepatic fibrosis.

Imaging tests

Physicians use a noninvasive assessment when carrying out imaging tests on hepatic fibrosis. The evaluation uses medical tools such as transitory elastography and is designed to use ultrasonography in measuring the stiffness of the patient's liver. Diagnosis of NASH-related HCC can be undertaken by the detection of Kupffer cells' dysfunction with the help of a contrast-enhanced ultrasonography. Another useful method of assessing or diagnosing advancement of NAFLD-related hepatic fibrosis is by the use of magnetic resonance imaging.[11] The fact that carrying out liver biopsy is almost impossible, all patients suffering from hepatic fibrosis triggered by NAFLD, the diagnosis is done through imaging tests and scoring systems to know the degree of hepatic fibrosis development. This diagnosis helps health experts to know if the patient is at risk of HCC.

Scoring systems for hepatic fibrosis

Different factors are used on the scoring systems to establish NAFLD/NASH-related HCCs disease stage. The NAFIC score, the FIB-4 index, and the NAFLD fibrosis score (NFS) increase with NASH advancement, and both the FIB-4 index and the NFS are applied as prognostic markers. Fingas et al. established in a study that the annual prevalence of HCC in NAFLD patients was close to 0.043% with the research findings further indicating that there was a close association between the incidence of patients' with HCC and people detected with a high level of hepatic fibrosis.[11] The study analysis was anchored on an AST-to-platelet ratio index (APRI). An APRI of >1.5 showed that the prevalence of being diagnosed with HCC was higher in patients with advanced hepatic fibrosis compared to those with APRI of ≤1.5 or patients lacking unconventional hepatic fibrosis.[11] Regarding the application of the FIB-4 index, research by Fingas et al. established that about 16.1% of patients diagnosed with NAFLD-related HCC had between F3 and F4 of advanced hepatic fibrosis irrespective of having normal levels of ALT.[11] The study results indicate that HCC and hepatic fibrosis can be predicted more effectively using the scoring systems mentioned above.

Blood biomarkers

Measuring the concentrations level of serum made from MnSOD, high sensitivity C-reactive protein, thioredoxin, cytokeratin 18 fragments, and adiponectin is another approach health experts employ for the diagnosis of NASH.[11] Cytokeratin 18 fragment is proven to be useful for diagnosing NASH-related HCC in large-scale studies. Another diagnosis marker found very effective in assessing the stage development of NAFLD/NASH-related HCC and viral hepatitis as well as the advancement of hepatic fibrosis in patients is a glycosylation marker.[11] However, further research is needed to identify a marker that is most efficient and effective in diagnosing NASH-related HCC.

  Treatment of Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma Top

In the recent past, development of HCC, NASH, resistance to insulin, and obesity has been linked to the JNK1.[6] JNK1 denotes a universally communicated triggered protein kinase of mitogen. Irregularly stimulated JNK activity is also associated with the occurrence of obesity, one of the primary factors leading to the onset of NASH-related HCC. Reactive oxygen species (ROS), TNF-α, and free fatty acids released in hyperinsulinemia environment are effective JNK activators which subsequently lead to phosphorylates IRS-1.[37]

Phosphorylates IRS-1 generated from JNK activation are the important elements of the biochemical pathway known to induce obesity resistance to insulin. The increase in the level of apoptosis and hepatic inflammation is also associated with activation of JNK. Starley et al. established that, unlike in patients with benign NAFLD, there was a significant increase in the levels of phosphorylated JNK in human patients clinically diagnosed with NASH.[37]

Therefore, in particular, the presence of NASH has positively related to the degree of histologic activity and also JNK activation. Models used in clinical mouse trials further confirmed that the development of steatohepatitis is promoted by JNK1.[37] In the mouse model, it was established that lack of JNK1 helped to prevent the gain of weight and advancement in the resistance of insulin as well. The absence of JNK in the research specimen further demonstrated protection against hepatic steatosis development besides playing a vital role in decreasing hepatic injury embodied in the comparison between the levels of serum ALT and response of wild-type mice to a diet of high-fat.[37]

