The liver is a complex organ that performs a wide range of essential functions to maintain normal health, including digestion, immune function and detoxification. There are more than 100 types of liver disease, ranging from common disorders, such as non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ARLD), to less common inherited disorders, such as haemochromatosis and primary biliary cholangitis. The liver has a high functional reserve, and, usually, liver disorders do not cause any obvious symptoms until the liver has suffered a substantial amount of tissue damage; typical symptoms include loss of appetite, weight loss and jaundice (Fan, 2010). The liver has a high capacity to regenerate damaged tissue, but it can eventually be compromised by permanent scarring (cirrhosis), which represents a common final stage of the different types of liver disease (Fan, 2010). Typically, cirrhosis is preceded by the deposition of fat within liver tissue, which can occur in individuals whether or not they consume alcohol. At present, there is little effective treatment for NAFLD. This article focuses on the role of coenzyme Q10 (CoQ10) deficiency and supplementation in NAFLD.
Non-alcoholic fatty liver disease
NAFLD is defined as the accumulation of fat, principally as triglyceride, in hepatic cells, exceeding 5–10% of liver weight (Chalasani et al, 2012). NAFLD is the most common liver disorder worldwide; its prevalence in the general population is estimated at 20–30%, but this rises to 60–70% in individuals with obesity and 70–90% in those with diabetes (Browning et al, 2004). NAFLD occurs in every age group, but especially in people in their 40s and 50s. The condition is closely linked to metabolic syndrome, which is a cluster of abnormalities, including increased abdominal fat, poor ability to use the hormone insulin, high blood pressure and high blood levels of triglycerides. NAFLD develops in four main stages:
- Simple steatosis characterised by initial fat deposition
- Non-alcoholic steatohepatitis (NASH) associated with liver inflammation
- Fibrotic scar tissue formation
- Cirrhotic liver scarring/liver failure (Benedict and Zhang, 2017).
Typically, 10–20% of cases progress to NASH, with 10–20% of these developing fibrosis and, ultimately, cirrhosis (Pappachan et al, 2017). Liver biopsy remains the gold standard for diagnosis of NAFLD.
Coenzyme Q10 and liver function
CoQ10 is a vitamin-like substance with a number of important cellular functions of relevance to liver metabolism and liver disorders. First, CoQ10 plays a key role in the biochemical process supplying all cells with the energy they require for normal functioning; specifically, CoQ10 is an intermediate in the electron-transport system, which generates energy in the chemical form of adenosine triphosphate (ATP), shuttling electrons from complexes I and II to complex III of the mitochondrial respiratory chain (Hargreaves, 2003). An adequate supply of CoQ10 is of particular importance in tissues with a high energy requirement, such as those of the liver and heart. Although CoQ10 is synthesised throughout the body, because of its size and high metabolic capacity, the liver is the main site of CoQ10 synthesis. In patients with liver disease where metabolic capacity has been compromised, reduction in CoQ10 production is, in addition to its direct effect on liver function, also likely to have a deleterious effect on heart function.
Second, CoQ10 is a major liposoluble antioxidant, protecting cell membranes, particularly those within mitochondria, from free radical-induced oxidative damage (Hargreaves, 2003). Such oxidative stress has been implicated in the pathogenesis of a number of liver disorders, particularly NAFLD. CoQ10 is the only endogenously-synthesised liposoluble antioxidant.
Third, CoQ10 has been shown to directly modulate the expression of a number of genes, including those involved in inflammation and cholesterol synthesis. Thus, CoQ10 modulates the expression of the protein complex nuclear factor kappa beta (NFkß), the so-called ‘master switch’ of inflammation (Pala et al, 2016). Similarly, clinical randomised controlled trials (RCTs) have shown that supplemental CoQ10, alone or in combination with other supplements, can significantly reduce total blood or low-density lipoprotein (LDL) cholesterol levels. Studies by Schmelzer et al (2011) (CoQ10 150 mg/day for 2 weeks) and Mohseni et al (2014) (CoQ10 200 mg/day for 12 weeks) reported significant reductions of approximately 15% in LDL cholesterol levels following CoQ10 supplementation. Additionally, Mazza et al (2018) showed that treatment with a combination of CoQ10 (30 mg/day for 8 weeks) and red yeast rice reduced total and LDL cholesterol levels by approximately 20%.
