9  
CHAPTER 2 
LITERATURE REVIEW 
 
 
2.1 Date Palm (Phoenix dactylifera L.) 
 
Date palms are a type of flowering plant in the Arecaceae (Palmae) family 
that produce dates, which are a type of sweet fruit that can be consumed. Dates are 
known botanically as Phoenix dactylifera L (Idowu et al., 2020).There are many 
references related to date palms in the Islamic holy book, the Qur’an and prophetic 
Sunnah. Date palm is mentioned as the ultimate superfood for the preservation of 
good health. This is clearly stated in the verses of Surah An-Nahl: “And from the 
fruits of the palm trees and grapevines, you take intoxicant and good provision. 
Indeed, in that is a sign for a people who reason.” (Al-Quran 16:66). Besides, a 
hadith narrated by Aisha reported that the prophet SAW as saying: “The ‘Ajwa’ 
dates of ‘Al-Aliya’ contain healing effects and are a remedy when taken first thing 
in the early morning.” (Sahih Muslim, 23/5083). 
There are four botanical stages of maturity after the cultivation of dates 
which are known by their Arabic names throughout the world as Kimri (unripe), 
Khalaal (full-size, crunchy), Rutab (ripe, soft), and Tamr (ripe, sun-dried) 
(Chandrasekaran & Bahkali, 2013). At the Kimri stage, the dates fruits remain 
green, hard, and have a bitter taste. The fruits rapidly grow in size, weight, and 
sugar content; this is also the time when acid activity is at its peak, and moisture 
content can reach up to 85%. The next six weeks comprise the Khalaal stage which 
the fruits remain hard and unripe, but their color changes to yellow, orange or red. 
10  
At the Khalaal stage, the fruits slowly gain weight. However, the sucrose content 
increases, moisture content goes down, and tannins will start to precipitate with the 
drawback of astringency. 
The tips of the fruit start to turn brownish at the Rutab stage. This third 
phase is characterized by a decrease in weight due to moisture loss, and a partial 
reversion of sucrose content to reducing sugar. The color and taste of the dates are 
indicated as half-ripe with browning of the skin and softening of the tissues. The 
moisture content goes down to about 35% and the dates at this stage are harvested 
and sold as fresh fruit. At the final stage, the dates turn into Tamr only when they 
are left to continue to ripen on the palm trees for another two to three weeks until 
the color turns from brown to black-brown, altogether with climatic conditions 
permitting. The Tamr stage is characterized by a moisture content at which the dates 
are self-preserving, with the upper limit at around 24-25%, which is a lower 
moisture content than Rutab (Biglari et al., 2008). 
Cultivation of date palms in Malaysia has not yet been widely explored and 
is only available in small-scale farms which privately owned by the locals. Being 
an agricultural country, planting date palms can provide diversification and 
commercialization of fruit tree plantations (Mohd et al., 2007). According to 
Kamarubahrin et al. (2018), date palm is still an extremely rare plant in Malaysia, 
added with limited research has been conducted on date palm due to the inadequacy 
of expertise either in date palm research and practice. A study suggests that 
technical feasibility should be conducted at the micro level to determine the most 
suitable location for date palm growth in Malaysia. By cultivating local date palm 
11  
plantations in Malaysia, the dependency on date fruit importation can be reduced 
and their prices can be lowered (Kamarubahrin & Haris, 2020). 
Date palm is a tree that commonly grows to a height between 10m to 15m 
and lives up to an age of over 100 years (Jahromi et al., 2007). The date palm is 
one of the three economically important crops of the palm family. Ashraf and 
Hamidi-Esfahani (2011) reported that the date fruit is mostly cultivated in semi- 
arid regions of the world. In addition, the production and cultivation of date palms 
have long been the most important agricultural activity in arid regions of the 
Arabian Peninsula, North Africa, and the Middle East, as one of the oldest fruit 
crops grown. The ability of these crops to survive the arid condition makes them 
the most suitable crops to be used in improving public health. In fact, the date palm 
has been successfully introduced outside of its origins such as in Australia, Asia, 
Mexico, United States, India and Pakistan, to be new production areas for date palm 
cultivation (Chao & Krueger 2007). It is believed that date palm is one of the oldest 
fruit crops and the first trees to be cultivated for at least 5000 years (Zohary & Hopf, 
2000). 
There are many types of dates found worldwide, commonly known are, 
Ajwa, Khalas, Ruthana, Segae, Sukkary, Sefri, Hilali, Khodry and Munifi 
(Rahmani et al., 2014). Since more people look for alternative treatments that are 
efficient and secure for curative purposes, dates have been documented as part of 
the human diet and considered natural remedies. It is known in Arabic as al-nakhl, 
which etymologically means “good, nourishing and nice smelling” (Zainan Nazri 
et al., 2016). Dates are cheap to produce and preserve and are also very rich in 
nutrition. Date fruits have wide scope and potential for consumption as a staple 
12  
food and can be the main income source because of their nutritional and economic 
value (Khan & Khan, 2016). 
The current scientific findings explore the various potential beneficial 
properties of the date palm to human health. Dates contain a high percentage of 
carbohydrates, 15 salts and minerals, a protein with 23 different amino acids, fat 
comprising 14 types of fatty acids, six vitamins and a high percentage of dietary 
fibre (Al Shahib & Marshall, 2003). Meanwhile, Hong et al. (2006) found that date 
fruits contain 6.5-11.5% total dietary fibers, about 2% proteins, 2% ash, 1% fat, and 
a rich source of phenolic antioxidants. Date fruits have a large potential to be 
specifically developed in the market as healthy and value-added food products. 
Hence nutritional values of dates fruits can be utilized to make the fruit an 
economically viable primary agricultural product (Ghnimi et al., 2017). 
 
 
Figure 2.1: Four major stages of maturity in date palm (Sources: 
https://www.sciencedirect.com/science/article/pii/S2352340919308698) 
13  
 
 
 
 
Figure 2.2: Date palm plantation in Malaysia (Source: Date Palm Agro Bhd) 
 
 
 
 
2.1.1 Nutritional Quality of Date Palm 
 
a) Sugar 
 
Dates are rich in carbohydrates as the major components, mainly the sugars, 
which are sucrose, glucose, and fructose, which constitute about 78%. As the dates 
contain almost half the number of sugars in the form of fructose, which is twice as 
sweet as glucose, this characteristic plays an important role in the flavour and 
desirability of the dates. The sugars in dates are easily digested and can immediately 
be transported to the blood after consumption and later metabolized quickly to 
release energy for assisting various cell activities in the human body (Ali et al., 
2012). Liu et al. (2000) reported that date flesh containing glucose and fructose is 
readily absorbed during the digestion process and can lead to a rapid boost of blood 
sugar. 
The amount of carbohydrates in dates varies depending on the variety and 
level of ripeness, with the Tamr (completely ripe) stage having the maximum 
14  
concentration. The dry date fruit has a large amount of sucrose, while the soft date 
fruit is primarily made up of inverted sugars (fructose and glucose). Thus, 
classification of the date fruits can be done based on their type of sugar contents 
which are inverted sugar types, mixed sugar types, and cane sugar types. Firstly, 
the inverted sugar types of dates, such as Barhi and Saidy contain mainly glucose 
and fructose. Secondly, Khadrawy, Halawy, Zahidi, and Sayer are examples of 
dates with a high proportion of mixed sugar varieties. Lastly, Deglet Nour and 
Deglet Beidha date varieties are dominated by cane sugar containing sucrose as the 
main sugar (Ghnimi et al., 2017). 
 
 
 
b) Dietary Fiber 
 
Dietary fibre is defined as plant foods that contain polysaccharides and 
lignin that are indigestible by enzymes in the human gastrointestinal tract. High 
value dietary fiber can be found abundantly in date fruits (Ghnimi et al., 2017). 
Consumption of 100g of dates can provide approximately 50-100% of the 
recommended amount of dietary fiber needed by the human body. Date fruits have 
been reported to contain 6.5% - 11.5% total dietary fibers, which is up to 90% of 
insoluble dietary fiber and 10% of soluble dietary fiber (Al-Shwyeh, 2019). Hong 
et al. (2006) mentioned that date fruits contain 84 – 94% of insoluble and 6 – 16% 
of soluble dietary fiber, to the total dietary fiber in date fruits. 
Both insoluble and soluble dietary fiber types have essential roles for the 
human body. The intestinal absorption of anti-nutritional factors such as cholesterol 
can be slowed down due to the formation of a viscous gel in the intestine, which is 
15  
contributed by the presence of soluble dietary fibers. Meanwhile, insoluble fibers 
allow bulking and aid fermentation and generation of short chain fatty acids in the 
intestine (Ötles & Ozgoz, 2014). In addition, Shafiei et al. (2010) identified that 
dates palm flesh contains water-insoluble fibers consisted of 49.9% lignin and 
20.9% polysaccharides. They reported that date fruits fibers have high antioxidant 
and antimicrobial activities due to associated lignin and tannins contents. 
 
 
 
c) Amino Acid 
 
Dates have been described to be a good source of essential amino acids and 
variations in amino acid contents are found in different date varieties (Al-Farsi et 
al., 2005). A normal level of amino acids can be provided by diet as they cannot be 
formed in the human body. Histidine and arginine are examples of amino acids that 
play crucial importance in relation to the proper physiological functioning of the 
human body (Al-Aswad, 1971). Assirey (2015) reported that although the 
concentration of protein in date varieties studied was low (1.72 – 4.73%), dates 
contain essential amino acids to be considered an important nutritional source. It 
was discovered that the amino acid composition of date extracts contained low 
quantities of threonine, isoleucine, serine, tyrosine, methionine, phenylalanine, and 
lysine and high concentrations of leucine, proline, valine, glycine, histidine, and 
arginine. 
16  
 
 
 
d) Mineral 
 
Calcium, potassium, and phosphorus—three minerals that are crucial for 
human bodies—were present in date fruits at the recommended amounts, according 
to studies. For the date types Begamjangi, Haleeni, Dashtri, and Peshnah, the 
average mineral concentrations (calcium, phosphorus, potassium, sodium, and 
magnesium) ranged from 156.7 to 93.7 mg/100 g. Several date fruit varieties, soil 
types, and environmental factors affect the mineral content, particularly magnesium 
and sodium (Aslam et al., 2019). Dates contain the appropriate amounts of calcium, 
potassium, and phosphorus, which are crucial for the metabolism of human cells 
(Sawaya et al., 1983). 
Based on a study by Assirey (2015), the results suggested that date palm 
flesh is an important nutritional source of high quantity minerals, with potassium 
as the predominant mineral. The potassium concentration was the highest which is 
289.6 – 512mg/100 g dry matter, followed by calcium, magnesium, phosphorus, 
and sodium with the lowest concentration. It was discovered that Ajwa dates 
contained the most minerals when compared to other cultivars, including Mabroom, 
Shalaby, and Safawy. Magnesium and calcium are necessary for the growth of 
strong bones and the metabolism of energy, and dates with high potassium and low 
sodium contents make them ideal for consumption by those with hypertension (Ali 
et al., 2012). 
17  
 
 
 
e) Vitamin 
 
There are at least six vitamins which are thiamine, riboflavin, niacin, 
ascorbic acid (vitamin C), pyridoxin, and vitamin A have been reported to be 
present in date fruit at visible concentrations (Al-Shahib & Marshall, 2003). 
According to Ali et al. (2012), higher concentrations of vitamins are present in fresh 
dates compared to dry dates because the vitamin content is lost during the drying 
process. However, dried dates can be regarded as a moderate source of riboflavin, 
pyridoxine, niacin, and folic acid, meanwhile thiamine, ascorbic acid and vitamin 
A are present in relatively low concentrations in the dried dates. A nutritional 
analysis of date fruits reported that dates represented small amounts of vitamin C 
(0.7 – 0.9 mg%) and vitamin A (0.7 – 1.2 mg%) (Parvin et al., 2015). 
 
