Copper content in Areca nut as an emerging etiology for liver disease – A Comprehensive Review


Suwarna Dangore Khasbage1, Rahul R. Bhowate2

1Professor, Oral Medicine and Radiology, Sharad Pawar Dental College,

Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha.

2Professor, Oral Medicine and Radiology, Sharad Pawar Dental College,

Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha.

*Corresponding Author E-mail:,



Areca nut (AN) is the fourth most widely used addictive substance and chewed regularly by at least 10% of the world population. AN cause many harmful effects on the human body in general as well as in the oral cavity. Amongst this one of the vital organs being damaged due to AN consumption is liver for which a number of mechanisms are reported to be responsible. Frequently alkaloids in AN are considered as the main culprit. But, other components like copper (Cu) content in AN is also believed to play a role in the pathogenesis of liver fibrosis. It is stated that an adult Indian chewing AN daily consumes over 5 mg of Cu per day, of which the substantial amount is absorbed. However, the recommended intake per day is 0.9 mg. Excess Cu acts by upregulating lysyl oxidase activity, which enhances collagen synthesis and inhibits collagen degradation leading to fibrosis of tissues. Another reason for liver toxicity could be reactive oxygen species generated by Cu content in AN. Thus, it may be stated that Cu in AN can be one of the risk factors inducing liver damage. The present review highlights the role of Cu content of AN in the development of liver fibrosis.


KEYWORDS: Areca nut, betel quid, copper, liver, toxicity.




The term ‘Liver disease’ describes the conditions that affect the morphology as well as the function of the liver. Basically, liver disease is classified according to its severity, as acute and chronic. Acute liver disease is usually a self-limiting episode of hepatocyte damage. Chronic liver disease occurs when permanent structural changes within the liver are present secondary to long standing cell damage, with the consequent loss of normal liver architecture.1


The etiology of liver disease is multi-factorial. The growing epidemiological evidence indicates that a number of risk factors like excessive alcohol drinking, hepatitis B and C infection, obesity, family history, intake of high doses of antibiotics modulate the risk of developing chronic liver diseases resulting in alcoholic as well as non-alcoholic fatty liver disease.2,3,4,5


Amongst the addictive substances, though alcohol is one of the common and well-known causative factors, areca nut (AN) consumption is also reported to be one of the risk factors for chronic liver disease in Indian population.6


Areca nut (AN) is a fruit of areca catechu palm tree, which is native of South Asia and Pacific Islands. It is chewed regularly by at least 10% of the world population of all the groups, and is the fourth most widely used psychoactive substance.7,8 It is possibly the second most consumed carcinogen after tobacco in the Indian subcontinent. It is either used alone or added with different tobacco or non-tobacco substances to make different combinations.9,10 Its method of consumption varies from region to region. Thus, its contents and harmful effect also vary to some extent. In Taiwan and parts of southern China, the green unripe AN is often chewed with betel inflorescence. In India, AN is consumed mostly with tobacco or in the form of commercially prepared products such as ‘Gutkha’ (with tobacco), ‘Pan masala’ (without tobacco).10,11,12


Irrespective of the form or method of consumption, it is well accepted that AN use is unsafe to human health due to presence of chemicals in it. As per the evaluation in 1985 by the International Agency for Research on Cancer (IARC) chewing BQ with tobacco was stated to be carcinogenic to humans. However, the new evaluation (2004) concluded that chewing AN alone is also carcinogenic to humans.10,13-15 The etiological role of AN in oral submucous fibrosis is extensively reported in the literature.16,17


AN consumption is also very common in India and reported to be consumed by 20 to 30% of the population in last 2-3 decades. India is the largest producer of AN producing nearly half of global AN production. India ranks first in both area (58%) and production (53%) of areca nut. It is estimated that nearly ten million people depend on AN industry for their livelihood in India.18


AN consumption and risk of liver disease:

AN contains water 30%, protein 5%, fat 3%, carbohydrate 47%, and total alkaloids with arecoline been the major alkaloid constitute 0.2% – 0.7%.19 Amongst these, alkaloids, flavonoids, tannins are the proven carcinogenic contents of AN. Arecoline is the main agent responsible for fibroblast proliferation. Under the influence of slaked lime, arecoline gets hydrolyzed to arecadine, which has pronounced effects on fibroblasts.10,20 Areca flavonoids, tannins, and catechins can cause increased fibrosis by forming a more stable and non soluble collagen structure by inhibiting collagenase enzyme activity.21,22 But, Areca catechu leaves extract has beneficial effects like scavenging the free radicals.23


In Taiwan, one of the ingredients of their betel quid preparation, ‘safrole’ is said to be responsible for liver damage as safrole is classified as a rodent hepatocarcinogen.24 In addition to this, AN is mutagenic, genotoxic, tumerogenic. It modulates function of hepatic detoxication.


