Fatty liver disease and primary liver cancer: disease mechanisms, emerging therapies and the role of bariatric surgery

KEYWORDS:

• NASH
• obesity
• metabolic syndrome
• primary liver cancer
• lifestyle intervention
• hepatocellular carcinoma
• nonalcoholic steatohepatitis
• bariatric surgery
• nafld
• obeticholic acid

1. Introduction

Nonalcoholic fatty liver disease (NAFLD), the precursor to nonalcoholic steatohepatitis (NASH), is a spectrum of liver diseases that clinically resembles alcohol induced fatty liver disease but occurs in those individuals who do not abuse alcohol. NAFLD is characterized by excess accumulation of triglycerides in the liver, which leads to steatosis (defined as >5% fat content in the liver), a defining feature of NAFLD. Progressive steatosis in NAFLD leads to inflammation, hepatocyte injury, and fibrosis which may progress to NASH, cirrhosis, and primary liver cancer, though the occurrence of liver cancer may occur before clinically apparent cirrhosis.

Liver-related mortality in NAFLD, overall the third most common cause of death in the NAFLD patient [1], is primarily from cirrhosis or hepatocellular carcinoma (HCC) [2], which can occur in the absence of cirrhosis [3]. NAFLD and NASH also potentially increase the risk of intrahepatic cholangiocarcinoma, though further studies are needed to establish this association [4].

2. Epidemiology of NAFLD and NASH

Based on imaging characteristics, the prevalence of NAFLD is in the range of 20–50% [5]. Due to its strong association with metabolic disorders, fatty liver has been reported in 40–80% of patients with type 2 diabetes and 30–90% of patients with obesity, though this varies widely between ethnic groups [6,7]. In one study of unselected patients in the southwest United States, 46% of patients (n = 156/328) were found to have NAFLD based on patient history and ultrasound liver findings. Among the 134 patients who subsequently underwent a liver biopsy, 40 had NASH, suggesting a prevalence of 12% in the adult population seeking routine health care [8]. With the continued worsening obesity epidemic and the high rate of obesity and metabolic disease in adolescents, the prevalence of NAFLD and NASH is likely to increase in coming years.

3. Diagnosis of NAFLD and NASH

NAFLD is the most common cause of abnormal liver enzymes in Western countries, and abnormal laboratory tests in a patient with obesity or insulin resistance should prompt further workup. Though there has been significant effort to develop prognostic clinical scores or imaging-based markers for the diagnosis and staging of NAFLD, a percutaneous liver biopsy remains the gold standard [3]. For high-risk patients, evaluation should include high-quality cross-sectional contrast imaging (CT or MRI) to evaluate liver morphology, sequalae of cirrhosis, and potential masses. While imaging is quite good at diagnosing steatosis [9], standard imaging techniques are not of sufficient quality to accurately and reproducibly diagnose fibrosis, and newer imaging technologies are being increasingly used in combination with conventional technologies and include ultrasound elastography, quantitative ultrasound-based techniques, magnetic resonance elastography, and magnetic resonance-based fat quantitation techniques.

4. Disease mechanisms of NAFLD and NASH

A distinct feature of NAFLD is the presence of steatosis and association with insulin resistance and obesity [10]. The weight gain from obesity results in expansion of adipose tissue and eventual death of adipocytes. This local cell death causes upregulation of a number of inflammatory markers and insulin resistance, impairing the ability of adipocytes to store fat and causes the release of fatty acids into the circulation with subsequent uptake up by hepatocytes [11]. In response to high circulating insulin levels – produced in response to systemic insulin resistance – and high levels of circulating free fatty acids, the liver begins to store excess levels of free fatty acids and produce triglycerides, causing glucoenogenesis, hyperglycemia, and additional insulin production [12]. In the setting of obesity and hyperinsulinemia, de novo lipogenesis (which is rare in the normal liver) can contribute up to 25% of total hepatic lipids and serves as important precursors to NAFLD [13].