The study findings indicate that applying a therapy of anti-JNK can help prevent the development of NASH and also reverse chronic steatohepatitis irrespective of continued exposure to a diet with high-fat levels. The inhibitors in JNK were previously applied in remedying human diseases, and therefore, the JNK basically holds the future of NASH therapy. Furthermore, previous research linked JNK activity to other numerous lines of cancer cell. Not long ago, conclusive suggestion indicated a positive association concerning the development of HCC and continued activation of JNK. In over 50% of HCC samples collected from individuals, overactivation of JNK 1 is normally represented.[37] In a research exercise, it was demonstrated that 56% of the samples gathered from human tissues, particularly those with HCC demonstrated increased activity of JNK 1 matched with the controlled study involving noncancerous liver tissue. The study results, therefore, show that JNK1 seems to the most main kinase contributing to HCC up-regulation. JNK 1's sustained overreaction triggers an aberrant rise or growth in different genes known to influence proliferation of hepatocyte. If more study is done on these genes, the world will, for the first time get a remedy for NASH-related HCC in JNK 1.[37] ROS, also popular for NASH pathophysiology is identified as a primary factor in JNK activation by boosting the activity of JNK through inactivating JNK phosphatases.

As previously mentioned, the research findings indicate that statins considerably reduce the patient's risk of developing HCC, especially in those people diagnosed with diabetes and as a result, is regarded a tertiary approach employed by medical experts to treat HCC triggered by NASH rather than the properties of anti-inflammatory in statin. Atorvastatin treatment showed an extraordinary effect in helping to mitigate against the JNK expression and other inflammatory cells in individual suffering from abdominal aortic aneurysms as well.[37],[38] Interestingly, treatment of diabetic patients with Metformin and statins has been shown to be protective against development of NASH-HCC.[3],[39],[40],[41]

Moreover, the use of pioglitazone (thiazolidinedione anti-diabetic agent) in treating diabetic patients with NASH has been shown to be effective in reversing hepatic fibrosis and hence protect from the development of NASH-HCC.[3],[42] In addition, Liraglutide and semaglutide (glucagon-like peptide anti-diabetic agents) have been found to be significantly effective in treating NASH in a large, multi-centre randomized double blind control trial. However, unlike pioglitazone they have no effect on hepatic fibrosis.[43] It is crucial to mention that once the patient with NASH develops HCC, treatment in this situation will be like treatment of HCC due to other etiologies. It depends on the stage of the disease, and it ranges from curative to palliative treatment options.[3]

  Prognosis of Hepatocellular Carcinoma Disease Caused by Nonalcoholic Steatohepatitis Top

The increased level of both the incidence and prevalence of HCC disease caused by NASH has had a significant impact on the technology used in the transplantation of liver today. A reflective group study among adult recipients of transplanted liver between 2002 and 2012 showed a 4-fold increase in the number of people suffering from HCC disease triggered by NASH going through the transplanted liver in relation to an increase of 2-fold in patients with HCC associated with HCV having the same surgery of liver transplantation.[37] In the decade period of research, it was established that HCC disease caused by NASH was the America's second in ranking influences of transplantations of liver progressively rising from the estimated 2002 rate of 8.3% in comparison to the 2007 rate of about 10.3% before a drastic shift was experienced leading to the increase in the relative proportion in 2012 to approximately 13.5%.[37] In 2017, the number of people with HCC disease related to NASH going through the process of liver transplantation in the United States alone went up surpassing the 6-fold.[37]

  Noncirrhotic Nonalcoholic Steatohepatitis/Nonalcoholic Fatty Liver Disease and the Development of Hepatocellular Carcinoma Top