 
 
f) Antioxidant 
 
The dates fruit has multiple medicinal advantages in the management of 
disease, as indicated by a review of preclinical tests. Among 28 fruits commonly 
consumed in China, date fruits were reported to have the second highest antioxidant 
activity (Guo et al., 2003). Antioxidants are chemicals or materials that can 
neutralize and inhibit the actions of free radicals and consequently prevent them 
from causing harm (Rahmani et al., 2014). Date fruits are a good source of natural 
antioxidants with antimicrobial properties that provides protection against several 
bacterial pathogens due to the presence of active phenolic compounds (Al-Shwyeh, 
2019). The consumption of one hundred grams of dates is estimated to have 
18  
between 250 and 450 mg of phenolic substances (Ghnimi et al., 2017). (Ghnimi et 
al., 2017). The wide range of phenolic compounds present in date fruits, including 
p-coumaric, procyanidins, sinapic acids, flavonoids and ferulic are responsible for 
triggering antioxidant activity (Mansouri et al., 2005). 
 
 
 
2.1.2 Potential Health Benefits of Date Fruits 
 
a) Prevention and Control of Diabetes Mellitus 
 
Diabetes mellitus is a metabolic condition characterized by chronic 
hyperglycemia caused by abnormalities in insulin production, insulin action, or 
both. Various kinds of diabetes mellitus, such as type 1, type 2, gestational diabetes, 
and others, are compared based on diagnostic criteria, aetiology, and genetics 
(Kharroubi & Darwish, 2015). Carbohydrates are classified based on their glycemic 
responses, which were referred to as the glycemic index (GI) and are a widely 
accepted measure of the effect of carbohydrate foods on human health (Jenkins et 
al., 2002). A high GI diet can cause hyperglycemia and hyperinsulinemia, which 
can increase the risk of developing chronic diseases. Meanwhile, low GI diets have 
been shown to improve blood glucose control, lower blood lipid levels, and reduce 
insulin demand, which is all thought to be important factors in the management or 
prevention of a number of chronic diseases (Brand-Miller, 2003). 
A study conducted by Alkaabi et al. (2011) reported that in healthy people, 
the mean range of GIs for five different types of dates in the Tamr stage—Fara'd, 
Lulu, Bo ma'an, Dabbas, and Khalas—was 46 to 55; in type 2 diabetic patients, it 
was 43 to 53. According to the findings, the tested dates would have low GIs in 
19  
healthy participants, while diabetic patients who consume dates do not experience 
substantial postprandial glucose excursions. Dates are therefore categorized as low 
GI foods due to their high fructose and dietary fibre content. In addition, Tahraoui 
et al. (2007) mentioned that in Middle Eastern, dates had been used as a traditional 
medicine to treat diabetes. 
A recent study found that consumption of fruit high in fructose was linked 
to an increase in plasma antioxidant capacity and plasma urate levels (Lotito & Frei, 
2007). So, it's probable that eating fructose-rich date fruits will temporarily raise 
the plasma urate levels, improving the antioxidant capacity of the blood. The 
increase in plasma antioxidant capacities would thus attenuate the deleterious 
effects of reducing sugars on the cellular macromolecules, such as glycation of 
proteins and lipid oxidation. 
Date sugars also show characteristics of being phenol-rich, powerful 
antioxidants, and strong inhibitors of alpha-glycosidase and alpha-amylase. Date 
sugar is directly related to the total phenolics present and inhibitory activity against 
DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) radical formation. Alpha- 
glucosidase inhibitors are commonly used to regulate blood glucose levels in type 
II diabetes by inhibiting membrane-bound intestinal alpha-glucosidases, which 
hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose in the 
small intestine. Alpha-Amylase is also considered a potential drug target for the 
development of anti-diabetic drugs. Salivary and pancreatic alpha-amylase 
inhibitors block the hydrolysis of complex starches to oligosaccharides. Because of 
the reduced rate of carbohydrate digestion caused by the inhibition of these enzyme 
systems, less glucose is absorbed into the circulatory system (Ranilla et al., 2008). 
20  
Regular consumption of date fruit which is rich in minerals involved in 
glucose metabolism, can be a potential preventive and treatment strategy for 
diabetes (Vayalil, 2012). The important minerals include magnesium (Mg), zinc 
(Zn), chromium (Cr), manganese (Mn), copper (Cu), and selenium (Se). Mg is 
important for insulin release, glycolysis, oxidative energy metabolism, and energy- 
dependent transport mechanisms. The common mineral Zn plays a crucial role in 
the production, secretion, and signaling of insulin. Whereas Mn and Cu, which are 
proven to alter glucose homeostasis when deficient, also aid in improving insulin 
action. Se is a crucial mineral that has been linked to actions that mimic insulin 
(Stapleton, 2001). It promotes glucose absorption and controls the pentose 
phosphate pathway, gluconeogenesis, glycolysis, and fatty acid production. Hence, 
regular consumption of date fruit would maintain these minerals at physiological 
levels in the body, which could prevent the onset of diabetes in healthy people as 
well as regulate it in people who are deficient in them. 
 
 
 
b) Cardiovascular Disease 
 
Cardiovascular diseases (CVDs) remain the leading cause of disease burden 
for almost all countries (Ruan et al., 2018). High blood pressure is correlated with 
the strongest evidence for causation among the risk factors for CVD, with a high 
prevalence of exposure (Fuchs & Whelton, 2020). The causes of essential 
hypertension remain unknown, however, there is a clear positive correlation 
between blood pressure and the risk of CVD, including stroke, myocardial 
infarction and heart failure (Carretero & Oparil, 2000). Date fruit is reported to have 
a potential protective effect on various conditions that lead to hypertension based 
21  
on its nutritional composition. Besides that, both eastern Africa and the Middle East 
have traditionally utilized date fruit as a meal and medicine to treat hypertension 
(Vayalil, 2012). Dates may significantly slow the onset and progression of 
cardiovascular disease by lowering hypertension, high cholesterol, and lipoprotein 
oxidation, improving serum antioxidant status, and minimizing the damaging 
effects of oxidative stress and probably inflammation on the vascular system 
(Vayalil, 2012). 
Date fruit is known as an excellent dietary source of potassium with very 
low sodium content. Hence, frequent date consumption would provide the 
necessary potassium levels to maintain the body's electrolyte balance and could 
prevent the onset and progression of hypertension. Mg and Ca are other major 
dietary minerals at a very high concentration in date fruit that can provide protection 
from hypertension. Magnesium acts as a natural calcium channel blocker, which 
may reduce blood pressure. Magnesium is also a cofactor for the 6-desaturase 
enzyme, which is the rate-limiting step in the conversion of linoleic acid, a 
precursor to prostaglandin, a molecule that relaxes blood vessels and inhibits 
platelets. When calcium is combined with other ions like sodium, potassium, and 
magnesium, an ionic balance to the vascular membrane will happen and causing 
vasodilation and lowering blood pressure (Al-Dashti et al., 2021) . 
c) Pregnancy 
 
Date fruit appears to be a good dietary choice as part of a well-balanced diet 
for pregnant women, containing a lot of good nutritional value and potential health 
benefits. Zainan Nazri et al. (2016) mentioned that date fruit could contribute 
significantly to a healthy pregnancy in women due to its properties that can prevent 
22  
anaemia, reduce stress, control blood pressure, regulate blood sugar levels, help to 
restore depleted calcium, expel toxins, increase strength and for immune resistance. 
In terms of cervical dilation, spontaneous labour, lower use of oxytocin, 
shorter apparent latent phase of the first stage of labour and fewer C-sections, 
women who consumed six dates per day for four weeks prior to the estimated date 
of delivery had significantly better childbirth than women who consumed none, 
according to Al-Kuran et al. (2011). In the last month of pregnancy, the uterine 
muscles are strengthened by stimulants found in dates. This is important for uterine 
dilation during labour and for reducing bleeding after delivery. Dates are considered 
by dieticians as the best food for pregnant women and women who are breast- 
feeding their infants since they also contain substances that reduce depression in 
mothers and increase nutrients in breast milk that children need for their health 
(Marwat et al., 2009). 
A recent non-randomised clinical trial was conducted among postpartum 
women to compare the effect of date fruit consumption and oxytocin immediately 
after placenta delivery. As a result, women who consumed 50 grams of oral dates 
had significantly less bleeding than those who were given 10 units of intramuscular 
oxytocin (Zainan Nazri et al.,2016). Due to the presence of compounds in date fruit 
that imitated the action of oxytocin, date fruit consumption after giving birth 
reduces the amount of bleeding compared to intramuscular oxytocin in the first hour 
following placental delivery. Besides, the oxytocin-like effect in date palms also 
can increase the sensitivity of the uterus and stimulates uterine contractions. Thus, 
dates can be considered a good food supplement alternative in normal delivery 
(Khadem et al., 2007). Accordingly, dates fruit consumption during late pregnancy 
23  
has been shown to positively affect the outcome of labour and delivery and is 
considered a safe supplement for mother and child. 
 
 
 
2.2 Goat Milk 
 
Dairy goat and sheep farming have become a vital economic activity in 
many countries in Middle East, Europe, Oceania and Asia. It has a beneficial effect 
on both health and physiological function by providing nutrition to children and 
elderly people. The nutritional and socioeconomic well-being of developing and 
underdeveloped countries are strongly influenced by goat milk (Yangilar, 2013). 
Goat milk has been produced in Malaysia for some time. As goat milk has a 
significant ideal market, dairy goat farming has developed dramatically in this 
country, with the majority of dairy goats imported from several countries (Devendra 
et al., 2012). 
As a comparison to cow milk, goat milk fat contains much more short-, 
medium-, and polyunsaturated fatty acids (Devendra, 2012). Goat milk has higher 
concentrations of monounsaturated, polyunsaturated, and medium-chain 
triglycerides than cow milk, all of which are recognized to be good for human 
health, especially for cardiovascular conditions (Haenlein, 2004). The diverse 
dietary nutritional contributions made by goat milk are particularly important for 
resource-poor farming families that are constantly on the edge of subsistence and 
vulnerability. The majority of milk is marketed informally in rural parts of the 
country (Devendra, 2012). Bhattarai (2012) mentioned that goats are highly 
contributed in supplying milk and milk products, which has a significant role in 
24  
rural economy sector and health purposes. In addition, the acceptance of goat milk 
and its products is excellent among consumers. Thus, more efforts in research and 
development are needed to explore the maximum benefits of goats, particularly 
their meat, milk, and milk product that have potential medicinal value for human 
health. 
 
