Malnutrition and Global Determinats

**67**

treatment.

**Chapter 5**

**Abstract**

**1. Introduction**

Malnutrition

*Francisco Javier Ros Forteza*

Wernicke Encephalopathy

in Elderly Related to Severe

Wernicke encephalopathy (WE) is the main neurologic complication of thiamine deficiency. Thiamine is a cofactor for several key enzymes important in energy metabolism. WE is a little-recognised and underdiagnosed condition, and the prevalence in the elderly is unknown. The classic triad of WE includes encephalopathy, oculomotor dysfunction, and gait ataxia. Diagnosis is clinical, and early treatment with thiamine is fundamental in preventing coma and death. In the cases reported in the literature, the cause of WE was fasting or malnutrition in 10.2% of cases. WE may in some cases constitute a public health problem. Being the prevalence unknown, we alert clinicians to keep severe malnutrition in elderly as a form

of precipitation of WE. We review the cases published in the literature.

Wernicke encephalopathy (WE) is the main neurologic complication of thiamine deficiency. Thiamine is a cofactor for several key enzymes important in energy metabolism [1]. Although the chronic alcoholism is recognised as the most common cause of WE, malnutrition has also been less documented [2] generating deprivation of other micronutrients (including in addition to albumin; thiamine; riboflavin; pyridoxine; vitamins B12, E and D; niacin; folate; ferritin; calcium; and magnesium mainly). WE is an acute syndrome characterised by mental confusion, ophthalmoplegia, and gait ataxia (classic triad), but they are not always present which likely leads to under-diagnosis [3]. In chronic alcohol abusers, they have also been used the following four Caine criteria: dietary deficiency, oculomotor abnormalities, cerebellar dysfunction, and either altered mental status or mild memory impairment. Two of the four criteria are sufficient for the diagnosis [4]. Structural diseases of the medial thalamus, hippocampus, or the inferior medial region of the temporal lobe should also be considered due to the similar neuroanatomical involvement to WE. Diagnosis is clinical, and early treatment is fundamental in preventing coma and death. Imaging studies can be helpful but should not delay

**Keywords:** Wernicke encephalopathy, elderly, severe malnutrition,

underdiagnosed condition, thiamine deficiency

#### **Chapter 5**

## Wernicke Encephalopathy in Elderly Related to Severe Malnutrition

*Francisco Javier Ros Forteza*

#### **Abstract**

Wernicke encephalopathy (WE) is the main neurologic complication of thiamine deficiency. Thiamine is a cofactor for several key enzymes important in energy metabolism. WE is a little-recognised and underdiagnosed condition, and the prevalence in the elderly is unknown. The classic triad of WE includes encephalopathy, oculomotor dysfunction, and gait ataxia. Diagnosis is clinical, and early treatment with thiamine is fundamental in preventing coma and death. In the cases reported in the literature, the cause of WE was fasting or malnutrition in 10.2% of cases. WE may in some cases constitute a public health problem. Being the prevalence unknown, we alert clinicians to keep severe malnutrition in elderly as a form of precipitation of WE. We review the cases published in the literature.

**Keywords:** Wernicke encephalopathy, elderly, severe malnutrition, underdiagnosed condition, thiamine deficiency

#### **1. Introduction**

Wernicke encephalopathy (WE) is the main neurologic complication of thiamine deficiency. Thiamine is a cofactor for several key enzymes important in energy metabolism [1]. Although the chronic alcoholism is recognised as the most common cause of WE, malnutrition has also been less documented [2] generating deprivation of other micronutrients (including in addition to albumin; thiamine; riboflavin; pyridoxine; vitamins B12, E and D; niacin; folate; ferritin; calcium; and magnesium mainly). WE is an acute syndrome characterised by mental confusion, ophthalmoplegia, and gait ataxia (classic triad), but they are not always present which likely leads to under-diagnosis [3]. In chronic alcohol abusers, they have also been used the following four Caine criteria: dietary deficiency, oculomotor abnormalities, cerebellar dysfunction, and either altered mental status or mild memory impairment. Two of the four criteria are sufficient for the diagnosis [4]. Structural diseases of the medial thalamus, hippocampus, or the inferior medial region of the temporal lobe should also be considered due to the similar neuroanatomical involvement to WE. Diagnosis is clinical, and early treatment is fundamental in preventing coma and death. Imaging studies can be helpful but should not delay treatment.

#### **2. Malnutrition among the elderly**

Nutrition is a significant determinant of health. Undernutrition presenting as malnutrition is a serious health concern for frail elderly people with many health problems [5].

#### **2.1 Diagnosis of malnutrition**

The following criteria for the diagnosis of malnutrition have been recommended in a consensus statement from the Academy of Nutrition and Dietetics (Academy) and the American Society for Parenteral and enteral Nutrition (ASPEN) [6].

Two or more of the following six characteristics:


#### **2.2 Population at risk**

The people most at risk are the frail elderly and with few or no social and environmental support [5]. These patients may have signs of nutritional deficiency living institutionalised or being hospitalised that can go unnoticed. They are clinical conditions that increase the use of thiamine and may precipitate WE in patients with marginal thiamine reserves such as poor dietary intake, unbalanced nutrition, prolonged intravenous feeding, terminal cancer, and gastrointestinal surgery.

#### **2.3 Epidemiology of malnutrition**

The epidemiology of malnutrition depends on the definition used, although in most studies it refers to the undernutrition concerning weight loss and deficiency of nutritional components. Housebound and institutionalised elderly people have most frequently been shown to be deficient in vitamins A, C, D, B complex, folic acid, and B12 as well as calcium, iron, and zinc [5].