There is new clinical evidence indicating that most individuals established to have HCC disease caused by NASH or diagnosed with NAFLD lack substantial evidence linking them with cirrhosis.[44]

According to the study findings from a research undertaken by Fingas et al. discovered that out of the total sampled participants, an estimated to 6 of the 8 respondents in the hepatic resection exercise lacked the symptoms and signs of HCC disease related to NASH, meaning that there was no evidence of cirrhosis.[11],[44] The research findings showed lower prevalence and incidence of cirrhosis in people suspected to suffer from HCC disease triggered by NASH as opposed to a controlled study carried out on people suffering from HCC disease contributed by HCV.

The gathered information from the research shows that at an earlier stage, people suffering from HCC disease, unlike those diagnosed with HCV-triggered HCC, experienced advancement levels of NASH. Investigation on 128 patients with HCC in a research done by Fingas et al. established a significant percentage of the participants diagnosed with HCC disease related to NASH not having fibrosis, contrary to patients found to suffer from HCC disease but at the same time, diagnosed with other chronic liver diseases.[44] The hypothesis advanced by medical experts indicating that explanation of the disease suffered by people with noncirrhotic NAFLD is found in malignant hepatic adenoma modification. Few previous works support the fact that the syndrome of metabolism manifests in people with HCC disease caused by NASH and the process is possibly a malignant process of transformation in hepatocellular adenoma [Figure 2].
Figure 2: Progression of NAFLD: NAFL can progress to NASH and potentially cirrhosis. Each stage is defined by specific risk factors and/or pathological mechanisms. Both NAFL and NASH are thought to be reversible. Adapted from Research Tools for Fatty Liver Diseases, Article from 2017 to 03-22. NAFL: Nonalcoholic fatty liver, NAFLD: NAFL disease, NASH: Nonalcoholic steatohepatitis

Click here to view

  Cirrhotic Nonalcoholic Steatohepatitis/Nonalcoholic Fatty Liver Disease and the Prevalence of Hepatocellular Carcinoma Disease Top

In the past two decades, numerous medical scholars tried to find out the link between the development of HCC, cryptogenic cirrhosis, and NASH and/or NAFLD. A meta-analysis study done by Fingas et al. showed that an estimated 60% of reported cases of people with HCC disease contributed by NASH and/or NAFLD were infected with cirrhosis either during or before the diagnosis period.[11] In the Fingas et al. meta-analysis, the evaluation of both longitudinal and cohort experiments were reviewed and the findings indicated that cirrhosis caused by NASH steadily contributed to an increase the individual's risk of developing HCC disease with a wide range of 2.4%−12.8%. Moreover, the research findings showed a lower patient's risk of being diagnosed with cirrhosis developing HCC because of NASH and/or NAFLD as opposed to the population diagnosed with chronic HCV estimated at 26.9% compared to the approximated 19.7% of NAFLD/NASH and HCV, respectively.[11]

In conclusion, the actual HCC disease associated with NASH and the incidence of NASH is probably underrated. From between 6.9% and 29% of diagnosed people with HCC disease, there was unestablished condition of liver etiology disease with further research on the link between the two types of organ infection being less valued against cryptogenic cirrhosis.[37] Consequently, the symptoms of people suffering from HCC disease triggered by NASH and who are coupled with other infectious illness such as cryptogenic cirrhosis when matched with individuals with the age and sex show a positive relationship with HCC disease caused by additional causal factors like alcoholic and viral etiology. Despite the fact that HCC disease prevalence, particularly that caused by NASH and/or NAFLD is yet to be established, the experienced persistent increase in the reported cases of diabetes and obesity among the target population positively indicates that there will be a further rise in the incidences of HCC cases to those of liver disease.