 
 
2.2.1 Nutritional Quality of Goat Milk 
 
Goat milk is very famous as a natural food resource that has excellent 
nutritional properties. Goat milk contains an average of 12.2% total solids, 
consisting of 4.1% lactose, 3.8% fat, 3.5% protein, and 0.8% ash. These reported 
data indicate that it has more fat, ash, and protein and less lactose than cow milk 
but provides a similar level of calories (70 kcal/100mL) for human nutrition as cow 
or human milk does (Park, 2006). Goat milk is responsible for better digestibility 
as compared to cow milk because its curd tension is below than cow milk (Bihaqi 
& Jalal, 2010). Coni et al. (1999) reported that goat milk differs from cow or human 
milk in terms of having better digestibility, alkalinity, buffering capacity, and 
certain therapeutic values in medicine and human nutrition. The advantage of goat 
milk consumption should be popularized due to its high nutritional value and this 
consequently can enhance the manufacturing and utilization of goat milk (Kumar 
et al., 2012). 
25  
a) Carbohydrate 
 
Goat milk has a basic composition with many similarities to cow milk, such as 
carbohydrates, lipids, protein, minerals and vitamins (Getaneh et al., 2016). Kunz et al. 
(2000) reported that the major carbohydrate in goat milk is lactose, with a content 
slightly lower than in cow milk. Glucose and galactose present in the mammary gland 
synthesized lactose, where the milk protein α-lactalbumin plays an essential role. 
Lactose is important because it aids intestinal absorption of calcium, magnesium, and 
phosphorus and the utilization of vitamin D (Lad et al., 2017). Goat milk also contains 
small amounts of oligosaccharides, glycopeptides, glycoproteins, and nucleotides. The 
prebiotic and anti-infective properties of milk oligosaccharides are beneficial to human 
nutrition when consumed (Lara-Villoslada et al., 2004). The oligosaccharide structures 
found in goat milk are most similar to those found in human milk. Thus, goat milk also 
can provide a significant complementary effect in infant nutrition (Lad et al., 2017). 
 
 
 
b) Protein and Amino Acid 
 
A soluble phase made up of whey proteins and an unstable micellar phase 
made up of casein are the two different phases of milk proteins. When comparing 
goat milk to cow milk, there are almost comparable amounts of the k-casein 
fractions, lower levels of the alpha s-casein, and higher amounts of the beta-casein 
fractions. Hence, beta-casein is the main protein found in goat milk (Diaz-Castro et 
al., 2010). Also, compared to cow milk, goat milk proteins are thought to be easier 
to digest and their amino acids are absorbed more effectively. When acidified, 
caprine milk produces a curd that is softer and more friable, which may be due to 
26  
the milk having a lower alpha s1-casein level. Goat milk curds that are smaller and 
more friable will be degraded by stomach proteases more quickly, which will 
improve their digestibility (Mestawet et al., 2014). Turkmen (2017) mentioned that 
goat milk has a better buffering capacity than cow milk due to its relatively higher 
content of protein, phosphate content, and non-protein N, which would be helpful 
for treating stomach ulcers. Additionally, goat milk contains greater concentrations 
of key essential amino acids, including cysteine, tyrosine and lysine, and the 
branched-chain AAs, isoleucine and valine which is important for human nutrition 
(Greppi et al., 2008). 
 
 
 
c) Mineral and Vitamin 
 
The vitamin and mineral content of goat milk is almost similar to that cow 
milk. Krstanovic et al. (2010) reported that goat milk has a higher content of 
Calcium, Potassium, Copper, Chloride, Phosphorus, Zinc, and Selenium than cow 
milk. Goat milk is a good source of vitamins such as vitamin D, vitamin E, 
thiamine, niacin and riboflavin. Goat milk, however has a low level of folate (Park, 
2006). The consumption of goat milk needs to be supplemented with folic acid 
because goat milk contains less than 10% of the amount of folic acid contained in 
cow milk (Getaneh et al., 2016). As with cow milk, goat milk is an excellent source 
of calcium and phosphorus to human nutrition. Both calcium and phosphorus of 
goat milk can be absorbed by human infants, thus providing a great excess of such 
minerals to the energy of young children due to the higher content of most of the 
minerals (Turck, 2013). 
27  
Vitamin A content in goat milk is similar to human milk but higher than in 
cow milk because goats convert all β-carotene from their foods into vitamin A in 
the milk (Conesa et al., 2008). Immune responses such as cell-mediated defense 
and antibody production require vitamin A for both innate and adaptive immune 
functions (Lad et al., 2017). Besides, goat milk also contains greater amounts of 
vitamin C than in cow milk, and this vitamin is well-known as a water-soluble 
antioxidant. 
 
 
 
d) Lipid 
 
The nutritional benefits of goat milk over cow milk are not due to variations 
in the minerals or proteins but from the lipids, especially the fatty acids within the 
lipids (Haenlein, 2004). The observation on fat globules of goat milk found a 
similarity to that of cow milk in lipids composition and properties, but goat milk 
lacks agglutinin. Goat milk fat contains much more butyric, caproic, caprylic, 
capric, lauric, myristic, palmitic and linoleic fatty acids than cow milk fat (Jenness, 
1980; Mollica et al., 2021). In addition, goat milk has higher values of free lipids 
than that of cow milk (Cerbulis et al., 1982; Mollica et al., 2021 ). 
Lad et al. (2017) mentioned that medium chain triglycerides (MCTs) are 
able to supply energy without being deposited in the fatty tissue of the body. The 
high amounts of short and medium chain fatty acids (MCT) in goat milk fat 
contribute significantly to human nutrition. Firstly, it may be more rapidly digested 
than cow milk fat because lipase attacks ester linkages of short or MCT more easily 
than those of longer chains. Secondly, these fatty acids have positive effects on 
28  
cholesterol metabolism, including hypocholesterolaemia action on tissues and 
blood via inhibition of cholesterol deposition and gallstone cholesterol dissolution 
(Alferez et al., 2001). 
 
 
 
2.2.2 Potential Health Benefits of Goat Milk 
 
a) Allergy and Anti-Inflammatory Effects 
 
The definition of allergy is an abnormal tissue reaction following exposure 
to foreign antigen (McCullough, 2003). Protein is the most common antigen. The 
most frequent protein sensitivity occurs in infants, with approximately 2-6 % 
incidence (Lara-Villoslada et al., 2004). According to the researcher, alpha s-1 
casein is often the cause of cow milk intolerance. Goat milk is less allergic because 
the level of the alpha s-1 casein goat milk is 89 % lower than that of cow milk. Goat 
milk has been proven to show improvements in colic, minor digestive disorders, 
asthma and eczema over cow milk and individuals with cow milk sensitivities 
(McCullough, 2003). Lara-Villoslada et al. (2004) reported a study about 
allergenicity of goat milk and cow milk in mice. The results demonstrated that goat 
milk provides immunological benefits in reducing specific markers involved in the 
allergic response (Lara-Villoslada et al., 2004). 
Albenzio et al. (2012) in their studies proved goat milk exhibited anti- 
allergy benefits upon drinking when a similar trial was taken among children with 
cow milk protein allergies. In addition to the lack of inflammatory effects with goat 
milk, those who drank goat milk had higher levels of the anti-inflammatory 
cytokine IL-10. IL-10, which inhibits the production of pro-inflammatory cytokines 
29  
like TNF-, is hypothesized to aid the immunological suppression and thereby 
limiting reactivity to antigens in cow milk (Albenzio et al., 2012). Besides, goat 
milk contributes to almost all biological reactions and utilizes antioxidant and anti- 
inflammatory effects on the human body. Due to the smaller size of the fat globules 
in goat milk, which is only one-ninth of the size of cow milk fat globules, goat milk 
does not cause irritation effect in the gut (Lad et al., 2017). Shea et al. (2004) 
supported that probiotics and prebiotics contents in goat milk help to maintain a 
healthy intestinal microflora which is important for protection against the 
pathogenic infection allergy that can cause negative effects, including many 
diseases. 
30  
b) Malabsorption Syndrome 
 
Physiological digestion and absorption of nutrients within the 
gastrointestinal tract is a complex process with the possibility of disturbances in 
gastrointestinal motility and related diseases that may lead to malabsorption. Milder 
motility disturbances can contribute to various symptoms, such as diarrhoea, 
constipation, and abdominal pain. Meanwhile, severe motility disturbances can 
induce impairment of nutrient absorption (Keller & Layer, 2014). According to Lad 
et al. (2017), goat milk contains medium chain triglycerides (MCTs) that may be 
used to treat the absorption disorders such as diarrhoea, coealic disease, liver 
disease, steatorrhoea (fat indigestion) and digestion problems due to gastrectomy. 
In an animal study, Alferez et al. (2001) examined the effect of goat and 
cow milk fat on the digestive processes connected to lipid metabolism. They 
discovered that rats given a diet high in medium-chain triglycerides from goat's 
milk digested fat more efficiently than those given a diet based on cow's milk. Goat 
milk consumption decreased cholesterol levels while maintaining normal levels of 
triglycerides and high-density lipoprotein. This is due to the presence of higher 
level medium chain triglyceride (MCT) (36% in goat milk vs 21% in cow milk), 
which decreases the synthesis of endogenous cholesterol. Consuming goat milk 
increases the body's absorption of iron and copper, according to Lad et al. (2017). 
Several research demonstrated that goat milk assimilates easily and increases the 
bioavailability of nutrients (Lad et al., 2017). 
31  
 
 
 
c) Nutritional Nourishing 
 
Approximately 35% of the daily calcium needed in a glass can be provided 
by consuming goat milk. In addition, a glass of goat milk provides up to 20% of the 
daily needs of riboflavin. Furthermore, goat milk also contains high levels of 
potassium and vitamin B12. According to the researchers, goat milk can be 
considered a functional and neutraceutical health drink. Goat milk can be a useful 
source of nutrients for people who have a cow milk allergy or intolerance, 
especially those who suffer from anaemia, osteoporosis, or malabsorption (Lad et 
al., 2017). According to Zago and Oteiza (2001), goat milk improves Zn 
bioavailability, which is a well-known mineral with antioxidant capacity. Regular 
consumption of goat milk may lead to a positive effect on genomic stability, even 
during the Fe-overloading feeding routine, which could be due to the high 
bioavailability of Mg and Zn (Diaz-Castro et al., 2009), altogether with goat milk’s 
better quality of fat content (Alferez et al., 2001). 
 
