Non-alcoholic Steatohepatitis and Risk of Hepatocellular Carcinoma
The rise of non-alcoholic fatty liver disease (NAFLD) as the predominant chronic liver condition globally has raised significant concerns. NAFLD is closely associated with sedentary lifestyles and other metabolic disorders such as obesity and diabetes. At the severe end of the disease spectrum, non-alcoholic steatohepatitis (NASH) can progress to cirrhosis and hepatocellular carcinoma (HCC), posing a serious health challenge to modern society. An increasing number of HCC cases originating from this progressive disease spectrum have been identified, with varying levels of severity and complications. It is imperative to update current guidelines to focus more on this emerging cause and highlight its unique features. Given the complex and multifactorial drivers of the disease, a better understanding of the progression from NASH to HCC is essential to improve future outcomes. This review explores the risks that promote disease progression and the currently available management strategies for monitoring and treating NASH-related HCC.
NAFLD affects approximately one-quarter of the global population, but only a small fraction of patients progress beyond the initial stages to more severe conditions, with end-stage liver disease affecting less than 13% of NAFLD patients. The disease spectrum ranges from non-alcoholic fatty liver (NAFL) to NASH, fibrosis, and then cirrhosis. Following this progression, patients may develop HCC and end-stage liver disease. Despite its widespread prevalence, the factors contributing to disease progression and their impact on clinical outcomes are not fully understood.
NASH is characterized by the accumulation of fat in hepatocytes (more than 5%) along with signs of cell injury, such as hepatocyte ballooning and lobular inflammation, detected through histological examination. However, these histological changes can also be observed in alcoholic hepatitis, and a liver biopsy is required for a definitive diagnosis, indicating limitations in current diagnostic methodologies. Recently, there has been a push to redefine NAFLD to more accurately reflect current knowledge. Metabolic-associated fatty liver disease (MAFLD) has been proposed as an alternative nomenclature, with diagnostic criteria based on the presence of hepatic steatosis plus any of the following: elevated body mass index (BMI), type 2 diabetes mellitus, or evidence of metabolic dysregulation.
Obesity negatively impacts NASH patients, with higher adiposity levels associated with increased severity of fibrosis and inflammation. Similarly, type 2 diabetes has been identified as a contributor to the development of NAFLD, and NAFLD is associated with an increased risk of diabetes. HCC is more frequently associated with risk factors such as age (over 65 years), diabetes, and metabolic syndrome.
The pathogenesis of NAFLD to HCC involves multiple factors. The foundation of all complications lies in the metabolic disturbance of NAFLD patients. Key factors include insulin resistance, lipotoxicity, oxidative stress, and DNA damage response. Insulin resistance, exacerbated by modern lifestyles and diets, decreases the effectiveness of insulin in regulating glucose metabolism and interferes with the metabolism of glucose, ketones, and lipids. This generates an excess of free fatty acids (FFAs) that disrupt the normal function of mitochondria in hepatocytes, playing a crucial role in the progression from NAFLD to HCC. Initially, reduced insulin activation and lipid buildup were associated with interference in the tricarboxylic acid (TCA) cycle and increased production of reactive oxygen species (ROS). In NASH patients, ROS production is nearly doubled due to persistent TCA cycle activity, despite suboptimal beta-oxidation, insufficient lipid esterification, and impaired ketogenesis. The adaptive capabilities of hepatocytes to regulate their metabolism and compensate for initial disturbances caused by increased FFAs and insulin resistance mean that changes in the TCA cycle may not be easily detected. The increase in ROS leads to inflammation, fibrogenesis, and DNA damage, highlighting the importance of diabetes and insulin resistance in predicting advanced stages of the disease, such as cirrhosis and HCC.
Lipotoxicity occurs when elevated levels of FFAs interfere with the glucose metabolism pathway, increasing the production of toxic byproducts and the likelihood of tumor formation in the liver. The regenerative capabilities of liver tissue complicate the measurement of the impact on cellular DNA and its role in causing HCC. HCC cells show an upregulation of genes promoting de novo lipogenesis, working with accumulated lipids from steatosis to increase ROS production, causing further oxidative stress in NASH patients and leading to HCC cells that adapt to the lipotoxic environment. Due to the elevated energy requirements of tumor cells, HCC cells can adopt a lipid-dependent metabolism, particularly in fatty liver tissue abundant in lipids. Understanding this process can explain the limitations of current anti-angiogenesis medications and propose additional treatment options for NASH and its progression to HCC.
