A Resinous Extract For Liver Health and Repair

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Nonalcoholic fatty liver disease (NAFLD) has quickly become the leading cause of liver disease in the Western world.[1] The current recommendations upon first diagnosis of NAFLD are diet and lifestyle management. While these are certainly the most important places to start, as a clinician, I find these recommendations to be difficult for some of my patients who are just beginning a new health journey. Fortunately, research has shed light on one particular intervention that may increase the beneficial effects of these diet and lifestyle changes.

What is NAFLD?

NAFLD is the accumulation of fat in more than 5% of liver tissue in the absence of secondary causes, such as alcohol or drug use.[2] The pathogenesis of fat accumulation is multifactorial and is often attributed to some combination of genetic predisposition, environmental factors such as a high-fat diet and sedentary lifestyle, and insulin resistance, with insulin resistance playing a prominent role.[3] Additionally, factors such as increased oxidative stress, inflammation, immune dysfunction, and intestinal dysbiosis can exacerbate and trigger the progression of NAFLD.[4] Each of these are valid areas to target treatment research, as the consequences of unchecked NAFLD can be severe.[5]

However, one novel resin procured from the island of Chios shows promise in benefiting multiple pathogenetic factors involved in the progression of NAFLD. Mastiha, or Chios mastic gum (CMG), is a resinous extract that’s indigenous to the Mediterranean. It has a long history of therapeutic usage, documented originally by Hippocrates.[6] Traditionally, CMG has been used for gastric disorders, predominantly peptic ulcers and indigestion. However, newer research has demonstrated CMG’s proficiency as an antioxidant, anti-inflammatory, hypolipidemic, and liver-supportive agent, making it a viable candidate to support the typical diet and lifestyle approaches prescribed for NAFLD.[7]

Studies have shown that CMG can benefit factors of metabolic dysregulation, with one study showing benefits with doses as low as 330 mg three times daily.

A Complementary Approach to Treating NAFLD

In one randomized controlled trial (RCT), researchers observed that six months of 2.1 g of mastiha supplementation reduced parameters of liver inflammation and fibrosis in severely obese subjects with NAFLD compared to placebo.[8] Another RCT saw similar results, with NAFLD subjects showing measurable improvement over six months of supplementation with CMG. This group of researchers attributed this to the improved antioxidant and inflammatory profiles that they measured.[9] The anti-inflammatory and antioxidant potential of CMG surely plays a role in its positive effects on NAFLD. Yet, as shown by the research, mastiha’s list of benefits seems especially tailored to address many of the factors involved in both the origin and progression of fatty liver disease.

Metabolic Syndrome, and Mastiha as an Aid to Lifestyle Recommendations

CMG provides multiple benefits for those struggling with metabolic syndrome, a primary factor in the development of NAFLD.[10] Studies have shown that CMG can benefit factors of metabolic dysregulation, with one study showing benefits with doses as low as 330 mg three times daily.[11] After eight weeks, CMG consumption significantly reduced fasting glucose levels, with greater effects in the obese population. Additional studies have revealed reductions in triglycerides, insulin levels, and liver enzyme measurements with 5 g of CMG per day over the course of six months.[12] Because insulin resistance is consistently a major factor in the development of NAFLD, these studies suggest that CMG supplementation could be of additional benefit alongside the traditional diet and lifestyle recommendations for these patients.

 CMG has been shown to increase levels of glutathione, the body’s master antioxidant, which aids in the balance of oxidation.

Oxidative Damage and Its Role in the Progression of NAFLD

Once triglycerides begin to accumulate in the hepatocytes and the liver becomes “fatty,” it also becomes more susceptible to secondary insults that can lead to the progression of NAFLD. For instance, the excess fat accumulation in the hepatocytes impairs the oxidative capacity of the mitochondria.[13] This alters the function of the electron transport chain and lends to increased generation of reactive oxygen species (ROS).[14] The imbalance of pro-oxidants and antioxidants leads to DNA and tissue damage, promoting the progression of NAFLD to nonalcoholic steatohepatitis (NASH).⁴ Increased ROS load also contributes to a state of increased inflammation through more pro-inflammatory cytokines. High ROS levels and reduced antioxidants lead to insulin resistance, further exacerbating the cycle of NAFLD to NASH.[15]

One standout mechanism for CMG against NAFLD is its antioxidant potential. CMG was traditionally utilized in food preservation because of its protection against oxidation, and researchers began to look deeper into it to observe whether it could have similar effects for us. Fortunately, they found that it did. CMG has been shown to increase levels of glutathione, the body’s master antioxidant, which aids in the balance of oxidation.[16]

Clinical trials have supported these in vitro results as well. CMG has been shown to significantly decrease oxidative LDL levels in patients of intestinal bowel disease (IBD), a disease associated with oxidative stress.[17] Another clinical trial observed a drastic increase in total antioxidant status following six months of CMG supplementation compared to placebo in obese individuals with NAFLD.⁹

               In one randomized, controlled clinical trial of NAFLD patients, CMG greatly improved microbiome diversity.