 
 
d) Cardiovascular Disease 
 
Monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), 
and medium chain triglycerides (MCT) contents in goat milk are better than that of 
cow milk, which is beneficial for cardiovascular conditions. At the same time, 
Haenlein (2004) also mentioned that goat milk has a lower level of cholesterol than 
cow milk. Goat milk has a balanced fatty acid profile, which may contribute to the 
prevention of atherosclerosis, heart attacks, strokes, and other heart complications. 
32  
Goat milk also has a high content of potassium which can reduce the blood pressure 
level. Goat milk is a good choice for preventing cardiac disorders because its fat 
can reduce total cholesterol levels. Alférez et al. (2019) concluded in their paper 
that the consumption of fermented goat milk improves haematological status and 
promotes beneficial metabolic response, which may reduce the severity of 
cardiovascular risk factors during anaemia recovery and iron overload to reduce the 
inflammatory response, macrophages activation, and atherosclerosis development. 
 
 
 
2.3 Metabolism of Iron 
 
2.3.1 Iron Bioavailability 
 
The amount of ingested iron absorbed and used by the body for 
physiological functions and storage is known as iron bioavailability. Dietary iron 
has two main forms, namely heme and non-heme. Heme iron comes from 
haemoglobin and myoglobin in animal source foods, whereas non-heme iron is 
found in both plant and animal sources. Heme iron is better absorbed than non- 
heme iron. Approximately 40 % of iron from animal sources is heme iron, whereas 
plant-source iron is exclusively non-heme iron. In adults with adequate iron stores, 
approximately 25 % of heme iron is absorbed (Monsen et al., 1978). Non-heme 
iron often absorbs significantly less efficiently than heme iron. The amount of 
absorption of all non-heme dietary iron that enters the common iron pool in the 
digestive system varies depending on the balance between absorption inhibitors and 
enhancers as well as the individual's iron status. 
33  
a) Factors Influencing Iron Bioavailability 
 
Enhancers and inhibitors in the diet significantly impact the bioavailability 
of dietary iron. Depending on the ratio of enhancers to inhibitors in the meal, the 
iron absorbed might range from 1% to 40%. (WHO, 2001). To increase the 
bioavailability of iron in normal diets, meal plans might be changed to favour 
enhancers, reduce inhibitors or both. It is recognized that various variables affect 
how well iron is absorbed from food. Heme iron absorption is more moderately 
influenced by the iron status of the host, but absorption of non-heme iron is strongly 
influenced by iron status and also affected by dietary factors. Animal tissue (meat, 
fish, and poultry), calcium salts, phytates, ascorbic acid, and polyphenols ((beans, 
coffee and tea) are dietary components that affect the absorption of non-heme iron. 
In addition, the amount of non-heme iron consumed also affects absorption 
capacity, with higher intakes resulting in a lower percentage of absorption. Iron 
absorption may also be influenced by other host factors such as hepcidin, 
inflammation or infection, and even genetic factors. Ascorbic acid and animal tissue 
are two dietary components that improve iron absorption, whereas phytic acid, 
polyphenols, and calcium salts inhibit it. 
34  
b) Method in Estimating Iron Bioavailability 
 
The study of iron bioavailability in humans can be imitated by using Caco-2 
cell line. Caco-2 cells are human epithelial cell line that behaves like intestinal cells 
derived from a human colonic adenocarcinoma. It is well established as an in vitro 
model in many research of iron absorption. This method is usually combined with a 
gastrointestinal model, a solubility test, or a dialysability test. For example, after the 
food sample has been digested, ferritin production in a monolayer of Caco-2 cells can 
be used to measure iron intake. These combined techniques have the benefit for 
allowing the researcher to study iron absorption and transport mechanisms. Wood and 
Tamura (2001) mentioned that many researchers are convinced that human absorption 
studies are the benchmark for evaluating human iron bioavailability. However, the 
studies of iron bioavailability in humans are usually high-cost as they may require 
tracer iron. There is an absence and limitation in published work that can prove the 
direct relation between estimates of relative iron bioavailability determined in the 
Caco-2 cell system with human iron absorption studies. However, Au and Reddy 
(2002) published a study that showed a significant correlation (r = 0.92) between iron 
uptake in Caco-2 cells from various food digests and human iron absorption. It is 
necessary to conduct more validation studies, especially regarding iron supplements, 
even though Beard (2007) believed that an in vitro approach using Caco-2 cells is 
promising in predicting iron bioavailability in human studies. In addition, the in vitro 
methods for evaluating iron bioavailability could be a rapid and low-cost alternative. 
Yun et al. (2004) demonstrated gastric and intestinal digestion and absorption 
using in-vitro digestion coupled with a Caco-2 cell culture model to replicate meal 
intake in human studies, such as egg meals with different ascorbic acid concentrations 
35  
and wheat rolls with various tannic acid concentrations. This study is conducted to 
determine how iron bioavailability using cell culture can be used to assess human iron 
bioavailability. The Caco-2 cells formed a ferritin substance that serves as a marker for 
cell iron uptake and is subsequently used as a functional indicator of iron bioavailability 
in both absorption and utilization of iron in the tested materials. This method found a 
strong significant correlation between iron uptake by Caco-2 cells model from the 
meals and humans. However, there is almost no possibility of having a concrete 
measure of iron bioavailability because iron is measured in the tested material and the 
percent of absorbable iron cannot be calculated from the ferritin concentration 
measured in Caco-2 cell lysate. On the other hand, this model can also be utilized to 
study the interactions between iron and enhancers or inhibitors. For example, a study 
was conducted to determine the effect of fructose on iron uptake in Caco-2 cell by 
adding fructose 1,6-biphosphate (F17BP) into iron and resulted to an increase in ferritin 
formation in Caco-2 cells (Rodriguez-Ramiro et al., 2019). It has been shown that 
cabbage has the highest relative bioavailability of iron, followed by broccoli, pepper, 
kale, and spinach. It is possible that the complex formation of the fructose contained in 
cabbage explains the higher iron bioavailability in that vegetable (Rodriguez-Ramiro 
et al., 2019). 
36  
2.3.2 Iron Absorption 
 
 
 
Figure 2.3: Diagram showing a generalized view of cellular iron homeostasis in 
humans. (Source: https://en.wikipedia.org/wiki/Human_iron_metabolism) 
 
Heme and non-heme iron make up dietary iron. The origin of heme iron is 
exclusively from animal sources, mainly from the breakdown of haemoglobin and 
myoglobin (Dunn et al., 2007), with approximately 40 % of iron from animal sources 
is heme iron (Du et al., 2000). On the other hand, non-heme iron comes from both plant 
and animal sources. 
 
Heme and non-heme iron are absorbed through different pathways, with the 
absorption process mostly taking place in the duodenum. Iron from non-heme sources 
is in the ferric form and must first be converted into ferrous iron before absorption, 
which is facilitated by the ferric reductase duodenal cytochrome b (DCYTB) (Hentze 
37  
et al., 2004). Then, ferrous iron enters the enterocytes through the apical membrane. 
The uptake of non-heme iron is mediated by divalent metal transporter I (DMT1), also 
known as divalent cation transporter I (DCT1). Heme iron is different from non-heme 
because it is already in the ferrous form. It is transported across the apical membrane 
by a mechanism that is still not well known among researchers. It was suggested that 
heme carrier protein (HCP1) assists in transporting heme iron. However, HCP1 has 
been shown to transport mainly folate (Qiu et al., 2006). Steinbicker and Muckenthaler 
(2013) explained that heme enters the enterocyte as an intact iron protoporphyrin 
complex. The iron is released from heme by the hemeoxygenase 1 (HO-1) once its is 
inside the enterocyte. Then, both sources of iron enter a common labile iron pool (Dunn 
et al., 2007). 
 
The iron is either stored as ferritin or exported out of the enterocyte by ferrotportin 
(FPN1) (Steinbicker and Muckenthaler, 2013). The excess iron that mostly stored as 
ferritin is lost through exfoliation of the cell. Approximately 10 % of the iron stored in 
ferritin is later exported out of the enterocyte (Lynch, 2000). FPN1 is expressed in the 
basolateral membrane of the enterocytes and in macrophages, liver, placenta and spleen 
(Lieu et al., 2001). Hepcidin is a peptide hormone that controls the surface expression 
of FPN1, which also regulates its function by triggering its internalization and 
degradation following iron replete conditions (Steinbicker and Muckenthaler, 2013). 
The ferrous iron exported by FPN1 is taken up and transported by the transport protein 
transferrin and converted to ferric iron due to ferroxidase activity. The ferroxidase 
activity in the enterocytes is provided by hephaestin, a homologue of ceruloplasmin. 
Meanwhile, the ferroxidase activity in non-intestinal cells is provided by ceruloplasmin. 
Steinbicker and Muckenthaler (2013) also explained that the mRNA expression for 
38  
DCYTB, DMT1, HO-1 and FPN1 is controlled by hypoxia inducible factor 2 (HIF-2), 
while posttranscriptional of DMT1 and FPN1 is regulated by iron regulatory proteins 
(IRPs) in response to intracellular iron levels. 
 
 
 
a) Inhibitors of Iron Absorption 
 
i) Phytate 
 
Phytic acid is also known as an iron absorption inhibitor. It is abundant in 
grains, legumes, nuts, and oil seeds. The salt form of phytic acids such as magnesium, 
calcium, or potassium salt is referred to as phytate (Brown et al., 2004). The mechanism 
of iron inhibition by phytate is due to its ability to bind to iron and subsequently form 
insoluble complexes that are unable to be absorbed at intestinal pH. (Minihane and 
Rimbach, 2002). The phytic acid molecule contains negative charge phosphate, which 
binds to metallic cations such as iron, calcium, and zinc, leaving them insoluble and 
decreasing bioavailability. 
Higher inositol phosphates (myo-inositol hexaphosphate-IP6 and myoinositol 
hexaphosphate IP5) level are the most common cause of inhibitory effects of phytates 
on iron absorption. Sandberg et al. (1999) studied the effects of inositol phosphates 
with different number of phosphorus groups on iron absorption and he found that IP5 
inhibited iron absorption but no effect with IP3 and IP4. The in vitro studies have also 
shown that even small quantities of 0.5 µmol of IP5 and IP6 can significantly reduce 
iron solubility, meanwhile, IP3 and IP4 did not (Sandberg et al., 1989). Hallberg et al. 
(1989) also mentioned that the effect of phytic acid on non-heme iron absorption is 
dose-dependent, similar with ascorbic acid. 
39  
 