The three functions of CoQ10 outlined above are of particular relevance to NAFLD; increased oxidative stress and inflammation have both been implicated in the pathogenesis of NAFLD (Spahis et al, 2016), while heart failure has been reported as one of the major causes of death in those with NAFLD (Francque et al, 2016). NAFLD is associated with heart failure, arrhythmias, valve dysfunction and atherosclerosis (Sirbu et al, 2016). ARLD is similarly associated with increased risk of cardiovascular disorders; these include alcoholic cardiomyopathy, arterial hypertension and atrial fibrillation (Milic et al, 2016).
Coenzyme Q10 deficiency
The body's daily requirement for CoQ10 has not been accurately quantified, but it has been estimated as 500 mg/day; this is based on a total CoQ10 body pool of 2 gm and average tissue turnover time of 4 days. Most of this daily requirement must be manufactured within the body, since a relatively small proportion, estimated at 5 mg/day (Weber et al, 1997), is derived from the normal diet. As people age, the capacity of the body to synthesise its own CoQ10 decreases; optimal production occurs around the mid-twenties, with a continual decline in tissue levels thereafter (Kalén et al, 1989). In addition to the normal ageing process, CoQ10 levels have also been shown to be depleted in a variety of disorders, as well as with the use of statin-type drugs. Reduced CoQ10 levels may be a particular problem in patients with statins prescribed for fatty liver disease, since, in addition to inhibiting cholesterol synthesis, statins also inhibit the production of CoQ10. Therefore, dietary supplementation with CoQ10 provides a mechanism to maintain adequate levels within the body and a rationale for the dosages of CoQ10 used in clinical trials, which are typically 200-400 mg/day.
Preclinical studies on coenzyme Q10 supplementation
A number of studies in animal models have demonstrated the ability of CoQ10 to reduce or prevent the development of liver cirrhosis following exposure to a variety of toxic insults, including medicinal drugs (Fouad and Jresat, 2012), toxic chemicals (Choi et al, 2009) and parasitic microorganisms (Othman et al, 2008). For example, Fouad and Jresat (2012) demonstrated the ability of CoQ10 to protect liver tissue against free radical-induced oxidative damage; when acute liver injury was induced in rats via administration of acetaminophen (more commonly known as paracetamol), subsequent administration of CoQ10 reduced cirrhotic tissue damage via its antioxidant and anti-inflammatory action. In rats prone to developing NAFLD, dietary supplementation with CoQ10 prevented further progression to cirrhosis, via down-regulation of markers of free radical-induced oxidative stress and inflammation (Tarry-Adkins et al, 2016). Similarly, in rats fed a high-fat diet, supplementation with CoQ10 reduced lipid synthesis and increased fatty acid oxidation, resulting in reductions in bodyweight gain; serum triglyceride levels; and total and LDL cholesterol levels (Chen et al, 2019).
