**1. Introduction**

Anaemia develops when the body's circulating erythrocytes or red blood cells (RBCs) fall below normal. According to the guidelines of the World Health Organization (WHO), anaemia is diagnosed with haemoglobin (Hb) concentration lower than the current cut-off level, defined as Hb <130 g/L for adult males, <120 g/L for non-pregnant women, and <110 g/L for children (6–59 months) [1]. The reduction in RBCs may lead to insufficient oxygen-carrying capacity of the blood to meet physiological needs, resulting in symptoms such as fatigue, weakness, shortness of breath, chest pain, reduced physical tolerance and restless leg syndrome [2]. In adults, anaemia may lead to increased morbidity and decreased work productivity and poor birth outcomes during pregnancy. In children, anaemia can cause impaired cognitive and behavioural development, and even increase mortality [1].

In 2019, the worldwide prevalence of anaemia for all ages was 22.8% (95% confidence interval (CI): 22.6–23.1) [3]. The global burden of disease measured in years living in disability for anaemia is 672.4 (95% CI: 447.2–981.5) per 100,000 population [4]. Women and children in low-income countries are the most vulnerable groups. This condition affected 29.9% (95% CI: 27.0–32.8) of women of reproductive age, of which 36.5% (95% CI: 34–39.1) of pregnant women suffered from anaemia compared to 29.6% (95% CI: 26.6–32.5) of non-pregnant women [5]. About 269 million children under five also had anaemia,

**Citation:** Ooi, S.L.; Pak, S.C.; Campbell, R.; Manoharan, A. Polyphenol-Rich Ginger (*Zingiber officinale*) for Iron Deficiency Anaemia and Other Clinical Entities Associated with Altered Iron Metabolism. *Molecules* **2022**, *27*, 6417. https://doi.org/10.3390/ molecules27196417

Academic Editor: Nour Eddine Es-Safi

Received: 31 July 2022 Accepted: 15 September 2022 Published: 28 September 2022

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with a global prevalence of 39.8% (95% CI: 36.0–43.8). The highest was in the African region, affecting 60.2% (95% CI: 56.6–63.7) of children [5].

Even in a wealthy society like Australia, anaemia remains a health risk. According to the Australian Health Survey last conducted in 2011–2012, 4.5% of the population aged 18 years and over had anaemia, with women having a relative risk of 2.56 times more than men [6]. The burden of anaemia is even higher among the Australian indigenous population, with a female-specific prevalence of 15.3% [7], signifying health inequality due to socioeconomic consequences.

Anaemia is not a disease per se but a manifestation of other underlying causes. Iron deficiency, which results from increased iron demands, deminished iron supply, blood loss or malabsorption of iron, is the most common cause of anaemia worldwide, accounting for nearly two-thirds of global anaemia cases [4,8]. Hence, iron deficiency anaemia (IDA) is a global health concern affecting millions worldwide, especially women and children in less developed regions. IDA is routinely treated with oral iron supplements such as ferrous sulphate but compliance issues due to gastrointestinal side effects often hamper its effectiveness [9,10].

In the broader context, ginger plants refer to all perennial flowering plants in the Zingiberaceae family, which include many aromatic herbs and spices such as turmeric, cardamom, and galangal. Currently, there are 1888 unique species in the Zingiberaceae family classified into 62 genera, of which 204 species belong to the *Zingiber* genera [11]. The ginger root commonly consumed worldwide is the rhizome of *Zingiber officinale* species. Accordingly, in this review, ginger only refers to the *Z. officinale* species.

*Z. officinale* has a long history of culinary and medicinal use, possibly even before formally recorded history. Wu [12] suggested that ginger cultivation originated around the Yangtze River and Yellow River basins in ancient China. However, this claim has yet to be widely accepted. The spice trade spread ginger to major civilisations from East Asia and India to the Greek, the Roman Empire, and beyond. Today, ginger is primarily used as a food, spice, herb, and flavouring agent, with a global trade volume of USD 1.06 billion in 2019, with China being the top exporter supplying over 57.8% of the world demand [13]. Three varieties of ginger are consumed as food and herbs: white (var. Roscoe), small white (var. Amarum) and red (var. Rubra), with *Z. officinale* Roscoe being the most common variety [14].

Ginger possesses several health-promoting properties and has been traditionally used in East Asia to ease fatigue and weaknesses. Contemporarily, ginger is considered a functional food that can confer health benefits beyond its nutritional values for preventing, managing, or treating disease [15–18]. As a rich source of natural polyphenols, ginger may potentially complement oral iron therapy in treating IDA and be a supportive dietary strategy for preventing IDA. Hence, there has been heightened commercial interest in using ginger, especially in China, as an ingredient for functional foods or ethnomedicine for IDA, as evidenced by the growing number of patents filled with the World Intellectual Property Organization in recent years (see Table A1 in Appendix A). However, there is a lack of research literature critically reviewing such potentials.

The objective of this narrative review is to inform translational research on the benefits of ginger and its bioactive polyphenols in the context of IDA and other clinical entities associated with altered iron metabolism based on available research. The ensuing sections first examine ginger's application as a functional food, followed by the pathophysiology of IDA and its treatment. These overviews provide context to support the subsequent review of the various beneficial properties of ginger and its polyphenols applicable to IDA based on pre-clinical and clinical evidence. To the authors' knowledge, this is the first attempt to comprehensively investigate the scope and depth of current literature on this underexplored topic.

#### **2. Ginger as a Functional Food**

#### *2.1. Nutritional Composition and Traditional Use*

Nutritional analysis has shown that ginger consists mainly of moisture, carbohydrate, protein, fibre, fat, and ash. It is rich in polyphenols and contains micronutrients including ascorbic acid, *β*-carotene, calcium, iron, and copper. However, it is worth noting that the nutritional composition of ginger can vary greatly depending on the varieties, origin, time of harvest, drying method, and storage condition. Table 1 shows the approximate nutritional composition of dried ginger powder reported in the literature [19,20]. Ginger is, however, valued beyond its nutritional benefits. It is believed that the Indian and Chinese populations have used ginger as a tonic for over 5000 years [21]. In Shen Nong Ben Cao Jing, the oldest surviving Chinese materia medica circa 100BC, ginger was classified as a middle category of herb with little or no toxicity and was mainly used in combination prescription to treat deficiency to prevent illness or resist worsening disease [22]. Incidentally, ginger is also used in traditional Ayurvedic medicine to treat many diseases such as diabetes, flatulence, intestinal colic, indigestion, infertility, inflammation, insomnia, nausea, rheumatism, stomach ache, and urinary tract infections [23].

**Table 1.** Nutritional composition of dried ginger powder as reported by Ajayi et al. [19] and Sangwan et al. [20].