Oxidative stress occurs when there is an increase in the production of free radicals or cytotoxic oxidants that damage tissues and cellular components due to unregulated oxidation. This leads to hepatocyte apoptosis, inflammation, fibrogenesis, and DNA damage. NASH patients suffer more oxidative insults to hepatocytes than other liver diseases, particularly those with both NASH and HCC. Normal physiological processes produce manageable amounts of free radicals, but NAFLD patients have excessive FFAs metabolized by hepatic mitochondria, leading to incomplete beta-oxidation, impaired ketogenesis, and overproduction of ROS. This saturation of ROS, along with inflammation, is often associated with oncological outcomes, observed in both NAFLD and hepatitis patients. Mitochondrial dysfunction can be interpreted as a response to the unhealthy environment faced by hepatocytes in a fatty liver, with elevated FFAs requiring an adjustment to the regular energy production mechanism. Mutations that affect the development of insulin resistance, rate of hepatic fat buildup, and promote metabolic reprogramming increase the risk of NASH-related HCC.
DNA damage response studies have shown that carcinogenesis might not only result from direct DNA damage but also from misinterpreted damage by anti-cancer mechanisms. Various mouse models have compared DNA repair enzymes with the impact of oxidation on DNA, proving an inverse relationship, suggesting that genetic inheritance or acquired characteristics of DNA repair enzymes may underlie variations in susceptibility to HCC and worsening of NAFLD. Genetic predisposition to hepatic fat accumulation in the form of single nucleotide polymorphisms (SNPs) also represents a significant risk for disease progression to HCC. Overexpression of DNA repair mechanisms, triggered by increased sensitivity to DNA damage, has been correlated with worse survival rates.
Fibrosis progression in NAFLD is more complex than a linear sequence of events. The time required to advance from one stage to the next is almost double for NAFLD patients compared to NASH patients. Fibrosis remains the most significant factor for predicting mortality in NAFLD patients, even when adjusting for confounding factors. Accumulation of fibrotic tissue is problematic, being the most important step toward cirrhosis and HCC. Fibrotic changes are formed as part of the normal healing process but, without natural degradation rates or with continuous injury, accumulate, increasing in density and entanglement, isolating hepatocytes into nodules, reducing blood flow, and disrupting normal liver function. Hepatic stellate cells produce this fibrotic tissue, transitioning from a standby state to actively secreting tumor growth factor-beta, producing collagen, and establishing an extracellular matrix. Monitoring these changes allows physicians to establish an accurate prediction of disease progression rate and assess severity levels, particularly when compared with liver steatosis and inflammation measurement, which are easily influenced by changes such as medication or lifestyle intervention.
Genetic factors play a significant role in NAFLD, NASH, and HCC susceptibility. Studies have identified SNPs such as phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), 17b-Hydroxysteroid dehydrogenase 13 (HSD17B13), and membrane-bound O-acyltransferase domain containing 7 (MBOAT7). PNPLA3 has the most concrete correlation with fibrosis and fatty hepatocytes based on histology grading. PNPLA3, TM6SF2, and MBOAT7 represent genetic variations related to fat buildup in liver cells, while an inhibited HSD17B13 variant is associated with a reduced risk of NAFL to NASH. Alteration to standard lipid metabolism can promote metaplastic changes in hepatocytes. Due to the rapid nature of tumor growth, the aggregated mass often outgrows vascularization, resulting in a low oxygen environment. To overcome this, the tumor modifies its genetic expression, increasing its lethality, resistance to treatment, and expanded metastasis regions. HIF-2a, due to its role in promoting disease progression in patients with both steatosis and HCC, could be a valuable target for the treatment of NAFLD-related HCC. A study by Desterke et al identified 25 genes involved in NASH development and 44 genes/proteins in the progression from NASH to HCC, organizing these genes into a “canonical pathway” that clarifies their roles in increasing triglyceride synthesis, cholesterol, and de novo fatty acids; promoting inflammatory processes and chemo-attraction; higher FFA accumulation due to mitochondrial disruption and beta-oxidation; and faster development of insulin resistance and cancer progression.