 
 
ii) Polyphenol 
 
Polyphenols are a class of natural chemicals that have phenolic structural 
characteristics (Tsao, 2010). Based on their chemical structure, Manach et al. (2004) 
categorized them as phenolic acids, flavonoids, polyphenolic amides and other 
polyphenols. The health advantages obtained are determined by the bioavailability of 
polyphenols and the amount consumed. The antioxidant content of various polyphenols 
found in our food sources, such as edible plants, is the most prevalent dietary source of 
antioxidants. The properties are critical for enhancing human health, especially in the 
prevention of degenerative diseases such as cancer, neurological diseases, diabetes, 
cardiovascular disease, and osteoporosis (Scalbert et al., 2005). Scalbert et al. (2005) 
also stated that fruits, vegetables, whole grains, tea, coffee, chocolate, red wine, 
legumes, and other foods possess a high concentration of polyphenols. 
Many fruits and foods naturally contain a group of phytonutrients called 
flavonoids (Manach et al., 2004). Flavanols may exist as simple monomeric 
(catechins), dimeric (theaflavins), or polymeric (procyanidins). Green tea, chocolate, 
red wine, and fruits like apricot, grapes, and berries are the main sources of catechins. 
However, theaflavin is a molecule found in black tea that is produced during green tea 
fermentation by the oxidation of monomeric flavanols (Manach et al., 2004). 
Polyphenols are also known to have anti-nutritional effects. Anti-nutritional 
factors can interact with nutrients, reducing their bioavailability. Polyphenols inhibit 
the absorption of iron that is released from meals by binding and forming complexes 
with iron which take place in the gastrointestinal tract (Schönfeldt et al., 2016). 
40  
 
 
 
iii) Calcium 
 
Calcium is an important mineral for human nutrition that cannot be produced in 
the body and must be gained from diet. Milk, yogurt, and cheese are examples of dairy 
products that are common sources of calcium. The effect of calcium on iron absorption 
has raised concerns because children and women are at risk of iron insufficiency, 
although the same populations are also advised to increase their calcium consumption. 
Calcium is unique among dietary nutrients; it is the only known dietary 
component that inhibits both heme and non-heme iron absorption. Regarding how 
calcium affects iron absorption, there is still some debate. According to Lynch (2000), 
the inhibitory effect of calcium on iron absorption is caused by the interaction of 
calcium and dietary components that alter iron bioavailability. Moreover, the 
interaction of calcium on luminal surface receptors during iron uptake may possibly be 
the cause of iron inhibition. Hallberg et al. (1991) postulated that the effect of calcium 
is at the mucosal level, in which both heme and non-heme iron undergo a common 
process. 
41  
b) Enhancers of Iron Absorption 
 
i) Ascorbic Acid 
 
Ascorbic acid is a water-soluble vitamin C present in food that has both 
enzymatic and non-enzymatic activities. It acts as a cofactor for several metabolic 
reactions in its enzymatic activities. Ascorbic acid, on the other hand, is a powerful 
antioxidant that aids in the scavenging of free radicals and reactive oxygen species 
(Lykkesfeldt et al., 2014). The majority of vitamin C intake comes from vegetables and 
fruits, particularly citrus fruits. High quantities of vitamin C have been found in kiwi, 
mango guava and broccoli. 
By converting iron from ferric to ferrous form, vitamin C is a common booster 
of non-heme iron absorption. As a result, iron is effectively transported across the 
enterocytes' apical membrane. Ascorbic acid also aids in iron chelation by forming a 
soluble compound across a wide pH range (Lynch and Cook, 1980). In addition, 
ascorbate, ascorbic acid salt, donates an electron, acting as a free radical scavenger and 
reducing iron oxidation states to ferrous ion form, which is the only bioavailable form 
for enterocyte cells (Smirnoff, 2018). ferrous ion form is the only iron that can be 
absorbed through iron transporters of intestinal enterocyte cells (Gulec et al., 2014). 
Kuhn et al. (1968) found that adding ascorbic acid to corn and wheat diets 
increased iron absorption. Using data from a 1970 study by Callendar and Marney, they 
discovered that adding 100 ml of orange juice to an egg meal increased iron absorption 
from 3.7 to 10.4%. Ascorbic acid's effect on the absorption of non-heme iron has also 
been demonstrated to be dose-dependent (Cook and Monsen, 1977). Even when 
inhibitors are present, ascorbic acid has a remarkable ability to overcome their 
42  
inhibitory effects. In research by Hallberg et al. (1989), adding 50 or 100 mg of ascorbic 
acid led to a noticeably higher rate of iron absorption from meals containing 25 and 
250 mg of phytate phosphorus as an inhibitor. 
 
 
 
ii) Animal Tissue 
 
Animal foods are well acknowledged as a well-known diet that can aid in non- 
heme iron absorption. To increase the bioavailability of iron in food, more animal tissue 
is being added to meals (Reddy et al., 2006). Bach et al. (2003) proved the influence 
of animal tissue on iron absorption by incorporating 50g of meat into a low 
bioavailability test meal, which increased iron bioavailability by more than 40%. The 
impact of adding meat (with or without ascorbic acid) to weaning gruel meals on the 
absorption of non-heme iron was examined by Hallberg et al. in 2003. They discovered 
that adding meat powder dramatically boosted gruel's ability to absorb iron by 85%. 
The overall amount of iron is absorbed more effectively due to the heme 
component of animal tissue found in meat, fish, and poultry. Animal tissue improves 
non-heme iron absorption in vegetarian diets and numerous potential mechanisms by 
which meat improves non-heme iron absorption has been postulated. One of the 
proposed mechanisms is the stimulation of gastric juice secretion. They also observed 
that the test subjects' ability to absorb iron was increased by the addition of gastric 
juice. Another suggested mechanism is the discharge of digestion products of animal 
tissue. According to Hurrell et al. (2006), animal tissue releases partially digested 
products that can bind iron via histidine and cysteine residues. The binding mechanism 
causes iron to become soluble, then increase iron absorption. In this approach, 
43  
inhibitors such as phytates and polyphenols found in meals are unable to bond with 
iron, preventing iron inhibition. 
 
 
 
iii) Fructose 
 
Fructose is a monosaccharide, a type of simple sugar that naturally exists in 
fruits, honey, and some vegetables. According to O'Dell (1993), fructose increases iron 
bioavailability via enhancing ferrous iron production. Christides and Sharp (2013) also 
discovered that fructose dramatically increases iron bioavailability in human intestinal 
epithelial cells by increasing ferrous iron production utilizing in vitro cell models of 
the gut and liver. The results reveal that when fructose is mixed with FeCl3, the 
ferrozine-chelatable ferrous iron levels increase by roughly 300%. This study also 
discovered that fructose increases the levels of iron-induced hepatic ferritin. 
 
 
 
2.3.3 Iron Transport and Cellular Uptake 
 
Transferrin is a glycoprotein, which is a major iron transport protein synthesized 
mainly by the liver. It has two domains for binding iron molecules and binds iron with 
very high affinity at a pH of 7.4 (Lane and Richardson, 2014). The ferric iron is taken 
up by transferrin and transported to target cells. The holotransferrin (HTF) is an iron- 
transport protein sourced from plasma, which is taken up into the cell by transferrin 
receptor (TfR), a transmembrane protein consisting of two identical subunit. Each of 
the two subunits of the TfR binds to one transferrin molecule. There are two types of 
TfR, namely TfR1 and TfR2. TfR1 is expressed in all tissues and is synthesized in the 
endoplasmic reticulum. Meanwhile, TfR2 is expressed only in hepatocytes, duodenal 
44  
crypt cells and erythroid cells (Lane and Richardson, 2014). Besides, TfR2 binds to 
transferrin with a lower strength of binding than TfR1 due to a mutation in its gene 
linked to hemochromatosis (Papanikolaou and Pantopoulos, 2005). At the target cell 
surface, TfR1 binds to the holotransferrin and the complex is then endocytosed. The 
release of the iron is mediated by acidification of the endosome by ATPase proton 
pump. The iron is released at a pH of approximately 5.5. Divalent metal transporter 1 
(DMT1) is the major iron transporter and plays a role in non-heme iron uptake in most 
types of cells (Yanatori et al., 2019). DMT1 transports the iron across the membrane 
of the endosome into the cytoplasm (Chahine and Pakdaman, 1995). The iron can be 
utilized for cellular purposes, or it can be stored in the primary iron storage protein 
ferritin. However, iron is also stored in hemosiderin at higher concentrations. The apo- 
transferrin-TfR1 complex then returns to the cell surface to be able to bind new 
transferrin. 
 
 
 
2.3.4 Iron Storage 
 
The body stores 0-15 mg/kg of iron, largely as the iron storage protein ferritin, 
with a small percentage of around 5% as hemosiderin. About half of the body's ferritin 
is found in the liver, with the remaining present in muscles and the reticuloendothelial 
system. According to Cullis et al. (2018), ferritin is a soluble protein that has 24 
subunits and a cavity that may store more than 4,000 iron atoms in the ferric form 
(Arosio et al., 2009). Mammalian ferritin is a heteropolymer composed of Heavy (H) 
and Light (L) chain components. The H-ferritin protein has a molecular weight of 21 
kDa, whereas the L-ferritin protein has a molecular weight of 19 kDa (Cullis et al., 
2018). Around 800 iron (Fe III) sites are filled when ferritin is 20% saturated in vivo 
45  
(Beard, 2001). Ferritin, with a high amount of H subunit, is found mostly in the heart, 
red blood cells, and the brain, and it has a ferroxidase site with high ferroxidase activity. 
The L-type chain, meanwhile, is primarily present in the liver and spleen, which have 
larger cavities for storing iron. It serves to accelerate the nucleation of iron and the 
turnover of the ferroxidase center (Hentze et al., 2010). The chemical interaction of 
ferritin with ferrous iron oxidizes it to ferric iron for deposition into its cavity. In the 
reaction that takes place at the ferroxidation center, ferritin uses dioxygen as an oxidant 
during the oxidation process. The iron oxide substance is kept in the central cavity. 
Because this process uses both ferrous and oxygen, it is considered to prevent the 
production and formation of free radicals in cells and tissues (Romeu et al., 2013). The 
body's metabolism then releases the iron that has been stored in ferritin when needed, 
primarily by proteolytic ferritin breakdown. In disease conditions such as iron 
deficiency, ferric iron in ferritin may be reduced to ferrous iron as an alternative 
approach that results in the release of iron (Arosio et al., 2009). 
 