The progression from NAFLD to NASH occurs when liver inflammation from widespread cell death causes liver fibrosis. Excess fatty accumulation contributes to cell death by causing mitochondrial damage [14], activating death agonist proteins [15], or activating death receptors [16]. The mitogen-activated protein kinase (MAP-K) pathway is broadly implicated in hepatic metabolism, and specifically activated in response to multiple causes of hepatic stress implicated in the development of NAFLD and its progression to NASH. Despite this, the specific role that the MAP-K pathway plays in the NAFLD-NASH pathway, and the potential therapeutic targets therein, is not yet clearly understood [17]. By whatever mechanism, significant cell death in NAFLD and NASH leads to the activation of the immune system, significant prolonged inflammation, and eventual hepatic fibrosis. These same mechanisms also contribute to the eventual progression to liver cancer.

5. Progression to primary liver cancer

5.1. Patients with cirrhosis

Primary liver cancer (predominantly HCC) develops in 2.4%-12.8% of patients with NAFLD cirrhosis annually [9,18]. The development of HCC results from a combination of chronic low-grade inflammation, insulin insensitivity, mitochondrial damage from excess fatty accumulation, and chronic cytokine dysregulation all contribute to the patient with NAFLD or NASH developing HCC [19]. These factors all result in DNA damage, and mutations in proto-oncogenes or tumor-suppressor genes and subsequent development of HCC [20]. Interestingly, NASH patients with HCC have been shown to have worse oxidative DNA damage in the liver than NASH patients without HCC [21].

5.2. Patients without cirrhosis

In contrast to the hepatitis C virus infection to HCC progression, a significant number of patients with NAFLD/NASH develop HCC before developing cirrhosis. One study of 1,168 patients undergoing hepatectomy for HCC noted that six of the eight patients with NASH did not have cirrhosis [22]. Another study, of 128 HCC patients seen over 12 years in France reported that 65% of patients with HCC and NAFLD did not have evidence of liver fibrosis (and therefore did not have NASH), compared with 26% of patients with HCC and other chronic liver diseases [23].

As a complicating factor, patients with both NAFLD and HCV have cumulatively worse outcomes. Specifically, the presence of NAFLD in the HCV patient is associated with an increased likelihood of developing HCC than in patients with NAFLD or HCV alone. Furthermore, NAFLD patients exhibit a poor response to HCV treatment [19,24]. Based on recommendations from the United States Preventative Health Task Force, all patients at high risk of HCV infection, and all adults born between 1945 and 1965 regardless of risk factors, should be screened for HCV [25].

6. Treatment of primary liver cancer

The treatment of primary liver cancer is surgical. All patients diagnosed with HCC should be evaluated at a high-volume multidisciplinary liver center [26]. Patients with a single solitary mass without major vascular invasion and an adequate functional liver remnant are candidates for primary resection. Patients with a borderline functional liver remnant can be considered for pre-operative portal vein embolization or other advanced techniques to improve the size and functionality of the future liver remnant [27]. Patients with limited and resectable multifocal disease or major vascular resection may be candidates for resection in the setting of a prospective protocol evaluating this strategy, and situational utilization of advanced surgical techniques may be indicated. Similarly, patients with cholangiocarcinoma that are physiologically able to undergo a hepatectomy and have a suitable future liver remnant should be considered for surgical resection.

Patients with HCC not amenable to primary resection should be evaluated at a liver transplant center. The Milan criteria [28] for transplantation are the most commonly used, and include a single lesion < 5 cm or 2–3 lesions < 3 cm, though recently many groups have advocated expanding these criteria as experience with transplantation has expanded [29]. Technically unresectable patients, and those that are not candidates for transplantation can be treated with liver directed therapies (transarterial chemoembolization, bland embolization, Y-90 radioembolization) and systemic chemotherapy.

7. Prevention of NAFLD/NASH associated primary liver cancer

There are currently no approved medications to treat or prevent the progression of NAFLD or NASH, though many are under study [30]. Obeticholic acid is derived from chenodeoxycholic acid (a primary bile acid) and is a potent agonist of Farnesoid Receptor X, a nuclear receptor that regulates the hepatic metabolism of glucose, lipids, and bile acids. It has been shown to improve cholestasis, and possibly fibrosis, in patients with primary biliary sclerosis [31]. In patients with NASH it has been shown to improve liver histology [32] and liver fibrosis [33], both of which will decrease the progression to HCC.