  Prevention of Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma Top

To prevent liver cancer associated with NAFLD/NASH-related HCC requires an application of a wide range of medical interventions. The main clinical prevention measures focus on inhibiting individual contact with factors of cancer-predisposing or getting rid of these influences through modification of personal lifestyle, vaccination at an early development stage, or by adopting environmentally-related interventions strategies in a manner designed for a particular etiology.[45] Furthermore, treatment and control of the underlying risk factors of NASH such as DM, dyslipidemia and obesity through dietary restrictions, weight reduction, and physical exercise have beneficial effects.[39]

The tertiary or secondary intervention approach involves early chemoprevention and detection of respective recurrence or occurrence of HCC in people presently exposed to agents of etiology.

The prevention measures applied in the tertiary HCC phase after radical therapy of the disease is aimed at either limiting recurrence of HCC resulting from the distribution of disseminative recurrence (residual tumor cells) or through de novo recurrence, popularly referred to as de novo carcinogenesis in residue liver cirrhotic/fibrotic.[45]

However, there have been many challenges related to the application of strategies designed for the diagnosis and progression of chemoprevention. Today, little success has been experienced in the use of secondary medical techniques to prevent the development of HCC in the past few decades due to human carcinogenesis' subtle mechanisms.[45] Validation of cancer development in patients based on mechanisms employed from preclinical research findings is not realistic because it is both logically and ethically challenging to persistently screen cancer-free characters with molecular evaluation till there is a development of liver cancer cells. To mitigate these difficulties, medical experts recommend the use of a reverse-engineering method in which physicians first establish clinically appropriate goals in medical cohorts with concluded continued follow-up and consequently authenticated in tentative systems.

Another hindrance to chemoprevention advancement is suboptimal animal simulations which sometimes fail to bear a resemblance to human disease. Consequently, the adopted prevention model leads to incorrect detection of biomarkers and chemoprevention goals. Improvements can be made on these HCC prevention methods by applying modeling strategies that are more sophisticated. Another limiting factor is comparatively challenging admission to liver biospecimens.[45] This problem is in incomparable to informal access to the samples from other human fleshy tissue such as in the case of the gastrointestinal tract, cervix, and skin cancer that have led to more innovative chemoprevention progression.

The challenge encountered in tissue sampling may be resolved by using liquid biopsy even if there is no concrete information regarding whether informative biomolecules can be accessed today. The primary issue faced in this HCC prevention approach is the conduct and design of medical tests for chemoprevention which is known to be a resource-intensive exercise.[45] For one to conduct and design appropriate chemoprevention clinical trials, he or she needs long periods of observation and extremely massive sample sizes for different reasons including the set high safety requirements for chemoprevention agents' suboptimal potency, absence of dependable substitute endpoints of absolute enduring medical outcomes, and deficient improvement in patient populations perceived as high risk.[46]

Nevertheless, there was decreased HCC incidence in the subgroup examinations of patients diagnosed with a chronic disease like portal hypertension or cirrhosis.[45] This approach supports the clinical model of development whereby patients categorized as high risk are established and involved in the trials of chemoprevention using reduced sample sizes designed to capture well the impact of chemoprevention approaches.

  Conclusions Top

The article identified NAFLD/NASH-related HCC and the related complications as the primary cause of liver diseases. The expected NASH and NAFLD incidence and prevalence are higher than earlier approximated. It is also evident from the article that NASH can develop into HCC. Overall, HCC prevalence in patients diagnosed with NAFLD is low despite the steady rise in HCC incidence in the developed world. Age, advanced fibrosis, iron deposition, diabetes, and obesity significantly trigger a rise of NASH-HCC. In most cases, cirrhosis contributes to the development of HCC from NASH. NASH complications are projected to rise following persistent diabetes and obesity epidemics. Clinicians can pursue HCC screening after the diagnosis of cirrhosis. Based on the recent diabetes data on epidemiology, researchers in this domain should consider using statins, pioglitazone, and Liraglutide to treat diabetic patients with NASH, there is a need for the study to elucidate more about the symptoms of the development of HCC pathways in insulin resistance settings. Active research should also be done to assess the likelihood of finding an effective HCC and NASH treatment.