 
 
2.3.5 Regulation of Iron Storage and Uptake 
 
a) Ferritin and Transferrin Receptor (TfR) 
 
Regulation of iron absorption, transport and storage occurs mainly at the 
translational level but some control mechanisms exist at the transcriptional level. 
Homeostasis of iron is accomplished through the iron regulatory proteins (IRPs) and 
iron-responsive elements (IRE) signalling pathway (Zhou & Tan, 2017). IRPs bind to 
IREs in target mRNAs to regulate the expression of genes involved in the metabolism 
of iron (Zhang et el., 2014). There are two types of IRPs, namely IRP1 and IRP2. Both 
46  
types of IRP are expressed in all tissues; however, IRP2 is expressed in lesser quantities 
in most tissues. The function of this protein depends on the intracellular iron 
concentration. The IREs are responsible as either enhancers or inhibitors of translation 
under different circumstances. They are located either at the 3’ untranslated region 
(UTR) or the 5’ UTR of the mRNA. The binding of IRP to the protein’s IRE located at 
the 3’ UTR leads to the stability of the mRNA resulting in translation and increased 
protein synthesis. Meanwhile, the location of IRE at the 5’ UTR causes the binding of 
IRP to the IRE blocks mRNA translation (Hentze et al., 2010). The IRE for ferritin is 
located at the 5’ UTR but the IRE for transferrin receptor (TfR) is located at the 3’ UTR. 
In a condition of iron deficiency, the IRP1 and IRP2 binds to the IRE for both ferritin 
and TfR, consequently decreasing iron storage and increasing iron intake. The ferritin 
translation is blocked and ferritin synthesis is prevented because the binding activity to 
the 5’ UTR impedes ribosome binding and translation of the protein. The binding to 
the 3’ UTR obscures the mRNA to endonuclease digestion, resulting in translation and 
increased protein synthesis. Therefore, there is increased stability of the TfR mRNA. 
In contrast, the binding activity of IRPs to the IRE is reduced in the presence of 
iron. There is increased translation of the ferritin mRNA and increased ferritin synthesis, 
thus allowing iron storage and reduced iron uptake. TfR mRNA, on the other hand, is 
rendered unstable, affecting the translation and synthesis of the protein. Iron regulates 
the function of IRP1, which is also capable of functioning as an isoform of cytoplasmic 
aconitase. According to Gourley et al. (2003), there is an assembly of [4Fe-4S] clusters 
taking place in a condition in which iron is presented that reduces the affinity of IRP1 
for the IRE. However, there is a disassembly of the [4Fe-4S] cluster in iron deficiency 
conditions. Thus, IRP1 has a strong affinity for the IRE, therefore, can easily bind IRE, 
47  
functioning as a DNA-binding protein. Unlike IRP 1, IRP2 does not have those [4Fe- 
4S] clusters and its regulation by iron occurs through degradation by proteasomes. In 
addition, ferritin is also a major predictor of iron absorption from meals. Hunt et al. 
(2010) reported that ferritin is entitled to at least 60 % of the variability in iron 
absorption from non-heme sources by affecting absorption by 10-15 folds. According 
to Armah et al. (2013), ferritin influences 35 % of the variability in non-heme iron 
absorption from whole diets. In contrast, Reddy et al. (2000) reported that ferritin 
accounted for 32 % of the variability in non-heme iron absorption. Ferritin is also said 
to be inversely related to iron absorption because as iron stored increases, the 
absorption of non-heme iron decreases and vice versa (Cook et al., 1991). 
 
 
 
b) The Role of Hepcidin in Iron Metabolism 
 
Hepcidin is an antimicrobial hormonal peptide, considered the main regulator 
of iron absorption. It is important in iron homeostasis, playing a key role in iron 
absorption, recycling and mobilization. Hepcidin is a systemic iron regulatory hormone 
composed of 25-amino acids and is mainly produced by the liver (Zhang et al., 2014). 
Hepcidin regulates iron homeostasis by controlling the iron export protein, ferroportin 
(FPN1) expression and function. FPN1 is a multi-domain transmembrane protein that 
acts as the main exporter of iron from the enterocyte, hepatocytes and macrophages. It 
is known that ferric iron in the diet must first be reduced to ferrous iron for non-heme 
iron absorption. Then, the divalent metal transporter 1 (DMT1) will be able to transport 
iron across the apical membrane into the enterocytes. Once inside the cell, FPN1 
exports the part of newly absorbed iron across the basolateral membrane into 
circulating blood (Abboud and Haile, 2000). Hepcidin has been shown to regulate the 
48  
expression of iron transporter in response to iron deficiency and anaemia conditions. 
Hepcidin is able to adjust iron export from enterocytes into the blood by regulating the 
expression of FPN1 on the basolateral membrane of enterocytes (Ganz and Nemeth, 
2011). According to Nemeth et al. (2004), hepcidin that is circulated can bind to FPN1 
on the plasma membrane to reduce iron influx into the blood in a feedback manner and 
cause the impaired release of iron from macrophages. These results are due to the 
binding of hepcidin to FPN1 which causes FPN1 to be internalized, dephosphorylated 
and degraded. 
Dysregulation of the hepcidin-FPN1 interaction is implicated in anaemia of 
inflammation and chronic disease, and also in the systemic iron overload disease such 
as hemochromatosis, because of the role of hepcidin in regulating iron homeostasis 
(Zhang et al., 2014). Anaemia of inflammation is linked to increased hepcidin levels 
and characterized by a decrease in iron absorption in the intestines and macrophage 
iron release, including an increase in reticuloendothelial iron. During infection or 
inflammation, the concentration of hepcidin is increased. The cytokine IL-6 is 
mentioned to contribute to the stimulation of hepcidin production in inflammation 
(Andrews, 2004). According to Steinbicker and Muckenthaler (2013), hepcidin is an 
acute-phase protein and the increased production of hepcidin is mediated by 
lipopolysaccharides (LPS) and cytokines mainly interleukin- 6 (IL-6). LPS may 
mediate hepcidin production by inducing endoplasmic reticulum stress and activating 
C-AMP responsive element binding protein H (CREBH) (Kroot et al., 2011). 
Hemochromatosis is a type of disorder mainly caused by insufficient production of 
hepcidin by the hepatocytes. It is characterized by inappropriately low levels of 
hepcidin and increased intestinal iron absorption and iron release from macrophages. 
49  
This condition leads to tissue iron accumulation and organ dysfunction mediated by 
iron due to an expanded circulating iron pool (Beutler, 2007). 
 
 
 
2.3.6 Iron Utilization and Recycling 
 
Mitochondria have been assigned crucial roles in the metabolism of iron 
because they assemble iron-sulfur (Fe-S) protein clusters, act as the site for heme 
synthesis, and participate in most of intracellular iron metabolism (MacKenzie et al., 
2008). Fe-S clusters are protein cofactors found in the mitochondria, nucleus and 
cytosol that participate in catalytic and regulatory processes in electron transport, 
tricarboxylic acid (TCA) cycle, amino acid biosynthesis and DNA replication and 
repair and the regulation of gene expression (Lill et al., 2012). The efficiency of Fe-S 
cluster synthesis is important to assist the cell in regulating iron homeostasis and 
maintaining proper intracellular iron distribution. Additionally, the synthesis of heme 
occurs mainly in developing red blood cells in the marrow, with a small fraction, 
approximately 15 %, occurring in the liver. The synthesized heme is incorporated into 
haemoglobin and other hemoproteins. The biosynthesis of heme occurs in the following 
four steps. Firstly, the formation of the pyrrole; secondly, assembly of the tetrapyrole, 
followed by modification of the tetrapyrole sidechains; and the final step in the heme 
biosynthetic pathway is the formation of protoporphyrin IX and insertion of iron 
(Ajioka et al., 2006). The insertion of iron into protoporphyrin IX is catalyzed by 
ferrochelatase (FECH). Ferrochelatase known as heme synthase is an Fe-sulfur protein 
located in the inner mitochondria membrane. 
50  
Macrophages are important in iron metabolism and recycling. Red pulp 
macrophages (RPMs) in the spleen, central nurse macrophages (CNMs) in bone 
marrow, and Kupffer cells (KCs) in the liver are the tissue macrophages responsible 
for iron recycling. After phagocytosis, they use heme oxygenase to catabolize the heme 
from senescent and damaged erythrocytes, releasing the iron. Macrophages retrieve 
iron for haemoglobin production. They are able to recycle 90-95% of bodily iron while 
also efficiently maintaining erythropoiesis. For example, haemoglobin production 
needs approximately 20 mg of iron per day, and iron recycling contributes significantly 
to daily iron demand (Steinbicker and Muckenthaler, 2013). The significant amount of 
iron gained through haemoglobin degradation is recycled by iron recycling 
macrophages, and also recycle other used-up cells into iron that can be used in 
hemoglobin synthesis, such as producing new erythrocytes (Kong et al., 2008). Most 
of the iron homeostasis and trafficking is contributed by these specialized macrophage 
functions. 
51  
2.4 Function of Iron 
 
Iron is essential for oxygen transport as well as the respiratory chain. 
Several of its functions are associated with its role in heme biosynthesis. Heme is 
made up of a ferrous iron that is inserted inside a protoporphyrin ring, which is 
made up of four pyrrole rings. It is an essential part of haemoglobin, which is 
necessary for the transportation of carbon dioxide and oxygen throughout the 
circulatory system. Haemoglobin, a tetrametric protein made up of four polypeptide 
chains (2 alpha and 2 beta globin chains), is found mostly in erythrocytes. It 
transports oxygen from the lungs to the tissues and carbon dioxide from the tissues 
back to the lungs. Heme is a cofactor for several enzymes, including catalases and 
peroxidases. It is also a component of cytochromes, which are electron transport 
proteins found mostly in mitochondria and perform significant functions in energy 
metabolism (Liu, 2014 Iron serves a variety of functions outside of cytochromes, 
such as participating in Fe-S clusters. Furthermore, Fe-S clusters are crucial 
components in the respiratory chain. Similar to cytochromes, Fe-S clusters play a 
role in electron transport. They also perform a number of additional biological 
functions, including as activating and binding to substrates, controlling gene 
expression, controlling enzyme activity, and disulfide reduction (Johnson, 2005). 
52  
 
 
 
2.5 Prevalence of Iron Deficiency Anaemia 
 
Iron deficiency anaemia (IDA) is a global health problem and the most 
frequent cause of anaemia in developed and developing countries, including 
Malaysia. According to the National Health and Morbidity Survey (NHMS) of 
2015, the overall occurrence of anaemia was recorded at 24.6%. NHMS 2015 data 
also revealed a higher prevalence of anaemia among women in their reproductive 
years, standing at 34.5% (Awaluddin et al., 2017). This statistic surpassed the 
global estimate of 29% provided by the World Health Organization (WHO, 2015). 
In response, the World Health Assembly aimed to decrease the prevalence of 
anemia among women of reproductive age by 50% by the year 2025 as part of its 
global nutrition objective (WHO. 2014). The study conducted by Loh and Khor 
(2010) stated that the overall prevalence of anaemia was 20.9% while IDA was at 
10.3%, indicating that about 50% of anaemia cases were caused by iron deficiency. 
Haniff et al. (2007), in their multicentre cross-sectional study, found that 
the overall prevalence of anaemia in Kuala Lumpur was 35% (cut-off level at 
11g/dL). The majority was in the mild type and the teenage group had a higher 
incidence, with more cases among Indians followed by Malays and Chinese being 
the least. A cross-sectional study conducted among 178 non-pregnant women aged 
between 18 to 35 years old at Universiti Sains Islam Malaysia discovered ninety- 
nine subjects (55.62%) were found to have Hb levels less than 12 g/dl. Sixty-five 
subjects (36.52%) were found to have ferritin levels of less than 30 ng/ml. The 
IDA prevalence in this study was higher than the previous report among non- 
pregnant females in Malaysia (Nurul, 2017). It has been reported that a moderately 
53  
high prevalence of anaemia is found among infants, young children and women of 
childbearing age. For example, among 490 preschool children in Kelantan, 38.9% 
were iron deficient (Siti Noor et al., 2006). 
Anaemia in pregnancy is one of the major public health problems in 
developing countries. More than half of the pregnant women in developing 
countries are estimated to be anaemic, which is 52% compared to 23% in 
industrialized countries. WHO reported that about 10.8 million in Africa, 9.7 
million in Western Pacific and 24,8 million pregnant women in South East Asia are 
anaemic. In Kelantan, Hassan et al. (2005) reported that 21.2% of women attending 
the antenatal clinic had IDA. A larger study conducted in Kuala Lumpur found that 
1066 of 73,048 pregnant women attending the antenatal clinic were anaemic and 
35% were associated with IDA (Loh, 2010). Haniff et al. (2007) reported that the 
prevalence was greater among pregnant women in the third trimester, especially 
from the urban residential areas and the prevalence showed an increasing trend with 
ongoing pregnancy. 
54  
2.5.1 Causes of Iron Deficiency 
 
a) Nutritional Factor 
 
The human body regularly gets iron from the foods consumed on a daily 
basis. If too little iron is consumed, over time human body can become iron 
deficient. Examples of iron-rich foods include red meat, eggs, leafy green 
vegetables and iron-fortified foods. For proper growth and development, infants 
and children need iron from their diets too. Nutritional iron deficiency (ID) occurs 
when physiological requirements cannot be fulfilled by iron absorption from diet 
supplies. Researchers also suggested a method of selective plant breeding and 
genetic engineering to improve dietary iron nutritional quality. Iron deficiency in 
the population can be controlled through targeted iron supplementation, iron 
fortification of foods, or both (Zimmermann & Hurrell, 2007). Insufficient 
bioavailable iron could be lost from the gastrointestinal tract and skin, in the urine, 
and through menstruation (Lynch, 2011). 
 