Nutritional deficiencies are ranked in the top 20 leading worldwide disease and disability burden in 2016, according to the Institute of Health Metrics Evaluation [7].

The prevalence of malnutrition in hospitalised adults has been extensively reported in the international literature and varies between 13 and 78% among acute-care patients [8]. The vulnerability in data may be due to terminology used, the diagnostic criteria, and variations in communities.

#### **2.4 Aetiology of malnutrition**

In examining the aetiology of malnutrition, we must consider risk factors that could cause the condition or exacerbate the underlying cause. Morley [9] has

**69**

*Wernicke Encephalopathy in Elderly Related to Severe Malnutrition*

developed a mnemonic *meals-on-wheels* for identifying potentially treatable causes

Medications; emotional problems (depression); anorexia nervosa (tardive) and abnormal attitudes to food; late-life paranoia; swallowing problems; oral problems; no money (especially those on fixed incomes); wandering and other dementiarelated behaviours; hyperthyroidism; hyperparathyroidism; entry problems (malabsorption); eating problems (physical and cognitive); low-salt, low-cholesterol

We know that malnutrition can lead to a weak immune system, which increases the risk of infections, a muscle weakness, a decreased bone mass, a higher risk of

According to Saunders J et al., 2011, the most relevant consequences of malnutrition on health include increased risk of infections, functional decline, delayed wound healing, cognitive decline, impaired respiratory function, muscle weakness and depression, delayed recovery from acute illness, and increased mortality [10].

• Potentially toxic food compounds that may contribute to neurological disor-

Thiamine (vitamin B1), as thiamine pyrophosphate (TPP), is an essential coenzyme in several important energy yielding reactions, including the transketolase

We cognize that the recommended daily allowance for an adult is 1.1 mg/dl and the current UK recommended nutrient intake for elderly people is 0.4 mg of thiamine per 1000 kcal [11]. Also, there is evidence that subclinical thiamine deficiency

The reported prevalence in the UK ranges from 8 to 31% for elderly people living at home and from 23 to 40% for those in nursing homes [13]. Biochemical thiamine deficiency has also been reported in 48% of patients admitted to an acute

Alcoholism is the most common cause of thiamine depletion in developed countries. Alcohol interferes with the active intestinal transport of vitamin B1. In chronic hepatopathy, the ability to store thiamine and transform it into its active form is diminished. The affinity of transketolase for thiamine pyrophosphate may be genetically decreased in some people, which predispose them to WE. A diet rich in carbohydrates or the administration of serum glucose in a patient with masked deficiency of vitamin B1 precipitates or aggravates EW, even to death. Thiamine reserves do not exceed 3 weeks, so it is not difficult to present a deficit in acute situations (e.g. post-surgery status, prolonged hospitalisation in intensive care unit,

*DOI: http://dx.doi.org/10.5772/intechopen.89997*

of malnutrition (adapted from Morley):

diets; and shopping (food availability).

hospitalisation, and an increased risk of death.

**3. Thiamine deficiency in elderly people**

reaction in the pentose phosphate pathway.

may contribute to anorexia in the elderly [12].

**3.1 Thiamine deficiency in developed countries**

**2.6 Neurological disorders associated with malnutrition**

• Neurological disorders caused by nutrient deficiency (**Table 1**)

**2.5 Consequences of malnutrition**

ders (**Table 2**)

geriatric unit [13].

hunger strikes, etc.) [14].

*Wernicke Encephalopathy in Elderly Related to Severe Malnutrition DOI: http://dx.doi.org/10.5772/intechopen.89997*

developed a mnemonic *meals-on-wheels* for identifying potentially treatable causes of malnutrition (adapted from Morley):

Medications; emotional problems (depression); anorexia nervosa (tardive) and abnormal attitudes to food; late-life paranoia; swallowing problems; oral problems; no money (especially those on fixed incomes); wandering and other dementiarelated behaviours; hyperthyroidism; hyperparathyroidism; entry problems (malabsorption); eating problems (physical and cognitive); low-salt, low-cholesterol diets; and shopping (food availability).

#### **2.5 Consequences of malnutrition**

*Malnutrition*

**2. Malnutrition among the elderly**

Two or more of the following six characteristics:

**2.1 Diagnosis of malnutrition**

• Insufficient energy intake.

• Loss of muscle mass.

**2.2 Population at risk**

• Loss of subcutaneous fat.

**2.3 Epidemiology of malnutrition**

**2.4 Aetiology of malnutrition**

acid, and B12 as well as calcium, iron, and zinc [5].

the diagnostic criteria, and variations in communities.

Nutrition is a significant determinant of health. Undernutrition presenting as malnutrition is a serious health concern for frail elderly people with many health problems [5].

The following criteria for the diagnosis of malnutrition have been recommended in a consensus statement from the Academy of Nutrition and Dietetics (Academy) and the American Society for Parenteral and enteral Nutrition (ASPEN) [6].

• Weight loss (according to Zawada, 1996) is considered to be clinically significant with the following parameters: >2% decrease of baseline body weight in

• Localised or generalised fluid accumulation that may mask weight loss.

The people most at risk are the frail elderly and with few or no social and environmental support [5]. These patients may have signs of nutritional deficiency living institutionalised or being hospitalised that can go unnoticed. They are clinical conditions that increase the use of thiamine and may precipitate WE in patients with marginal thiamine reserves such as poor dietary intake, unbalanced nutrition, prolonged intravenous feeding, terminal cancer, and gastrointestinal surgery.