Shows a summary of the article [Table 1]. Abbreviations used in this article are shown in [Table 2].
Table 1: Take-home message

Click here to view
Table 2: Abbreviations list

Click here to view

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: Current concepts and future challenges. Nat Rev Gastroenterol Hepatol 2019;16:411-28.  Back to cited text no. 1
Zheng KI, Fan JG, Shi JP, Wong VW, Eslam M, George J, et al. From NAFLD to MAFLD: A “redefining” moment for fatty liver disease. Chin Med J (Engl) 2020;133:2271-3.  Back to cited text no. 2
Younossi ZM, Henry L. Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma. JHEP Rep 2021;3:100305.  Back to cited text no. 3
Paik JM, Golabi P, Younossi Y, Mishra A, Younossi ZM. Changes in the global burden of chronic liver diseases from 2012 to 2017: The growing impact of NAFLD. Hepatology 2020;72:1605-16.  Back to cited text no. 4
Hardy T, Wonders K, Younes R, Aithal GP, Aller R, Allison M, et al. The European NAFLD Registry: A real-world longitudinal cohort study of nonalcoholic fatty liver disease. Contemp Clin Trials 2020;98:106175.  Back to cited text no. 5
Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol 2013;10:656-65.  Back to cited text no. 6
Kucukoglu O, Sowa JP, Mazzolini GD, Syn WK, Canbay A. Hepatokines and adipokines in NASH-related hepatocellular carcinoma. J Hepatol 2021;74:442-57.  Back to cited text no. 7
GBD 2015 Obesity Collaborators; Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377:13-27.  Back to cited text no. 8
NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: A pooled analysis of 1698 population-based measurement studies with 19·2 million participants. Lancet 2016;387:1377-96.  Back to cited text no. 9
Moriguchi M, Seko Y, Takahashi A, Itoh Y. Epidemiology of hepatocellular carcinoma in nonalcoholic fatty liver disease. Hepatoma Res 2019;5:43.  Back to cited text no. 10
Fingas CD, Best J, Sowa JP, Canbay A. Epidemiology of nonalcoholic steatohepatitis and hepatocellular carcinoma. Clin Liver Dis (Hoboken) 2016;8:119-22.  Back to cited text no. 11
Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology 2014;59:2188-95.  Back to cited text no. 12
Mittal S, Sada YH, El-Serag HB, Kanwal F, Duan Z, Temple S, et al. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol 2015;13:594-601.e1.  Back to cited text no. 13
Sadler EM, Mehta N, Bhat M, Ghanekar A, Greig PD, Grant DR, et al. Liver transplantation for NASH-related hepatocellular carcinoma versus non-NASH etiologies of hepatocellular carcinoma. Transplantation 2018;102:640-7.  Back to cited text no. 14
Khan FZ, Perumpail RB, Wong RJ, Ahmed A. Advances in hepatocellular carcinoma: Nonalcoholic steatohepatitis-related hepatocellular carcinoma. World J Hepatol 2015;7:2155-61.  Back to cited text no. 15
Goh GB, McCullough AJ. Natural history of nonalcoholic fatty liver disease. Dig Dis Sci 2016;61:1226-33.  Back to cited text no. 16
Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021;7:6.  Back to cited text no. 17
Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med 2018;24:908-22.  Back to cited text no. 18
Campani C, Nault JC. Molecular mechanisms of liver carcinogenesis related to metabolic syndrome. Hepatoma Res 2022;8:3.  Back to cited text no. 19
Sutti S, Albano E. Adaptive immunity: An emerging player in the progression of NAFLD. Nat Rev Gastroenterol Hepatol 2020;17:81-92.  Back to cited text no. 20
Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021;592:450-6.  Back to cited text no. 21
Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, Tiribelli C, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. Hepatology 2016;63:827-38.  Back to cited text no. 22
Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: A pathological analysis. Hepatology 2009;49:851-9.  Back to cited text no. 23
Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011;9:428-33.  Back to cited text no. 24
Benson AB, D'Angelica MI, Abbott DE, Anaya DA, Anders R, Are C, et al. Hepatobiliary cancers, version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021;19:541-65.  Back to cited text no. 25
Vogel A, Cervantes A, Chau I, Daniele B, Llovet JM, Meyer T, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29:v238-55.  Back to cited text no. 26
Hasin-Brumshtein Y, Sakaram S, Khatri P, He YD, Sweeney TE. A robust gene expression signature for NASH in liver expression data. Sci Rep 2022;12:2571.  Back to cited text no. 27
Onzi G, Moretti F, Balbinot SS, Balbinot RA, Soldera J. Hepatocellular carcinoma in non-alcoholic fatty liver disease with and without cirrhosis. Hepatoma Res 2019;5:7.  Back to cited text no. 28
Farrell A, Ryan M, Howell J. Epidemiology of non-alcoholic fatty liver disease-related hepatocellular carcinoma: A western perspective. Hepatoma Res 2020;6:18.  Back to cited text no. 29
Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: Old questions and new insights. Science 2011;332:1519-23.  Back to cited text no. 30
Oda K, Uto H, Mawatari S, Ido A. Clinical features of hepatocellular carcinoma associated with nonalcoholic fatty liver disease: A review of human studies. Clin J Gastroenterol 2015;8:1-9.  Back to cited text no. 31
Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. QJM 2010;103:71-83.  Back to cited text no. 32
Suzuki A, Diehl AM. Nonalcoholic Steatohepatitis. Annu Rev Med 2017;68:85-98.  Back to cited text no. 33
Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 2010;51:1961-71.  Back to cited text no. 34
Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-21.  Back to cited text no. 35
Yoneda M, Fujii H, Sumida Y, Hyogo H, Itoh Y, Ono M, et al. Platelet count for predicting fibrosis in nonalcoholic fatty liver disease. J Gastroenterol 2011;46:1300-6.  Back to cited text no. 36
Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: A weighty connection. Hepatology 2010;51:1820-32.  Back to cited text no. 37
Banini BA, Sanyal AJ. Treatment of NASH: What helps beyond weight loss? Am J Gastroenterol 2017;112:821-4.  Back to cited text no. 38
Negro F. Natural history of NASH and HCC. Liver Int 2020;40 Suppl 1:72-6.  Back to cited text no. 39
Kim G, Jang SY, Nam CM, Kang ES. Statin use and the risk of hepatocellular carcinoma in patients at high risk: A nationwide nested case-control study. J Hepatol 2018;68:476-84.  Back to cited text no. 40
Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol 2016;65:589-600.  Back to cited text no. 41
Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: A randomized trial. Ann Intern Med 2016;165:305-15.  Back to cited text no. 42
Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): A multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387:679-90.  Back to cited text no. 43
Viganò L, Conci S, Cescon M, Fava C, Capelli P, D'Errico A, et al. Liver resection for hepatocellular carcinoma in patients with metabolic syndrome: A multicenter matched analysis with HCV-related HCC. J Hepatol 2015;63:93-101.  Back to cited text no. 44
Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018;68:526-49.  Back to cited text no. 45
Singal AG, El-Serag HB. Hepatocellular carcinoma from epidemiology to prevention: Translating knowledge into practice. Clin Gastroenterol Hepatol 2015;13:2140-51.  Back to cited text no. 46


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Epidemiology of ...
Etiology and Pat...
Nonalcoholic Ste...
Clinical Feature...
Diagnosis of Non...
Treatment of Non...
Prognosis of Hep...
Noncirrhotic Non...
Cirrhotic Nonalc...
Prevention of No...
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded142    
    Comments [Add]    

Recommend this journal