 
 
b) Blood Loss 
 
Red blood cells in the blood contain iron, thus, if a person loses blood, their 
iron level will drop. Due to their prolonged and substantial blood loss, women who 
have heavy menstrual cycles are more likely to develop iron deficiency anaemia. 
Iron deficiency anaemia can also be brought on by slow, ongoing blood loss within 
the body, such as caused by colorectal cancer, peptic ulcers, hiatal hernias, colon 
polyps, or other conditions. Aspirin is frequently used as an over-the-counter pain 
medication, and also can cause gastrointestinal bleeding. Johnson-Wimbley and 
55  
Graham (2011) state that patients with intestinal angiodysplasia, for example, who 
have gastrointestinal blood loss that exceeds their ability to absorb iron, may 
develop iron deficiency anaemia that is unresponsive to oral iron supplementation. 
The most common cause of iron-deficiency anaemia is continuous blood loss, 
particularly in older patients  (Warner & Kamran, 2021). 
 
 
 
c) Inability to Absorb Iron 
 
In the human small intestine, iron from the diet is absorbed into the 
bloodstream. Iron deficiency anaemia can be caused by an intestinal problem, such 
as celiac disease, which impairs the intestine's capacity to absorb nutrients from the 
food that has been digested. The majority of ingested nutrients, including lipids, 
carbohydrate and proteins, as well as micronutrients like iron, vitamins, and 
minerals, as well as water and electrolytes, are absorbed in the small intestine. 
Surgery to bypass or remove a portion of the small intestine may impair a patient's 
capacity to absorb iron and other nutrients. Disorders of malabsorption lead to 
decreased iron absorption and develop iron deficiency anaemia (Saboor et al., 
2015). Malabsorption can be caused by premucosal (luminal), mucosal, and 
postmucosal (postabsorptive). Premucosal causes lead to maldigestion, meanwhile, 
mucosal and postmucosal conditions are related to actual malabsorption 
(Vaníèková et al., 2012). 
56  
d) Pregnancy 
 
Many pregnant women develop iron deficiency anaemia without iron 
supplements because their iron stores must serve both their own increased blood 
volume and as a source of haemoglobin for the developing foetus. Anaemia in 
pregnancy is more than 20% of the population worldwide, and Garzon et al. (2020) 
claim that this is a significant public health issue. Compared to a woman who is not 
pregnant, pregnant women require more iron. This is due to an exponential rise in 
the amount of iron required to raise plasma volume, produce more red blood cells, 
maintain fetal-placental unit growth, and compensate for iron lost during birth. 
During the start of pregnancy, roughly 40% of women exhibit low or absent iron 
stores, and up to 90% of women have iron reserves of less than 500 mg (Fisher and 
Nemeth, 2017). 
 
 
 
2.6 Pathological Effect of Iron Deficiency Anaemia 
 
a) Cognitive Development 
 
The most frequent nutrient deficiency in children between the ages of 6 and 
24 months is iron insufficiency (ID). This is the period when the brain grows the 
most and numerous neurodevelopmental processes are at their peak. Since this is 
the period when the brain grows the most, getting enough iron in diet is essential at 
this point. Dopaminergic-peptidergic areas have a significant localization of iron 
(globus pallidus, substantia nigra, red nucleus, thalamus, caudate nucleus and 
nucleus accumbens). Iron insufficiency results in lower non-heme iron 
concentrations in the brain and decreases dopamine D2 receptors (Noor Fadzilah, 
57  
2013). The role of iron in the development of the hippocampal and the action of 
neurotransmitters, particularly in the dopaminergic system, is a reason for the 
impact of iron shortage on cognition. 
Another proposed mechanism is connected to the high concentrations of 
iron found in the cerebellum and basal ganglia, which are crucial for motor function 
and play a role in myelin synthesis and maintenance (Lozoff, 2000). A deficiency 
of iron can affect cognitive function and is associated with neurophysiological 
impairments in infants, pre-schoolers and school-age children, adolescents and 
adults. The main cognitive impairments caused by iron shortage include those 
referring to intelligence, sensory perception, and attention span, as well as those 
related to emotions and behaviour, which are frequently directly linked to the 
presence of iron deficiency anaemia (Lobera, 2014). 
Throughout the first two years of life, iron deficiency anaemia (IDA) is 
associated with poor psychomotor development and behavioural abnormalities, 
such as decreased levels of responsiveness to people and stimuli, impatience, and 
inhibition. Several studies show that effects were seen during infancy last for a very 
long time. According to reports, preschoolers who were previously anaemic are less 
energetic, more restrained, and shy than the corresponding controls (Oyarzun, 
1993). Children have been found to have worse fine-hand motions and poorer 
academic achievement (Walter, 2003). Besides, a chronic ID group showed 
significantly lower scores on language, environmental sound perception, and motor 
measures when compared with infants with normal nutritional iron status at 6 
months and 14–18 months (Beltran-Navarro, 2012). 
58  
b) Reduced Work Capacity and Productivity 
 
Poor working ability and reduced work tolerance are two common anaemia 
signs. Those with low iron levels were much less productive than employees with 
normal haemoglobin levels. According to studies examining the connection 
between haemoglobin concentration and work capacity, anaemic individuals have 
lower work tolerance than those with normal haemoglobin concentrations (Gardner 
et al., 1977). The decreased work capacity in anaemic patients may be mostly 
explained by haemoglobin alterations rather than by changes in iron status 
(Edgerton et al., 1981). A very helpful critical overview of the evidence, especially 
the laboratory findings on humans and animals, is provided by Haas and Brownlie 
(2001). The major conclusions are that IDA in humans results in decreased maximal 
physical working capacity and decreased endurance. The majority of laboratory 
investigations on both animals and humans show that IDA lowers aerobic work 
capacity. 
Research also shows that IDA impairs aerobic capacity and endurance. 
Animal and human studies suggested a strong causal relationship between all levels 
of iron deficiency and voluntary physical activity. The connection between anaemia 
and work capacity may be caused by iron's involvement in energy production. The 
respiratory chain, which involves the transport of oxygen, and numerous enzymes, 
all contain iron. Hemoglobin, which contains iron and is a component of red blood 
cells, is essential for carrying oxygen from the lungs to the body's tissues. Another 
iron-containing protein called myoglobin, found in the cytoplasm of muscle cells, 
aids in the transport of oxygen to the mitochondria. Iron is necessary for the electron 
59  
transfer chain-related cytochromes in mitochondria and enzymes like 
dehydrogenases that oxidize substrates (Haas & Brownlie, 2001). 
c) Adverse Pregnancy Outcome 
 
One of the main causes of anaemia in infants and young children is iron deficiency 
during pregnancy. The last trimester of pregnancy is when pregnant women are 
most at risk for anaemia and iron deficiency. This happens because iron transfer 
from mother to fetus is supported by an increase in maternal iron absorption during 
pregnancy which is regulated by the placenta (Harris, 1992; Starreveld, 1995). 
Because iron is used for the physiological expansion of the maternal red blood cell 
mass, serum ferritin typically decreases significantly between the 12th and 25th 
week of gestation. During 30 weeks of gestation, the foetus receives the majority 
of the iron, increasing the need for iron. There are more transferrin receptors in the 
placenta when the mother's iron status is low, which allows the placenta to absorb 
more iron. Excessive iron transport to the fetus may be prevented by the placental 
synthesis of ferritin. Poor dietary iron consumption during pregnancy increases the 
risk of iron shortage, especially in the third trimester when the foetus is dependent 
on the mother's iron stores. 
In a recent study, Lin (2018) discovered that pregnant women with anaemia 
had higher rates of polyhydramnios, preterm birth, low birth weight ( 2500 g), 
newborn problems, and NICU hospitalization. Affected mothers frequently 
experience breathing issues, dizziness, exhaustion, palpitations, and problem 
sleeping (Lee et al., 2004). Moreover, they have a higher risk of bleeding, pre- 
eclampsia, and perinatal infections. Besides that, behavioural issues and postpartum 
cognitive impairment were reported (Milman, 2012; Murray-Kolb, 2013). 
60  
Intrauterine growth retardation, preterm, and low birth weight are examples of 
adverse perinatal outcomes that all have high mortality risks, especially in 
impoverished countries (Bhutta et al., 2005). Iron deficiency also has been linked 
to abnormalities in the implantation and growth of the embryo in animals, 
particularly in the development of lungs, heart and brain (Noor Fadzilah, 2013). 
 