The epidemiology of malnutrition depends on the definition used, although in most studies it refers to the undernutrition concerning weight loss and deficiency of nutritional components. Housebound and institutionalised elderly people have most frequently been shown to be deficient in vitamins A, C, D, B complex, folic

Nutritional deficiencies are ranked in the top 20 leading worldwide disease and disability burden in 2016, according to the Institute of Health Metrics Evaluation [7]. The prevalence of malnutrition in hospitalised adults has been extensively reported in the international literature and varies between 13 and 78% among acute-care patients [8]. The vulnerability in data may be due to terminology used,

In examining the aetiology of malnutrition, we must consider risk factors that could cause the condition or exacerbate the underlying cause. Morley [9] has

• Diminished functional status as measured by handgrip strength.

1 month; >5% decrease in 3 months, or > 10% in 6 months.

**68**

We know that malnutrition can lead to a weak immune system, which increases the risk of infections, a muscle weakness, a decreased bone mass, a higher risk of hospitalisation, and an increased risk of death.

According to Saunders J et al., 2011, the most relevant consequences of malnutrition on health include increased risk of infections, functional decline, delayed wound healing, cognitive decline, impaired respiratory function, muscle weakness and depression, delayed recovery from acute illness, and increased mortality [10].

#### **2.6 Neurological disorders associated with malnutrition**


#### **3. Thiamine deficiency in elderly people**

Thiamine (vitamin B1), as thiamine pyrophosphate (TPP), is an essential coenzyme in several important energy yielding reactions, including the transketolase reaction in the pentose phosphate pathway.

We cognize that the recommended daily allowance for an adult is 1.1 mg/dl and the current UK recommended nutrient intake for elderly people is 0.4 mg of thiamine per 1000 kcal [11]. Also, there is evidence that subclinical thiamine deficiency may contribute to anorexia in the elderly [12].

The reported prevalence in the UK ranges from 8 to 31% for elderly people living at home and from 23 to 40% for those in nursing homes [13]. Biochemical thiamine deficiency has also been reported in 48% of patients admitted to an acute geriatric unit [13].

#### **3.1 Thiamine deficiency in developed countries**

Alcoholism is the most common cause of thiamine depletion in developed countries. Alcohol interferes with the active intestinal transport of vitamin B1. In chronic hepatopathy, the ability to store thiamine and transform it into its active form is diminished. The affinity of transketolase for thiamine pyrophosphate may be genetically decreased in some people, which predispose them to WE. A diet rich in carbohydrates or the administration of serum glucose in a patient with masked deficiency of vitamin B1 precipitates or aggravates EW, even to death. Thiamine reserves do not exceed 3 weeks, so it is not difficult to present a deficit in acute situations (e.g. post-surgery status, prolonged hospitalisation in intensive care unit, hunger strikes, etc.) [14].


*Source: Diop et al. [15] (completed by Ros Forteza).*

**Table 1.**

*Neurological disorders caused by nutrient deficiency.*

#### **3.2 Wernicke encephalopathy**

For WE and Korsakoff syndrome (KS), there are the acute phase and the residual state, respectively, of the same pathological process. Both are the result of thiamine deficiency.

It can occur at any age, and although it is more frequent in men, women are more susceptible [1].

Thiamine has an important role in catabolism of carbohydrates and neurotransmitter formation. Its utilisation depends on the individual's metabolic rate, increasing with a higher energy requirement [16].

In the gastrointestinal tract, this nutrient is actively absorbed at the duodenum level and then transported through the blood–brain barrier by passive and active processes [17].

**71**

cell death [18].

*Wernicke Encephalopathy in Elderly Related to Severe Malnutrition*

*Lathyrus sativus* Spastic paraparesis (lathyrism)

*Potentially toxic food compounds that may contribute to neurological disorders.*

**Food compound Potential neurological disorder when ingested**

myopathy, epilepsy

In its biologically active form (thiamine pyrophosphate), it is an essential coenzyme for various enzymes of catabolism of glucose-6-phosphate, such as transketolase, pyruvate dehydrogenase, and α-ketoglutarate dehydrogenase [17, 18]. The first enzyme participates in the pentose-phosphate pathway, and its catalytic activity results in reduced ribose-5-phosphate and nicotinamide adenosine dinucleotide (NADPH) molecules. Both are crucial in the synthesis of various other compounds (e.g. nucleic acids and glutathione), and any cell requires optimal levels of these enzymes. The other two enzymes catalyse glycolysis and Krebs cycle reactions, respectively. These metabolic pathways result in the formation of adenosine triphosphate (ATP) molecules, vital in providing energy for cell metabolism. Low levels of mentioned enzymes lead to lower energy synthesis and

Alcohol Fetal alcohol syndrome, retarded mental development in childhood,

Konzo (tropic ataxic neuropathy)

delirium, cerebral atrophy, dementia, Wernicke encephalopathy, Korsakoff syndrome, visual problems (amblyopia), ataxia, peripheral neuropathy,

As thiamine reserves (30–50 mg) do not exceed 3 weeks, it is not difficult for a deficit to occur in acute situations. In some cases, low levels of magnesium, an essential cofactor of thiamine into its active diphosphate and triphosphate forms,

Only a subset of thiamine-deficient alcohol abusers develop WE. Investigators have found that in alcohol abusers with WE, the thiamine-dependent enzyme transketolase has an altered affinity for thiamine. Variants in the high affinity thiamine

The classic triad of WE includes encephalopathy, oculomotor dysfunction, and gait ataxia; these were recognised in only one-third of patients. The encephalopathy is characterised by profound disorientation, indifference, and inattentiveness. The ocular signs consist of nystagmus that is both horizontal and vertical and mainly evoked by gaze; this is the most common feature, weakness, or paralysis of the lateral rectus muscles and weakness or paralysis of conjugate gaze. Usually there is some combination of these abnormalities, according to Adams and Victor's, 2014. Ataxia primarily involves stance and gait and is likely due to a combination of polyneuropathy, cerebellar involvement, and vestibular dysfunction [1].