Another nuclear receptor family involved in liver disease are the peroxisome proliferator-activated receptors (PPAR). Elafibranor, a PPAR α/δ agonist, has been demonstrated to be more effective than placebo at inducing resolution of NASH, and also reducing liber fibrosis [34]. Liraglutide, an antidiabetic GLP-1 agonist, in a phase 2 clinical trial, resulted in histological resolution of NASH in 39% of patients, compared with only 9% of patients treated with placebo [35]. More recent studies, in several different countries, have found similar results [36–39]. Pioglitazone, a PPAR-γ agonist, improved NASH histology both in patients with prediabetics and with type 2 diabetes, with a greater improvement in fibrosis in those with type 2 diabetes [40], and is endorsed by multiple international societies for the treatment of patients with NAFLD [41–44]. In fact, due to its effect on liver fibrosis, both NICE [42] and the AASLD [44] recommend using Pioglitazone regardless of whether or not a patient is diabetic.

There are currently no approved medications to prevent the progression from NAFLD or NASH to HCC. As detailed above, however, there are multiple medications that in multiple clinical trials have shown the ability to improve various metrics of NAFLD or NASH, though there is not long enough follow up in any of these trials to report changing development of HCC. Current national guidelines agree on the use of pioglitazone, and as of now no other medications are widely recommended [40–43].

Current treatment of NAFLD and NASH consists of lifestyle modification, weight loss via diet and exercise, and bariatric surgery. Bariatric surgery is safe, provides durable weight loss, and reverses or improves many end-organ complications of metabolic syndrome, particularly type 2 diabetes [45–51]. The two most commonly performed bariatric procedures in the United States are laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass. In a cohort of 4,112 patients propensity matched obese patients at the University of Virginia, individuals who had undergone bariatric surgery had lower rates of on new-onset NASH (6.0% vs 10.3%, p < 0.01) and HCC (0.05% vs 0.34%, p = 0.03) over a median follow up of 7.1 years [49]. In a separate prospective cohort study on 94 patients who underwent sleeve gastrectomy with biopsy proven NAFLD at the time of index operation had a statistically significant decrease in steatosis grade, hepatocyte ballooning, lobular infiltration, and fibrosis stage on follow-up biopsy performed a year following surgery [51]. Importantly, other investigators have reported that sleeve gastrectomy and Roux-En-Y gastric bypass are similarly effective at improving liver function [50], allowing the bariatric surgeon evaluating a patient with NAFLD/NASH to choose the procedure best suited for their specific patient.

8. Expert opinion

The molecular underpinnings of the evolution from NAFLD to NASH to liver cancer (with or without cirrhosis) are well understood [5,19,52], and multiple studies are underway targeting specific parts of this progression [30,36–39,53]. NAFLD and NASH typically occur in patients with metabolic syndrome. While liver disease is the 3rd most common cause of death in these patients, cardiovascular disease is the most common [1]. Medications that find success will not only interfere with the development of liver specific disease in these patients, but those that halt and reverse the progression of metabolic syndrome overall.

Bariatric surgery is cost effective [54], improves markers of obesity, and improves survival from the major causes of death in the obese patients including cardiovascular disease [55], malignancy [56], and liver disease [49]. As we continue to pharmacologically halt and reverse liver injury, control hypertension, improve insulin sensitivity, control plaque buildup in the vasculature, and prevent peripheral neuropathy, we must also work to improve coverage for, and access to, bariatric surgery [57]. The incidence of NAFLD, NASH, and the associated primary liver cancer, are only increasing. The molecular underpinnings of this transformation are well described and will likely soon be actionable. Work to target this transformation can, and should, occur alongside work to connect the patient with metabolic syndrome patient with a bariatric surgeon who can provide life-altering treatment today.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

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Funding

This paper was not funded.