 
 
d) Pica 
 
Patients with a rare illness known as pica experience cravings for unhealthy 
substances that pose serious health concerns. A pregnant woman was the first 
recorded case of pica in the sixth century AD (Coltman, 1969). Although the precise 
cause of pica is unknown, iron deficiency is recognized to be strongly linked to the 
condition (Kathula, 2008). Several hypotheses have been postulated to explain pica. 
It was initially described in iron-deficient animals and thought to be a response to 
nutritional deficiencies (Hyslops, 1977). Pica has been seen in men and women of 
all ages and ethnicities, but it is more common in lower socioeconomic levels and 
is most noticeable in people with developmental difficulties (Grotegut et al., 2006). 
Patients in several reported cases of pica have admitted to consuming items such as 
ice cubes, clay, dried spaghetti, chalk, starch, paste, tomatoes, lemons, cigarette 
butts, hair, lead, and laundry starch. (Coltman, 1969; Hackworth and Williams, 
2003; Kushner et al., 2004; Grotegut et al., 2006). Pica causes serious health 
problems that frequently call for medical attention. These patients are at risk for 
metabolic and electrolyte disorders, lead and mercury poisoning, hypokalemia, 
parasitic infections, tooth wear, intestinal blockage, and a variety of gastrointestinal 
issues. (Barker, 2005; Grotegut et al., 2006; Khatula, 2008) 
61  
2.7 Prevention of Iron Deficiency Anaemia 
 
Similar to other nutritional deficiencies, iron deficiency mainly results from 
poverty. It affects a significant percentage of persons in particularly vulnerable 
groups, even in wealthy countries. A wide range of sectors and organizations must 
contribute ideas and resources to provide prevention initiatives, particularly in the 
case of iron shortage. For example, the agriculture, health, commerce, industry, 
education, and communication sectors should be included in any strategy. 
Consecutively, these sectors need to collaborate with communities and non- 
governmental groups. Targeted initiatives should be made to minimize poverty, 
increase access to a variety of meals, enhance health care and sanitation, and 
encourage improved feeding and caring behaviours, particularly in rural areas. They 
are essential components of any health program to enhance nutritional health 
generally but are particularly crucial for the development of the status in the 
Malaysian population. 
62  
a) Dietary Improvement through a Food-Based Approach 
 
The most ideal and long-lasting strategy for reducing micronutrient deficiency is 
an approach that is focused on nutrition. These strategies aim to enhance the dietary 
consumption of micronutrients. Hence, food-based methods should include 
strategies to increase the year-round availability of micronutrient-rich foods, 
guarantee that households, particularly those at risk, have access to these foods, and 
alter feeding habits. The ability of these food-based approaches to provide a variety 
of nutritional advantages is one of the greatest strengths. These advantages can 
therefore result in both immediate impact and long-term sustainability. Food 
production, preservation, processing, marketing, and preparation should appear 
first in actual food-based systems. Secondly, they should address feeding practices, 
such as intra-family food distribution and care for vulnerable groups. 
In order to combat iron deficiency, initiatives should be made to increase 
access to and availability of foods high in iron. Organs and flesh of cattle, birds, 
fish, and poultry, as well as non-animal foods such as legumes and cruciferous 
vegetables, are some examples. The focus should be on meals that improve iron 
absorption or utilization. Examples include those of animal origin and non-animal 
foods - such as some fruits, vegetables, and tubers - that are good sources of 
vitamins A and C and folic acid. Finally, to boost the demand for and consumption 
of such foods, effective nutrition education may be required. This includes 
providing information on health and nutrition for both supply and demand aspects 
of programs. 
Because there is limited information available about the amounts of 
phytates and iron-binding polyphenols in various diets, it is difficult to interpret 
63  
iron bioavailability. Such information is vitally required to promote healthy food 
choices among consumers. The age of the target group, seasonal availability, and 
other factors that affect food intake and meal patterns should all be considered when 
making recommendations. It should be highlighted that without additional data on 
meal composition and eating habits, food-frequency surveys are not a reliable 
source from which to determine a person's predicted iron status. The bioavailability 
of iron is influenced by the techniques used in food preparation and processing. All 
inositol phosphates reduce the ability of the body to absorb iron in proportion to the 
total number of phosphate groups; therefore, processing procedures that lower the 
number of phosphate groups improve the bioavailability of non-haem iron. 
Building food-based approaches around the needs and activities of women 
can be especially effective. This is important because women play multiple 
responsibilities, including being the primary carers and providers of food. For 
example, encouraging home gardens and small animal husbandry, as well as 
advancing technologies for food preservation and home or community processing, 
can be particularly helpful in improving iron status. These approaches are 
strengthened by initiatives to increase women's income and by improved nutrition 
education. The major objective of dietary modification is to enhance and maintain 
the iron status of a population, involves behavioural changes that increase the 
selection of foods that are rich in iron and result in meal patterns that are favourable 
to increased bioavailability. Although sometimes difficult to achieve, such changes 
in dietary habits can bring about important sustainable improvements, not only in 
iron status but also in nutrition in general. 
64  
b) Iron Supplementation 
 
According to the authors of a study on the impact of ID on children's 
cognitive development, the effectiveness of short-term iron therapy in anaemic 
children under the age of two is debatable (Grantham-McGregor, 2001). Iron 
treatment appears to be more helpful for anaemic children older than two years of 
age. Regarding the behavioural issues linked to ID, it appears that early iron 
supplementation of infants with moderately low birth weight has no effect on 
cognitive skills at age 3.5 years but significantly reduces the prevalence of 
behavioural issues (Lobera, 2014). For other authors, iron seems to have a modest 
effect on linear growth in deficient populations. The effects of iron supplementation 
on immunological function, physical performance, thermoregulation, cognition, 
and restless leg syndrome have been observed (Lobera, 2014). These effects are 
independent of an increase in haemoglobin. Considering the cognitive functions, 
the point is whether improvement can be achieved through iron supplementation. 
The advantages of iron supplementation in an urban population of 
nonanemic, iron-deficient adolescent girls were documented by Bruner et al. in 
1996. The addition of iron supplements enhanced verbal learning and memory. 
Another study found that the decreased cognitive performance in healthy formerly 
iron-deficient children may persist even after iron therapy (Lobera, 2014). The 
scientists hypothesized that long-lasting changes in myelination and energy 
metabolism, perhaps especially in the hippocampus, might account for these long- 
term effects on an important aspect of human cognitive development. 
Devaki et al. (2007) evaluated two groups of teenagers (nonanemic ID and 
iron-deficient anaemic) after 8 months of iron supplementation. Cognitive function 
65  
and academic performance significantly improved as a result of the 
supplementation. Ebenezer et al. (2013) reported that there is no significant impact 
on concentration levels and test scores in a shorter follow-up trial with 6 months of 
iron supplementation. When contrasting anaemic children with children who are 
iron-rich, it appears that anaemic youngsters develop their motor skills more 
quickly. In contrast to iron-sufficient children, children with ID appear to have a 
dose-response relationship between haemoglobin and cognitive function, which has 
not been observed in those without ID. 
In a study by Christian et al. (2010), it was found that prenatal iron/folic 
acid supplementation was favourably associated with fine motor performance in 
offspring in a region where ID was common. Friel et al. (2018) administered an 
iron supplement to breastfed infants aged 1–6 months. Regarding the development 
impacts, that supplementation resulted in improved developmental indices and 
visual acuity at 13 months of age. After controlling for background factors, children 
with severe, chronic ID in infancy demonstrated poorer motor functioning, written 
expression, mathematics achievement, and some particular cognitive processes 
(spatial memory, selective recall, and tachistoscopic threshold), and this occurred 
10 years after treatment. 
Children between the ages of 16 and 24 months who had received iron in a 
timely manner performed better on neurodevelopmental tests, according to 
Matiashvili et al. (2012). There have been some reports of cognitive function gains 
in preschoolers following iron supplementation. According to Landim et al. (2016), 
feeding low-income preschoolers cookies supplemented with heme iron may boost 
their cognitive development. Moreover, after iron supplementation in children, 
66  
Pollitt (2001) observed improvement in cognitive brain function. Young children 
with IDA have been found to benefit from iron treatment in the short term in terms 
of their mental or psychomotor development, but the impact of longer-term 
treatment is yet unknown. In addition, supplementing with a combination of iron 
and folic acid tends to improve young teenage girls' cognitive abilities (Thompson 
et al., 2013). 
 
 
 
2.8 Beneficial Effect of Date Palm on Iron Deficiency Anaemia 
 
Numerous scientific studies reported that date fruit is a good source of many 
nutrients and are able to alleviate symptoms of IDA (Alfe´reza et al., 2006; Abdel 
Rahman, 2006; Onuh et al., 2012). The date palm has been shown to be rich in iron 
(Eldaim & Elnadi, 2014) and was reported can increase the haemoglobin level in 
rats (Onuh et al., 2012; Zen et al., 2013). Date palm also has been described as a 
major source of iron among fruits and berries (Sahari et al., 2007). Date fruit has 
huge potential in maintaining human health due to its properties as energy-rich food 
and a source of a variety of beneficial minerals (Al Farsi et al., 2005). It is also a 
significant source of dietary fibres, essential vitamins and minerals (Al Shahib & 
Marshall, 2003). Moderate concentrations of manganese, iron, phosphorus and 
calcium per 100 g of dates provide over 7% of the daily requirement (Al-Farsi & 
Lee, 2008). Consumption of date palm would contribute significantly to the daily 
requirement of many of these components, such as carbohydrates and minerals (Fe, 
Mg, Ca, Zn, P, Cu, Se, I, etc.) and provides reasonable amounts of vitamins such 
as niacin, B6, and folate (Vayalil, 2012). Therefore, daily consumption of dates can 
67  
be a good alternative for the treatment of deficiency-related diseases, particularly 
anaemia. 
 
 
 
2.9 Beneficial Effect of Goat Milk on Iron Deficiency Anaemia 
 
The children who consumed goat milk gained more weight, height, skeletal 
mineralization, and blood serum contents of vitamin A, calcium, thiamin, 
riboflavin, niacin and haemoglobin as compared to those who consumed cow milk 
suggesting that goat milk supplies adequate amounts of vitamin A, thiamine, 
riboflavin and pantothenic acid (Díaz-Castro et al., 2015). Park (2006) reported that 
goat milk is deficient in iron, vitamin B6, B12, C, D, and folic acid compared to 
cow milk. Alfereza et al., (2006) demonstrated that milk and other dairy products 
obtained from cows, being rich in calcium, interfere with the absorption of Fe from 
the diet. However, recent studies have found that goat milk does not only increase 
Fe bioavailability in anemic rats but also minimizes the interference of Fe 
absorption by improving the metabolic and digestion of Ca and also minimizes the 
possible interactions of Fe with other minerals such as Ca, P and Mg, in comparison 
with cow milk-fed animals fed (López-Aliaga et al., 2000). 
68  
2.10 Promotion of Alternative Medicine 
 
There is a lack of valid experimental data and scientific design of the efficacy 
of alternative medicine toward human health. These gaps arise mainly due to a lack of 
interest in therapeutic properties hidden in traditional herbs, foods and medicine among 
researchers and leading industries. However, several issues involving side effects of 
conventional treatment involving modern drugs have initiated efforts to find better 
treatments that involve the usage of more effective methods and alternative medicine. 
Therefore, modern researchers and scientists have come up with the idea of disease 
prevention through foods or plant-based and healthy lifestyles. The release of the WHO 
Traditional Medicine Strategy 2002–2005 also plays a major role in the significant 
advances in research regarding the effect of traditional and complementary medicine 
products on health (WHO, 2013). This highlight attracts many researchers in 
developing countries to get involved in this sector supported by the development of 
biotechnology sectors. Traditional and complementary medicine sector now plays a 
significant role in the economic development of a number of countries (WHO, 2013). 
Dates have gained popularity in recent years due to their multiple health benefits; as a 
result, numerous in vitro and animal studies, as well as the identification and 
quantification of several classes of phytochemicals, are being conducted worldwide 
(Vayalil, 2012). The high value of goat milk has also drawn attention to its use as a 
crucial component of human nutrition, according to Clark & Garca (2017).