In one study of 106 autopsied alcohol abusers, the Caine criteria (two of four being enough: dietary deficiency, oculomotor abnormalities, cerebellar dysfunction, either altered mental status or mild memory impairment) increased the diagnostic sensitivity for WE from 22% using the classic triad to 85% [4].

Other signs in patients with WE may also be present as vestibular dysfunction without hearing loss; the presence of spontaneous nystagmus with absent caloric responses appears to be a relatively specific finding in WE [21]. Additionally, peripheral neuropathy, hypothermia, and cardiovascular signs and symptoms such as tachycardia, exertional dyspnoea, elevated cardiac output, and EKG abnormali-

ties can be detected [1]. These reverse with thiamine administration.

have been implicated with thiamine deficiency in WE [19].

transporter gene have also been implicated [20].

*DOI: http://dx.doi.org/10.5772/intechopen.89997*

Cyanogenic glucosides from insufficiently processed

*Source: Diop et al. [15] (completed by Ros Forteza).*

cassava roots

**Table 2.**

*Wernicke Encephalopathy in Elderly Related to Severe Malnutrition DOI: http://dx.doi.org/10.5772/intechopen.89997*


#### **Table 2.**

*Malnutrition*

**Macronutrients**

Vitamins

Vitamin B6 (pyridoxine)

Vitamin B12 (cobalamin)

Vitamin D3 (cholecalciferol)

Vitamin E (alpha-tocopherol)

**Minerals**

Total energy 2200

Vitamin B3 (niacin) 15 mg

**Nutrient RDA\* Neurological disorder when deficient**

In childhood: long-term mental deficit

Pellagra including dementia and depression. Neuropsychiatric

dysfunction in children and elderly. Neuropsychiatric disorders.

growth retardation, deaf-mutism, and physical disability).

1.6 mg Polyneuropathy. neuropsychiatric disorders including seizures, migraine, chronic pain, and depression

2.0 μg Progressive myelopathy with sensory disturbances in the legs. Ataxia. Dementia. Neuropsychiatric disorders

Increased vascular risk (in hyper-homocysteine)

Decrease in IQ and lower school performance

abnormalities, and depression. Visual disturbances

10 mg Ataxia, myopathy, retinopathy/ophthalmoplegia

Folate 180 μg Neural tube defects (myelomeningocele) of the fetus, cognitive

Iodine 150 μg Iodine deficiency disorders: Cretinism (severe mental retardation,

Vitamin B1 (thiamine) 1.1 mg Beriberi, polyneuropathy, Wernicke encephalopathy, Korsakoff syndrome

disorders

5 μg Myopathy

Iron 15 mg Delayed mental development in children

Selenium 55 mg Adverse mood states, myopathy

Zinc 12 mg Delayed motor development in children, behavioural

Manganeso 2 mg Behavioural and memory abnormalities. Seizures

Magnesium 400 mg Behavioural, sleep, and memory abnormalities. Tremor and

weakness. Depression. Seizures

(kcal)

Vitamin A 600 μg Night-blindness

NE

**70**

*\**

**Table 1.**

**3.2 Wernicke encephalopathy**

*Recommended daily allowance for an adult. Source: Diop et al. [15] (completed by Ros Forteza).*

*Neurological disorders caused by nutrient deficiency.*

ing with a higher energy requirement [16].

thiamine deficiency.

more susceptible [1].

processes [17].

For WE and Korsakoff syndrome (KS), there are the acute phase and the residual state, respectively, of the same pathological process. Both are the result of

It can occur at any age, and although it is more frequent in men, women are

Thiamine has an important role in catabolism of carbohydrates and neurotransmitter formation. Its utilisation depends on the individual's metabolic rate, increas-

In the gastrointestinal tract, this nutrient is actively absorbed at the duodenum level and then transported through the blood–brain barrier by passive and active

*Potentially toxic food compounds that may contribute to neurological disorders.*

In its biologically active form (thiamine pyrophosphate), it is an essential coenzyme for various enzymes of catabolism of glucose-6-phosphate, such as transketolase, pyruvate dehydrogenase, and α-ketoglutarate dehydrogenase [17, 18]. The first enzyme participates in the pentose-phosphate pathway, and its catalytic activity results in reduced ribose-5-phosphate and nicotinamide adenosine dinucleotide (NADPH) molecules. Both are crucial in the synthesis of various other compounds (e.g. nucleic acids and glutathione), and any cell requires optimal levels of these enzymes. The other two enzymes catalyse glycolysis and Krebs cycle reactions, respectively. These metabolic pathways result in the formation of adenosine triphosphate (ATP) molecules, vital in providing energy for cell metabolism. Low levels of mentioned enzymes lead to lower energy synthesis and cell death [18].

As thiamine reserves (30–50 mg) do not exceed 3 weeks, it is not difficult for a deficit to occur in acute situations. In some cases, low levels of magnesium, an essential cofactor of thiamine into its active diphosphate and triphosphate forms, have been implicated with thiamine deficiency in WE [19].

Only a subset of thiamine-deficient alcohol abusers develop WE. Investigators have found that in alcohol abusers with WE, the thiamine-dependent enzyme transketolase has an altered affinity for thiamine. Variants in the high affinity thiamine transporter gene have also been implicated [20].