Previous studies showed that aqueous extract of AN caused loss of cytoarchitectural integrity of cells in the liver lobules of experimental rats. At low dose AN causes activation of the local immune system (kupffer cell activation), manifested as mild chronic inflammation while at high dose there is inactivation of the immune system leading to suppression of T-cell activity and decreased release of cytokines.19,25


One of the reasons for liver damage in AN habitual is ingestion of Aflatoxin B1 infected AN, as Aflatoxin B1 is a known hepatotoxin.26 Infestation of AN by Aspergillus flavus is reported in literature similar to that of the infestation and presence of aflatoxin at levels exceeding the normal limit is reported in pea nuts.27 Apart from all these factors, AN also contains a significant amount of Cu that also take part in the pathogenesis of fibrotic conditions. Accordingly, a number of studies reported effect of Cu content of AN in oral submucous fibrosis.28 Similarly, the liver is also susceptible to the AN induced damage and consequently its cu content.8,29 However, to our knowledge, scanty literature is available reporting the role of Cu in AN on risk of liver fibrosis.


Ingress of Cu in AN:

Inclusion of cu in AN is due to multiple reasons. 1. External Cu from sprayed Bordeaux mixture (BM) penetrate the cuticle and enters the nut. 2. Cu through the soil reaches the root and further the nuts and attributes to the increased Cu content in it and 3. Increased cu in commercial products during processing.


Figure 1- Showing process of ingress of Cu in riped AN


Bordeaux mixture is a fungicide which is prepared by adding milk of lime to a solution of Cu sulfate until alkaline reaction is obtained.30 Because of this the areca palms are able to withstand the heavy rainfall. The spray gives a coating on the tender nut and prevents it from rotting and falling off. (Figure 1) Post monsoon, the riped nuts are picked though, Bordeaux mixture is absorbed in nuts and leaves.31 This Cu incorporated in the nut and leaves is again absorbed by the plant as the leaves and nut shed off and gets decomposed and absorbed within the soil.31,32 Nonetheless Cu has low solubility, which enables it to persist in the soil for years. Thus, the Cu from the soil is mostly transported via the plant root and thereby again is incorporated in the nut.23 Accordingly Badilla‑Ohlbaum R et al reported significantly higher Cu contents of stems and leaves for plants growing in the high‑Cu soils.33



Alexander AJ et al32 have suggested that the farmers can be made aware about the health effects of Bordeaux mixture and Cu‑free fungicidal alternatives can be utilized. On contrary to this, Kumar et al34 revealed that the Cu content in the areca nuts treated with fungicide (1.77ppm) was not very high compared to those not treated with fungicide (1.36ppm) in their study, the difference being a meagre 0.41ppm.34


Studies have also shown that summer AN has lower concentrations of Cu content as compared to spring AN as Bordeaux mixture is not sprayed in regions of dry terrain as the crop is not likely to get diseased and damaged by the heavy rain fall.31,35


The Cu content of various constituents of quid are variable with highest amount of Cu in betel leaf. [36] The processed form of betel nut ie the freeze-dried products pan masala, gutkha, mawa) contain higher concentration of Cu as compared to raw form, because Cu is added to it as a preservative. Previous studies stated that the Cu levels in commercial products are significantly higher than that of raw areca nuts.28,32,37-40


Mathews P et al stated that the Cu content increased significantly with maturity for a given weight while the moisture content was getting reduced as the nut matures. Understandably, the nut becomes more concentrated with its mineral and chemical constituents.37 Authors have correlated this to the increased prevalence of OSMF after the launch of commercial AN product in younger patients with relatively shorter duration of chewing habit.37


Cu content in AN and risk of liver disease:

Cu is an essential trace metal necessary for the functioning of several key enzymes involved in human metabolism.41,42 But, its effect in the body is like a two-edged sword.


At one end it is essential for maintaining most of the body functions and at the other end it becomes potentially toxic if consumed in excess.


The recommended intake of Cu per day is 0.9mg.43 However, it is stated that an adult Indian chewing AN daily consumes over 5 mg of Cu per day, of which the substantial amount is absorbed.44 This excess Cu is harmful; implicated in the pathogenesis of several fibrotic conditions including liver fibrosis. The role of Cu in the pathogenesis of OSMF is considered due to discovery of high Cu content in areca nut.29 Similar mechanism has been implicated in hepatic fibrosis.


Previous studies proposed a mechanism for epithelial atrophy in oral submucous fibrosis mediated by arecoline and Cu. Cu (II) in combination with arecoline, forms arecoline Cu complex. Arecoline gets oxidized along with the reduction of Cu (II) to Cu (I). The reduced Cu (I) in turn donates an electron to O2 resulting in formation of superoxide radical. The superoxide radical leads to cytotoxicity of epithelial cell resulting in epithelial atrophy.31,45


Cu is an integral part of Cu/Zn-superoxide dismutase, an enzyme which also serves as an important antioxidant defense mechanism in the body. Yet, when Cu is present in high concentrations, it generates reactive oxygen species that induce oxidative damage to the cell.46-48 The high Cu content can generate reactive oxygen species by Fenton and Haber–Weiss reaction.41,49-51 The propensity of copper for catalyzing production of reactive oxygen and nitrogen species represents a major molecular mechanism triggering hepatocellular-damaging effects, which become significant when the capacity of the liver to maintain these metals in storage forms is exceeded. It is well known fact that the free radicals play a considerable role in the development of hepatic fibrosis by acting in different cell types and in different signaling pathways.52



The liver plays a central role in the maintenance of body copper homeostasis but an AN habitual consumes excess Cu than the recommended intake per day which may act as a unfavorable factor enhancing the risk of liver disease.



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Received on 30.04.2021            Modified on 28.11.2021

Accepted on 19.04.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(10):4847-4850.

DOI: 10.52711/0974-360X.2022.00814