Clinical studies on coenzyme Q10 supplementation in fatty liver
With regard to clinical studies, Yesilova et al (2005) found that blood CoQ10 levels were depleted in patients with NAFLD, with the decrease in CoQ10 correlating with increased liver inflammation and cirrhosis. Farhangi et al (2014) reported the first RCT supplementing CoQ10 in patients with NAFLD. The study comprised 41 patients with NAFLD (31 men and 10 women) aged 20–65 years, diagnosed via ultrasonography. Patients supplemented with CoQ10 100 mg/day for 4 weeks showed significant reductions (p<0.05) in the levels of biochemical markers of inflammation and oxidative stress (serum aspartate aminotransferase and total antioxidant capacity), as well as waist circumference. The most recent RCT (Farsi et al, 2016) comprised 41 patients with NAFLD (28 men and 13 women) aged 19–54 years with BMI in the range of 25–35 kg/m2. NAFLD status was established by absence of alcohol consumption, elevated liver enzyme levels and ultrasonography. The grade of hepatic steatosis, defined as the percentage of hepatocytes containing fat droplets, was categorised via a four-point grading system of normal, mild, moderate and severe. Individuals given CoQ10 100 mg/day for 3 months showed significant reductions (P<0.05) compared with those receiving a placebo in the levels of blood markers for liver inflammation and damage—aspartate aminotransferase (P=0.012), gamma-glutamyl peptidase (P=0.039), high-sensitivity C-reactive protein (P=0.02) and tumour necrosis factor (TNF)-alpha (P=0.049)—as well as a lower percentage of liver cells with fat droplet inclusions (reduction in NAFLD grade, P=0.046). CoQ10 was well-tolerated, with no significant adverse effects reported.
Other clinical studies on coenzyme Q10 of relevance to fatty liver
As noted above, the risk of developing cardiovascular disease is substantially increased in patients with NAFLD, with heart failure being a major cause of death. To date, there have been no RCTs to investigate the effect of CoQ10 supplementation specifically on heart failure in NAFLD. However, two clinical RCTs are relevant to this issue, namely Q-SYMBIO and KISEL-10.
The Q-SYMBIO study was carried out in 420 patients with chronic heart failure of New York Heart Association (NYHA) class III and V. Patients were prescribed supplementation with CoQ10 300 mg/day (in three daily 100 mg doses) for 2 years as an adjuvant to conventional medication of angiotensin converting enzyme (ACE) inhibitors and beta blockers. The effect of this intervention on symptoms and biomarker status (hence the trial acronym Q-SYMBIO) were assessed. Assessment included clinical examination, echocardiography and pro-brain natriuretic peptide (pro-BNP) status. The primary long-term endpoint was time to first major adverse cardiovascular event (MACE), which included unplanned hospitalisation due to worsening heart failure and cardiovascular death. Supplementation with CoQ10 significantly reduced the relative risk of MACE by 42%, with a reduction in both cardiac-related deaths (43%) and all-cause mortality (42%). The authors concluded that these beneficial effects of CoQ10 resulted from improved cellular energy provision within heart tissue (Mortensen et al, 2014).
The KISEL-10 study was carried out on normal older individuals (70–88 years old) from the Kinda region of Stockholm (Alehagen et al, 2013); 440 participants received supplementation with CoQ10 200 mg/day (Bio-Quinone 100 mg) and 200 μg/day selenium (SelenoPrecise) or placebo, over a 5-year period (hence the trial acronym KISEL-10). Clinical examination, echocardiography and biomarker measurements were carried out at 6-month intervals. Quality of life was quantified using the Short Form-36 (SF-36), Cardiac Health Profile (CHP) and Overall Quality of Life (Overall-QoL) questionnaires. Supplementation with CoQ10 and selenium resulted in a significant reduction in the number of days in hospital, and it significantly slowed the deterioration in health-related quality of life. Echocardiography showed significantly better cardiac function in supplemented participants, whose risk of cardiovascular mortality was significantly reduced by 53%. Further analysis of data from the original study has subsequently been reported (Alehagen et al, 2018); there were significant reductions in the blood levels of C-reactive protein and sP-selectin as markers of inflammation, as well as copeptin and adrenomedullin as markers of oxidative stress, in addition to levels of pro-BNP. The authors of the KISEL-10 study concluded that the reduction in cardiovascular mortality risk in older people was, in part, the result of a reduction in the fibrosis of cardiac tissue (Alehagen et al, 2018).
The Q-SYMBIO and KISEL-10 studies, thus, provide a rationale that supplementation with CoQ10 may reduce the risk of heart failure in patients with NAFLD, or prevent cardiovascular disease developing in these patients where this is not already present. Additionally, these studies provide further evidence for the systemic antioxidant, anti-inflammatory and anti-fibrotic activity of CoQ10, which is of relevance to NAFLD.