The classic triad of WE includes encephalopathy, oculomotor dysfunction, and gait ataxia; these were recognised in only one-third of patients. The encephalopathy is characterised by profound disorientation, indifference, and inattentiveness. The ocular signs consist of nystagmus that is both horizontal and vertical and mainly evoked by gaze; this is the most common feature, weakness, or paralysis of the lateral rectus muscles and weakness or paralysis of conjugate gaze. Usually there is some combination of these abnormalities, according to Adams and Victor's, 2014. Ataxia primarily involves stance and gait and is likely due to a combination of polyneuropathy, cerebellar involvement, and vestibular dysfunction [1].

In one study of 106 autopsied alcohol abusers, the Caine criteria (two of four being enough: dietary deficiency, oculomotor abnormalities, cerebellar dysfunction, either altered mental status or mild memory impairment) increased the diagnostic sensitivity for WE from 22% using the classic triad to 85% [4].

Other signs in patients with WE may also be present as vestibular dysfunction without hearing loss; the presence of spontaneous nystagmus with absent caloric responses appears to be a relatively specific finding in WE [21]. Additionally, peripheral neuropathy, hypothermia, and cardiovascular signs and symptoms such as tachycardia, exertional dyspnoea, elevated cardiac output, and EKG abnormalities can be detected [1]. These reverse with thiamine administration.

Imaging studies should not delay treatment, especially a MRI. However, diagnostic imaging can be helpful by providing evidence of WE in many patients and may rule out alternative diagnoses [20].

Typical findings include lesions surrounding the aqueduct and third ventricle and within the medial thalamus, dorsal medulla, tectal plate, and mammillary bodies. Lesions may also be seen in atypical areas such as the cerebellum, cranial nerve nuclei, dentate nuclei, caudate, red nuclei, splenium, and cerebral cortex. Abnormal T2 signal disappears within as little as 48 h after treatment with thiamine [20]. Mammillary body atrophy is a relatively specific abnormality in patients with chronic lesions of WE [22] and can be detected within 1 week of the onset of WE [23].

There are no laboratory studies that are diagnostic of WE. WE is primarily a clinical diagnosis. WE should be considered in the differential diagnosis of all patients presenting with acute delirium or acute ataxia [20]. Also, structural diseases in the medial thalami, hippocampi, or inferior medial temporal lobes should be considered because of the neuroanatomic overlap with WE. These include topof-the-basilar stroke, hypoxic–ischemic encephalopathy after cardiac arrest, herpes simplex encephalitis, and third ventricular tumours [24, 25].

The diagnosis of WE is difficult to confirm and, when untreated, most patients progress to coma and death. Therefore, diagnostic testing (measurement of biochemical thiamine deficiency [13]) should not delay treatment, which should immediately follow the consideration of the diagnosis [20].

Patients with suspected WE require immediate parenteral administration of thiamine. A recommended regimen is 500 mg of thiamine intravenously, infused over 30 min, 3 times daily for two consecutive days and 250 mg intravenously or intramuscularly once daily for an additional 5 days, in combination with other B vitamins. There are no randomised studies to support a particular dosing regimen. Administration of glucose without thiamine can precipitate or worsen WE; thus, thiamine should be administered before glucose. Subsequently daily 100 mg oral thiamine should be continued until patients are no longer considered at risk [20].

The disappearance of nystagmus and an improvement in ophthalmoparesis within hours or a day of the administration of thiamine confirms the diagnosis. Ataxia recovery begins during the second week, and confusion declines over days and weeks according to Adams and Victor, 2014. MRI resolves with clinical improvement. Only a minority of such patients (fewer than 20% in Victor's series) recover entirely.

#### **4. Wernicke encephalopathy in elderly related to severe malnutrition**

#### **4.1 Justification and literature**

The absence of a nutritional assessment method that can be considered a "gold standard" makes it very difficult to task. Also unfortunately there is no data in the medical records about nutritional evaluation nor in publications outside the field of nutrition, and healthcare professionals receive little education on nutrition. For these reasons all healthcare professionals should be involved and not just the nutritionist in this public health problem.

There are few cases published in the literature of WE in elderly related to malnutrition [26–32].

Magalhães Scoralick et al. describe a case of a 63-year-old man with grade IV chagasic mega oesophagus who developed WE. There was no past of alcohol, and the patient had not received nutritional therapy, and he was not taking a vitamin

**73**

*Wernicke Encephalopathy in Elderly Related to Severe Malnutrition*

discharged on oral thiamine with clinical improvement [30].

supplement. The deficiency of vitamins B1 and B6 was found. The patient recovered from the acute symptoms; however 3 months after his admission, he died [26]. Another case of WE was due to dual deficiency of both thiamine (vitamin B1) and niacin (vitamin A PP) in an 80-year-old woman regular consumer of alcohol

Differently, a case of autopsy-proven acute nonalcoholic thiamine-deficient encephalopathy without medical treatment antemortem. The patient was found dead in his room; he was a 62-year-old man and had BMI 11.7, and vitamin B1 and

On the other hand, other authors report a WE and pellagra in an alcoholic and malnourished patient. He was a 61-year-old man and had a vitamin deficiency of B1 and niacin. Thiamine and nicotinic acid were administered. Finally, the patient was transferred to a rehabilitation facility, where he gained the support of an alcohol

Also the case of a 65-year-old female, nonalcoholic with a 43-Kg weight loss (25% of baseline weight) over several weeks. On admission, she received a continuous intravenous glucose infusion, and 4 days later she developed symptoms suggestive of WE. A brain MRI demonstrated signal change in the medial thalami and mammillary bodies. The patient received intravenous thiamine therapy and was

We highlight a series of five elderly patients whose brain showed typical features of WE at the autopsy. All five were females with a mean age of 67 +/− yearsold. One case was alcoholic, but the other four were nonalcoholics and developed the disease after prolonged malnutrition. WE was diagnosed clinically only in one