Hormonal factors also impact NAFLD prevalence and outcome severity. Sex has long been identified as an independent risk factor for NAFLD development, with male patients having a higher risk and more rapid progression to advanced stages compared to female patients. HCC also has a higher onset in males than females. However, this comparison often does not distinguish menopause status, which represents a shift in hormonal balance. Post-menopausal women have a higher prevalence of NAFLD, and women undergoing hormone replacement therapy (HRT) seem to have lower NAFLD prevalence, suggesting a protective effect of these hormones. Thyroid hormone levels can also have a protective effect in NAFLD, with hyperthyroidism associated with lower NAFLD prevalence and hypothyroidism identified as having an increased risk of prevalent NAFLD. However, conflicting results exist regarding which thyroid hormones are relevant and their levels’ significance. Elevated free tetraiodothyronine (T4) is associated with poor survival outcomes in HCC, while increased thyroid-stimulating hormone (TSH) levels are correlated with larger tumors. Elevated free triiodothyronine (T3) is associated with HCC progression, indicating that thyroid function can be considered a potential risk factor for NAFLD and a possible marker for disease progression in HCC.
Lifestyle choices significantly impact NASH disease progression. A correlation has been observed between NAFLD and living locations with a large variety of food options, consumption of processed foods, unbalanced diets high in meat/fat, and low in fresh fruits, and little regular exercise. Epidemiological studies have established a strong association between an unhealthy lifestyle and NAFLD presence. Studies documenting NAFLD-related HCC prevalence data are less rigorous, with a relative level of selection bias applied in available data. Cryptogenic cirrhosis shows many similarities with NASH-related cirrhosis, leading to an underestimation of NAFLD, and increased awareness of the disease could inflate the growing curve representing the number of patients diagnosed annually. A United States study collected information on 170,540 adult patients from a transplant waitlist database over 15 years (2002–2017), with 17% of patients listed with HCC, and of those, roughly 16% had no discernible etiology. However, 24,431 patients had identifiable causes, with 2520 patients (10.3%) identified as having NASH as the cause of HCC. This study features a large sample size of NASH-HCC patients, allowing an approximate proportion of NASH within the varied etiologies of HCC in an American population.
NASH-related HCC fuels debate regarding its monitoring and management. The progressive nature of this metabolic disease necessitates close monitoring for early intervention. However, the low proportion of NAFLD patients developing HCC raises questions about the practicality and cost-effectiveness of repetitive monitoring. Documented reports have established a significant correlation between non-cirrhotic steatosis/steatohepatitis patients and HCC, showing that NASH alone could progress to HCC, contradicting the idea that pre-cirrhosis monitoring is premature. In the absence of cirrhosis, NAFLD and metabolic syndrome are the most common causes of HCC, compared to viral hepatitis and other causes. Around one-third of NAFLD-related HCC patients have no evidence of cirrhosis. Tumor size in non-cirrhotic HCC patients often appears larger, possibly due to late detection of the tumor, arguing for more aggressive screening. Liver transplantation’s viability as a treatment option is limited by high recurrence rates, organ donor shortage, rejection or immunosuppressant complications, cost, and possible surgery complications. Further studies are required to establish more reasonable guidelines, improve diagnostic/monitoring methods, and develop a thorough understanding of the mechanisms dictating neoplastic transformation of hepatocytes. NAFLD patients with HCC have a significantly reduced lifespan compared to viral hepatitis patients, with worse mortality outcomes.
Disease progression in NAFLD patients is relatively slow, with most patients spending years without symptoms. The main preventative measure is introducing lifestyle changes, highly dependent on patient motivation. The management of NAFLD/NASH-related HCC is not yet addressed by major guidelines, mainly due to the complexity of NASH management compared to viral hepatitis. Current evidence suggests differences in outcomes between NAFLD-related HCC and HCC of other etiologies. Studies have proposed a stage-based approach to diagnosis and treatment of NAFLD, introducing novel, noninvasive biomarkers to identify histological disease progress. From lipid signatures specific to NASH to biomarkers detecting advanced fibrosis, recommendations include pharmacological treatment during the intermediate stage, screening for HCC and esophageal varices at the late stage of NASH, and lifestyle interventions and diet regimen control across all stages. Imaging technology has also been a focus for noninvasive diagnosis and staging of NAFLD. Abdominal ultrasound (US) examination is a common test used to screen and monitor HCC, particularly in patients with fibrotic tissue, with follow-up examinations repeated every 4 to 6 months. According to the American Association for the Study of Liver Diseases guideline, computer tomography (CT) or magnetic resonance imaging should be used for further verification of HCC if abnormal US and alpha-fetoprotein (AFP) levels are found in severe fibrosis patients (stages 3–4). Confirming NASH diagnosis still requires a liver biopsy, the diagnostic gold standard, despite its invasiveness and cost. Abdominal US often lacks sensitivity due to large amounts of abdominal fat compromising accuracy, particularly in patients with very elevated BMI. Cost-effectiveness is crucial when discussing the feasibility of monitoring techniques, particularly in complex diseases like NASH requiring long-term follow-ups. Studies aiming to document factors increasing accuracy, improving risk assessment, reducing cost, and identifying therapeutic targets are needed.