GI Dysbiosis Can Exacerbate NAFLD and Mastiha Could Help

Alterations in the commensal bacteria of the gut lead to many known ailments, so it is not surprising that dysbiosis is associated with NAFLD. In NAFLD, the gut microbiome is dramatically altered in an adverse direction. While the microbiome picture in NAFLD studies can vary, Clostridium leptum is one strain that is decreased in NAFLD and NASH. Interestingly, C. leptum metabolizes bile acids, and a decrease in conversion of primary bile acids to secondary bile acids is a hallmark of NAFLD. Decreased secondary bile acids decrease the activation of several nuclear receptors that can cause metabolic dysfunctions, including glucose imbalances, known to be a primary cause of NAFLD origination.

In one randomized, controlled clinical trial of NAFLD patients, CMG greatly improved microbiome diversity. The same study also observed decreases in cholic acid levels in the CMG group, suggesting that CMG improves the microbiota’s ability to metabolize bile acids.[18]

NAFLD is generally referred to as a “multiple hit” disease, with metabolic dysfunction often triggering the process, and factors such as oxidative stress, dysbiosis, and/or inflammation exacerbating it, contributing to a negative feedforward cycle (i.e., these conditions worsen the others).[19] Fortunately, CMG has proven beneficial against each of these hits. It has performed well in clinical trials of NAFLD and shown multiple benefits as a hepatoprotective agent. With no current pharmaceutical regimen offered for patients suffering from NAFLD (outside of the occasional use of vitamin E and insulin sensitizers[20]), CMG could be considered as a supplement to the current diet and lifestyle recommendations to improve patient outcomes.

[1] Rinella ME. Nonalcoholic fatty liver disease: a systematic review [published correction appears in JAMA. 2015 Oct 13;314(14):1521]. JAMA. 2015;313(22):2263-73.

[2] Cobbina E, Akhlaghi F. Non-alcoholic fatty liver disease (NAFLD) – pathogenesis, classification, and effect on drug metabolizing enzymes and transporters. Drug Metab Rev. 2017;49(2):197-211.

[3] Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1 Suppl):S47-S64. doi:10.1016/j.jhep.2014.12.012

[4] Dallio M, et al. Immunity as Cornerstone of Non-Alcoholic Fatty Liver Disease: The Contribution of Oxidative Stress in the Disease Progression. Int J Mol Sci. 2021;22(1):436.

[5] Mundi MS, et al. Evolution of NAFLD and Its Management. Nutr Clin Pract. 2020;35(1):72-84.

[6] Pachi VK, et al. Traditional uses, phytochemistry and pharmacology of Chios mastic gum (Pistacia lentiscus var. Chia, Anacardiaceae): A review [published correction appears in J Ethnopharmacol. 2021 Jun 12;273:113961]. J Ethnopharmacol. 2020;254:112485.

[7] Papada E, Kaliora AC. Antioxidant and Anti-Inflammatory Properties of Mastiha: A Review of Preclinical and Clinical Studies. Antioxidants (Basel). 2019;8(7):208.

[8] Amerikanou C, et al. Effect of Mastiha supplementation on NAFLD: The MAST4HEALTH Randomised, Controlled Trial. Mol Nutr Food Res. 2021;65(10):e2001178.

[9] Kanoni S, et al. Nutrigenetic Interactions Might Modulate the Antioxidant and Anti-Inflammatory Status in Mastiha-Supplemented Patients With NAFLD. Front Immunol. 2021;12:683028.

[10] Fukazawa T, et al. Effects of Chios mastic gum and exercise on physical characteristics, blood lipid markers, insulin resistance, and hepatic function in healthy Japanese men. Food Sci Biotechnol. 2018 Jan 12;27(3):773-80.

[11] Kartalis A, et al. Effects of Chios mastic gum on cholesterol and glucose levels of healthy volunteers: a prospective, randomized, placebo-controlled, pilot study (CHIOS-MASTIHA). Eur J Prev Cardiol. 2016 May;23(7):722-9.

[12] Triantafyllou A, et al. Chios mastic gum modulates serum biochemical parameters in a human population. J Ethnopharmacol. 2007 Apr 20;111(1):43-9.

[13] Delli Bovi AP, et al. Oxidative Stress in Non-alcoholic Fatty Liver Disease. An Updated Mini Review. Front Med (Lausanne). 2021;8:595371.

[14] Bigarella CL, et al. Stem cells and the impact of ROS signaling. Development. 2014;141:4206-18.

[15] Kaliora AC, Dedoussis GV. Natural antioxidant compounds in risk factors for CVD. Pharmacol Res. 2007;56(2):99-109.

[16] Dedoussis GV, et al. Antiatherogenic effect of Pistacia lentiscus via GSH restoration and downregulation of CD36 mRNA expression. Atherosclerosis. 2004;174:293-303.

[17] Papada E, et al. Antioxidative efficacy of a Pistacia lentiscus supplement and its effect on the plasma amino acid profile in Inflammatory Bowel Disease: A randomised, double-blind, placebo-controlled trial. Nutrients. 2018;10:1779.

[18] Kannt A, et al. Mastiha (Pistacia lentiscus) Improves Gut Microbiota Diversity, Hepatic Steatosis, and Disease Activity in a Biopsy-Confirmed Mouse Model of Advanced Non-Alcoholic Steatohepatitis and Fibrosis. Mol Nutr Food Res. 2019;63(24):e1900927.

[19] Buzzetti E, et al. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65(8):1038-48.

[20] Musso G, et al. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology. 2010;52(1):79.

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