We present the case [32] of an 81-year-old autonomous woman with 10 years of schooling and body mass index (BMI) previously of 23.2. There was no history of tobacco and alcohol use. Her medical history included hypertension, acute biliary pancreatitis, and hiatal hernia diagnosed 18 years previously. Her surgical history incorporated cholecystectomy and anti-reflux surgery 15 years previously. She was being treated with candesartan, pantoprazole, domperidone, ursodeoxycholic acid, mirtazapine, mexazolam, and brotizolam. Two to three weeks after an influenza episode, she developed anorexia, dehydration, mental confusion, altered sleep–

On physical examination, the patient showed somnolence, but easily aroused, disorientation in time but not space, incoherent speech, strabismus, persistent horizontal-rotary nystagmus, dysphagia for liquids, and hypotonia. A second head CT scan at 24 h revealed a suspected lacunar stroke of the right tectal plate (**Figure 1A**), requiring examination with brain MRI. A transthoracic echocardiog-

She started treatment with thiamine at high doses (500 mg IV every 8 h for 2 days, 500 mg IV every 24 h for 5 days), then at 100 mg IV every 8 h during the remaining days of hospitalisation, combined with a multivitamin solution [vitamins A, B, H (biotin), and F] and protein-calorie supplementation. We observed a significant clinical improvement, with decreased nystagmus, improved verbal expression, and corrected sleep pattern. A brain MRI

(**Figure 1B**-**G**) performed at day 5 of admission revealed diffuse hyperintensity of the tectum, periaqueductal region, medial thalami, mammillary bodies, and structures adjacent to the diencephalon and cortical convexity with brain

with severe malnutrition; vitamin D and B6 deficits were also found [27].

*DOI: http://dx.doi.org/10.5772/intechopen.89997*

B12 deficits were detected [28].

case [31].

**4.2 Special case report**

abstinence education programme [29].

wake cycle, and visual and gait impairment..

raphy and lumbar puncture had normal results.

atrophy, which were indicative of WE.

#### *Wernicke Encephalopathy in Elderly Related to Severe Malnutrition DOI: http://dx.doi.org/10.5772/intechopen.89997*

supplement. The deficiency of vitamins B1 and B6 was found. The patient recovered from the acute symptoms; however 3 months after his admission, he died [26].

Another case of WE was due to dual deficiency of both thiamine (vitamin B1) and niacin (vitamin A PP) in an 80-year-old woman regular consumer of alcohol with severe malnutrition; vitamin D and B6 deficits were also found [27].

Differently, a case of autopsy-proven acute nonalcoholic thiamine-deficient encephalopathy without medical treatment antemortem. The patient was found dead in his room; he was a 62-year-old man and had BMI 11.7, and vitamin B1 and B12 deficits were detected [28].

On the other hand, other authors report a WE and pellagra in an alcoholic and malnourished patient. He was a 61-year-old man and had a vitamin deficiency of B1 and niacin. Thiamine and nicotinic acid were administered. Finally, the patient was transferred to a rehabilitation facility, where he gained the support of an alcohol abstinence education programme [29].

Also the case of a 65-year-old female, nonalcoholic with a 43-Kg weight loss (25% of baseline weight) over several weeks. On admission, she received a continuous intravenous glucose infusion, and 4 days later she developed symptoms suggestive of WE. A brain MRI demonstrated signal change in the medial thalami and mammillary bodies. The patient received intravenous thiamine therapy and was discharged on oral thiamine with clinical improvement [30].

We highlight a series of five elderly patients whose brain showed typical features of WE at the autopsy. All five were females with a mean age of 67 +/− yearsold. One case was alcoholic, but the other four were nonalcoholics and developed the disease after prolonged malnutrition. WE was diagnosed clinically only in one case [31].

#### **4.2 Special case report**

*Malnutrition*

WE [23].

recover entirely.

**4.1 Justification and literature**

malnutrition [26–32].

nutritionist in this public health problem.

may rule out alternative diagnoses [20].

Imaging studies should not delay treatment, especially a MRI. However, diagnostic imaging can be helpful by providing evidence of WE in many patients and

Typical findings include lesions surrounding the aqueduct and third ventricle and within the medial thalamus, dorsal medulla, tectal plate, and mammillary bodies. Lesions may also be seen in atypical areas such as the cerebellum, cranial nerve nuclei, dentate nuclei, caudate, red nuclei, splenium, and cerebral cortex. Abnormal T2 signal disappears within as little as 48 h after treatment with thiamine [20]. Mammillary body atrophy is a relatively specific abnormality in patients with chronic lesions of WE [22] and can be detected within 1 week of the onset of

There are no laboratory studies that are diagnostic of WE. WE is primarily a clinical diagnosis. WE should be considered in the differential diagnosis of all patients presenting with acute delirium or acute ataxia [20]. Also, structural diseases in the medial thalami, hippocampi, or inferior medial temporal lobes should be considered because of the neuroanatomic overlap with WE. These include topof-the-basilar stroke, hypoxic–ischemic encephalopathy after cardiac arrest, herpes

The diagnosis of WE is difficult to confirm and, when untreated, most patients

Patients with suspected WE require immediate parenteral administration of thiamine. A recommended regimen is 500 mg of thiamine intravenously, infused over 30 min, 3 times daily for two consecutive days and 250 mg intravenously or intramuscularly once daily for an additional 5 days, in combination with other B vitamins. There are no randomised studies to support a particular dosing regimen. Administration of glucose without thiamine can precipitate or worsen WE; thus, thiamine should be administered before glucose. Subsequently daily 100 mg oral thiamine should be continued until patients are no longer considered at risk [20]. The disappearance of nystagmus and an improvement in ophthalmoparesis within hours or a day of the administration of thiamine confirms the diagnosis. Ataxia recovery begins during the second week, and confusion declines over days and weeks according to Adams and Victor, 2014. MRI resolves with clinical improvement. Only a minority of such patients (fewer than 20% in Victor's series)