Safety of coenzyme Q10
The safety of CoQ10 has been assessed by Hidaka et al (2008) and Hosoe et al (2007). CoQ10 is generally well-tolerated, with no serious adverse effects reported in long-term use. Very rarely, individuals may experience mild gastrointestinal disturbance. There are no known toxic effects, and CoQ10 cannot be overdosed. CoQ10 is well-tolerated in healthy adults at an intake of 900 mg/day and in rats at a dose of up to 1200 mg/kg/day. Furthermore, Yamaguchi et al (2009) reported that CoQ10 had no genotoxic activity. However, CoQ10 is not recommended for pregnant or lactating women, in whom its effects have not been extensively studied. The safety of CoQ10 has been confirmed in more than 200 RCTs, for a wide range of disorders.
Bioavailability of coenzyme Q10
Bioavailability is defined as the proportion of an ingested substance that reaches the blood circulation. Due to its relatively large molecular size and lipid solubility, the bioavailability of CoQ10 is intrinsically low. CoQ10 is absorbed from the intestinal tract via the same mechanism as other lipid-soluble nutrients, via a lipid carrier through mucosal cells initially into the lymph, and thence into the bloodstream. Thus, absorption is optimised when CoQ10 is dissolved in a carrier oil, preferably soya or palm oil. The delayed peak concentration of CoQ10 in blood is a consequence of this initial absorption into the lymphatic system. However, incorporation of supplemental CoQ10 in liposomal, micellular or nanoparticle form cannot increase its absorption through intestinal cells into the lymph. CoQ10 cannot be made more water soluble, as any alteration to the molecular structure means that the molecule is no longer CoQ10. When supplemental CoQ10 is first produced, via a yeast fermentation process, it is obtained in the form of crystals, which cannot be absorbed from the digestive tract. It is essential that these crystals are dispersed into single CoQ10 molecules and remain dispersed during the product's shelf-life, to enable optimum bioavailability. Adding CoQ10 crystals to a carrier oil without such dispersal, a cost-saving technique used by some manufacturers, is inadequate. Disparity in the findings of clinical trials supplementing CoQ10 in diabetes undoubtedly results from the use of supplements with inadequate bioavailability and/or insufficient dosage or treatment duration. These issues have been addressed in the recent clinical study of CoQ10 bioavailability by López-Lluch et al (2019). The bioavailability of seven different supplement formulations containing 100 mg of CoQ10 was evaluated in 14 young healthy individuals. Bioavailability was measured as area under the curve of plasma CoQ10 levels over 48 hours after ingestion of a single dose. Measurements were repeated in the same group of 14 volunteers in a double-blind crossover design with a minimum 4-week washout between intakes. Bioavailability of the formulations showed large differences that were statistically significant. The best absorbable formulation was a soft-gel capsule containing ubiquinone (Bio-Quinone Q10). The matrix used to dissolve CoQ10 and the proportion and addition of preservatives such as vitamin C affected the bioavailability of CoQ10.
Conclusion
There is considerable evidence from pre-clinical studies in a number of animal model systems for the capacity of supplemental CoQ10 to reduce or prevent liver tissue damage by a variety of toxic agents, and these data provide a plausible rationale for the supplementation of CoQ10 in patients with liver disease. Although only two clinical RCTs supplementing CoQ10 in NAFLD, together comprising some 82 patients, have been carried out to date, the results of significantly reduced biomarkers of liver tissue injury have been sufficiently encouraging to consider such a novel therapeutic approach in the future management of patients with NAFLD.
CPD reflective questions
- Reflect on the role of coenzyme Q10 (CoQ10) in normal liver function
- Consider how the information in this article could best be used to benefit patients with non-alcoholic fatty liver disease (NAFLD)
- How could the information in this article be used to inform fellow healthcare professionals, who may be unfamiliar with the background to NAFLD or CoQ10?
- Are there other liver disorders that could potentially benefit from supplementation with CoQ10?