Certain cancer-targeted biomarkers, such as circulating tumor DNA or extracellular vesicles, have shown potential screening capabilities for HCC. Research related to telomere shortening has found indications of hepatocyte dysfunction, fibrosis generation, and interference in the metabolic pathway of lipids, all factors related to disease progression risks. Despite liver biopsy being the gold standard for NAFLD and NASH diagnosis, HCC should be screened by imaging techniques when possible. While liver biopsy has the highest diagnostic accuracy, HCC is easy to notice under contrast-enhanced imaging compared to NAFLD. The invasiveness of biopsy introduces a risk of spreading cancer cells and bleeding, risking incorrect assessment due to sampling location. Future progress will likely phase out biopsies and expensive imaging tests in favor of targeted cellular components, such as proteomic and genomic measurements, and cost-effective serum exams.
Treatment strategy guidelines for HCC traditionally follow the format of matching treatment options to disease stages, like the Barcelona Clinic Liver Cancer guidelines. However, studies with more flexible approaches, administering therapy from the next disease stage concurrently with the current stage’s treatment, have provided different advantages and disadvantages to the established stage hierarchy system. Changes to current therapy methods will rely on the development of new strategies or increased feasibility of existing ones. Immunotherapy has untapped potential but its reliability has not been proven and is still being tested in clinical trials. The greatest progress in HCC management has been the improvement in diagnostic methods and screening, allowing established treatment methods to have a greater impact on survivability by treating the tumor in earlier stages, as HCC is conventionally identified in later stages.
Established treatment methods for NAFLD-related HCC can be divided into three categories: lifestyle changes, surgery, and pharmacology. Lifestyle changes, mainly diet control and frequent exercise, positively impact slowing or reversing NASH progression, but once HCC is confirmed, more significant measures are needed. Further study on the impact of behavioral changes in NAFLD-related HCC patients is necessary. Surgical options for HCC patients include liver resection, ablation, chemoembolization, radioembolization, and liver transplantation. Liver resection is limited to smaller-scaled tumors, with thresholds for operable size and the number of tumors varying in different countries. Thermal ablation is mainly used in early HCC, and embolization can be used from early to advanced HCC. Radiofrequency ablation (RFA) has been thoroughly researched, with 5-year survival rates of about 40% to 70% by itself, but combination with other methods, such as chemoembolization, has been investigated. Transcatheter arterial chemoembolization (TACE) plus CT-guided RFA has produced very good results, with overall survival rates of 96.1%, 76.7%, and 41.3% for 1, 3, and 5 years, respectively. Liver transplant carries fewer risks for the patient compared to resection and may sometimes help treat the underlying cause of liver disease. The Milan criteria, featuring over 17 thousand patients, established a 5-year survival rate ranging between 65% and 78%. However, the main disadvantages of transplantation are donor shortage and possible immune response/rejection.
Drug treatment for end-stage HCC patients can be subcategorized into first-line and second-line drugs. First-line includes two tyrosine kinase inhibitors (TKIs), sorafenib (established) and lenvatinib (novel), with a life expectancy increase of about 10 weeks. Additionally, atezolizumab and bevacizumab have been administered as a combination therapy in a Phase III study, obtaining FDA approval, with overall survival numbers superior to sorafenib. Second-line drugs include regorafenib (TKI), cabozantinib (TKI), and ramucirumab (anti-angiogenic), with an average increase in life expectancy of 3.6, 10.2, and 8.5 months, respectively. Ramucirumab is a phase III trial drug presenting an alternative to sorafenib, effective in patients with AFP levels over 400, but with no difference in efficacy. Nivolumab belongs to the novel immunotherapy category, with an overall response rate of 20%, currently in phase III clinical trial, performing significantly better than sorafenib.
The continuous rise in NAFLD prevalence worldwide warrants the need to coordinate appropriate healthcare measures. However, the lack of disruptive symptoms renders its early development relatively unnoticed by those affected, conducive to the progression of simple steatosis to NASH and/or fibrosis, ultimately evolving into HCC. The role played by lipotoxicity, insulin resistance, and mitochondrial activity reveals a possible route of pharmacology research for NASH management. However, the mechanism underlying the neoplastic change among NAFLD patients is poorly understood; therefore, future studies are suggested to focus on NASH-related HCC investigations.
doi.org/10.1097/CM9.0000000000001888
Was this helpful?
0 / 0