**4. Wernicke encephalopathy in elderly related to severe malnutrition**

There are few cases published in the literature of WE in elderly related to

Magalhães Scoralick et al. describe a case of a 63-year-old man with grade IV chagasic mega oesophagus who developed WE. There was no past of alcohol, and the patient had not received nutritional therapy, and he was not taking a vitamin

The absence of a nutritional assessment method that can be considered a "gold standard" makes it very difficult to task. Also unfortunately there is no data in the medical records about nutritional evaluation nor in publications outside the field of nutrition, and healthcare professionals receive little education on nutrition. For these reasons all healthcare professionals should be involved and not just the

progress to coma and death. Therefore, diagnostic testing (measurement of biochemical thiamine deficiency [13]) should not delay treatment, which should

simplex encephalitis, and third ventricular tumours [24, 25].

immediately follow the consideration of the diagnosis [20].

**72**

We present the case [32] of an 81-year-old autonomous woman with 10 years of schooling and body mass index (BMI) previously of 23.2. There was no history of tobacco and alcohol use. Her medical history included hypertension, acute biliary pancreatitis, and hiatal hernia diagnosed 18 years previously. Her surgical history incorporated cholecystectomy and anti-reflux surgery 15 years previously. She was being treated with candesartan, pantoprazole, domperidone, ursodeoxycholic acid, mirtazapine, mexazolam, and brotizolam. Two to three weeks after an influenza episode, she developed anorexia, dehydration, mental confusion, altered sleep– wake cycle, and visual and gait impairment..

On physical examination, the patient showed somnolence, but easily aroused, disorientation in time but not space, incoherent speech, strabismus, persistent horizontal-rotary nystagmus, dysphagia for liquids, and hypotonia. A second head CT scan at 24 h revealed a suspected lacunar stroke of the right tectal plate (**Figure 1A**), requiring examination with brain MRI. A transthoracic echocardiography and lumbar puncture had normal results.

She started treatment with thiamine at high doses (500 mg IV every 8 h for 2 days, 500 mg IV every 24 h for 5 days), then at 100 mg IV every 8 h during the remaining days of hospitalisation, combined with a multivitamin solution [vitamins A, B, H (biotin), and F] and protein-calorie supplementation. We observed a significant clinical improvement, with decreased nystagmus, improved verbal expression, and corrected sleep pattern. A brain MRI (**Figure 1B**-**G**) performed at day 5 of admission revealed diffuse hyperintensity of the tectum, periaqueductal region, medial thalami, mammillary bodies, and structures adjacent to the diencephalon and cortical convexity with brain atrophy, which were indicative of WE.

#### **Figure 1.**

*Published with permission of the editor. Source: Ros Forteza et al. [32].* Baseline findings*: (A) head CT at 24 h: Hypodensity in the right tectal plate. (B) Axial T2-weighted MRI sequence. (C) Axial FLAIR MRI sequence: Lesion to the midbrain periaqueductal region. (D) Axial FLAIR MRI sequence: Bilateral thalamic lesions. (E) Axial FLAIR MRI sequence: Tectal lesion. (F) Sagittal T1-weighted MRI sequence: no alterations. (G) Axial FLAIR MRI sequence: Lesion to the superior frontal cortex and pia mater.* Findings at resolution: *(H) axial T2-weighted MRI sequence: Regressing periaqueductal lesion. (I) Axial FLAIR MRI sequence: no thalamic lesion. (J) Axial FLAIR MRI sequence: no bulbar lesion. (K) Axial FLAIR MRI sequence: no lesion to the cortex or pia mater.*

At day 6 of admission, the patient was awake, with no spontaneous verbal response, exotropia of the right eye, and mild horizontal-rotatory nystagmus. Other tests were apparently normal. The BMI was 15.6.

Extensive work-up revealed a decrease in haemoglobin, vitamin B1 (27 ng/mL), vitamin B12, vitamin D, magnesium, sodium, and albumin. Intrinsic factor antibody test and serological test for syphilis yielded negative results.

Thiamine was maintained at 100 mg IV every 8 h; pantoprazole was withdrawn, and ranitidine started at 150 mg at night. The patient also started treatment with oral vitamin B12 at 5 mg/day, cholecalciferol 667 IU/day, magnesium 10 mL/12 h, calcium carbonate 500 mg/12 h, and 0.9% saline solution. During the first 2 weeks of admission, her speech improved, and she was able to produce sentences; nystagmus manifested only at extreme lateral gaze. Ataxic gait was later identified, and she started rehabilitation.

At 1 month of admission, an awake EEG revealed slow background activity, suggesting diffuse brain dysfunction (grades 2–3). From the second month of treatment, our patient presented good general appearance, fluent and coherent speech,

**75**

**4.3 Future perspectives**

*Wernicke Encephalopathy in Elderly Related to Severe Malnutrition*

WE was fasting or malnutrition in 10.2% of cases [33].

recovery was excellent with vitamin supplementation.

lead to vitamin B12 malabsorption [36].

and an MMSE score of 23. The patient participated in craft activities and regular

The neuropsychological evaluation showed that autobiographical memory was preserved. We were able to apply only three subtests of the Wechsler Adult Intelligence Scale (WAIS-III): matrix reasoning, similarities, and digit span; results were higher level, average level, and average level, respectively. No areas of deficit

At 3 months of admission, a brain MRI scan demonstrated complete remission

The age of our patient was atypical with clinical presentation of the classic triad. In this case, WE was caused by severe malnutrition [2]. The patient lost 33% of her body weight, with a BMI of 15.6 [BMI below 16 corresponds to grade 3/severe thinness according to the WHO classifications (1995, 2000)]. Protein-calorie deficiency is not always present; in a review of 625 cases reported in the literature, the cause of

Brain MRI showed typical findings of WE, although this test is more sensitive for detecting WE lesions in non-alcoholic than in alcoholic patients [34]; clinical

Regarding the pathophysiology of these symptoms, thiamine reserves were depleted in 2–3 weeks due to caloric restriction. In the event of thiamine depletion, the function of the thiamine-dependent enzyme systems deteriorates, and blood thiamine levels decrease. This damage occurs 4 days after the onset of thiamine deficiency and eventually progresses to programmed cell death. At 14 days, brain lesions develop [2]. It is probable that some subjects with genetically reduced transketolase activity require higher levels of thiamine and therefore present a higher

Additionally, the low level of magnesium (a thiamine cofactor) also contributed to the genesis of this clinical picture. Many cases of WE may also have magnesium (Mg) depletion, and it is known that in elderly people, Mg intake may be suboptimum. If a depletion of Mg reserve impedes the phosphorylation of thiamine, Mg depletion could have an effect on other enzymes hose activities depending on Mg [35]. Other vitamin deficiencies were vitamin B12 and vitamin D. It is recognised that long-term use of pantoprazole suppresses gastric acid production, which may

This case is special because being the clinical picture of several weeks of evolution, the first diagnostic hypothesis was vertebrobasilar stroke. WE was diagnosed in a context of severe malnutrition little evident in a nonalcoholic patient, despite symptoms (complete classic triad present) and neuroimaging findings being more typical (except alterations of cerebral cortex) of an alcoholic patient [34]. There was also no atrophy of the mammillary bodies, a very specific pathological finding in chronic EW and KS and present in up to 80% of alcoholic patients with a history of EW [37–39]. We propose that WE should be considered in elderly patients with mental status changes of unknown cause and risk for thiamine deficiency, even in nonalcoholic patients. Infusion of thiamine should be started immediately when the disorder is suspected, even in the absence of typical symptoms. With this case, we aim to raise awareness of the need to identify this preventable, treatable, and high-mortality disease.

Nowadays, despite the caloric density, the diet is often of poor nutrition quality and does not meet recommended dietary guidelines for micronutrient intake, mak-

ing this an at-risk population for micronutrient malnutrition [40].

risk of WE in situations of increased demand or lower absorption [34].

*DOI: http://dx.doi.org/10.5772/intechopen.89997*

of the brain lesions (**Figure 1H**–**K**).

rehabilitation sessions.

were identified.

*Malnutrition*

**74**

**Figure 1.**

*to the cortex or pia mater.*

she started rehabilitation.

At day 6 of admission, the patient was awake, with no spontaneous verbal response, exotropia of the right eye, and mild horizontal-rotatory nystagmus. Other

*Published with permission of the editor. Source: Ros Forteza et al. [32].* Baseline findings*: (A) head CT at 24 h: Hypodensity in the right tectal plate. (B) Axial T2-weighted MRI sequence. (C) Axial FLAIR MRI sequence: Lesion to the midbrain periaqueductal region. (D) Axial FLAIR MRI sequence: Bilateral thalamic lesions. (E) Axial FLAIR MRI sequence: Tectal lesion. (F) Sagittal T1-weighted MRI sequence: no alterations. (G) Axial FLAIR MRI sequence: Lesion to the superior frontal cortex and pia mater.* Findings at resolution: *(H) axial T2-weighted MRI sequence: Regressing periaqueductal lesion. (I) Axial FLAIR MRI sequence: no thalamic lesion. (J) Axial FLAIR MRI sequence: no bulbar lesion. (K) Axial FLAIR MRI sequence: no lesion* 

Extensive work-up revealed a decrease in haemoglobin, vitamin B1 (27 ng/mL), vitamin B12, vitamin D, magnesium, sodium, and albumin. Intrinsic factor anti-

Thiamine was maintained at 100 mg IV every 8 h; pantoprazole was withdrawn, and ranitidine started at 150 mg at night. The patient also started treatment with oral vitamin B12 at 5 mg/day, cholecalciferol 667 IU/day, magnesium 10 mL/12 h, calcium carbonate 500 mg/12 h, and 0.9% saline solution. During the first 2 weeks of admission, her speech improved, and she was able to produce sentences; nystagmus manifested only at extreme lateral gaze. Ataxic gait was later identified, and

At 1 month of admission, an awake EEG revealed slow background activity, suggesting diffuse brain dysfunction (grades 2–3). From the second month of treatment, our patient presented good general appearance, fluent and coherent speech,

tests were apparently normal. The BMI was 15.6.

body test and serological test for syphilis yielded negative results.

and an MMSE score of 23. The patient participated in craft activities and regular rehabilitation sessions.

At 3 months of admission, a brain MRI scan demonstrated complete remission of the brain lesions (**Figure 1H**–**K**).

The neuropsychological evaluation showed that autobiographical memory was preserved. We were able to apply only three subtests of the Wechsler Adult Intelligence Scale (WAIS-III): matrix reasoning, similarities, and digit span; results were higher level, average level, and average level, respectively. No areas of deficit were identified.

The age of our patient was atypical with clinical presentation of the classic triad. In this case, WE was caused by severe malnutrition [2]. The patient lost 33% of her body weight, with a BMI of 15.6 [BMI below 16 corresponds to grade 3/severe thinness according to the WHO classifications (1995, 2000)]. Protein-calorie deficiency is not always present; in a review of 625 cases reported in the literature, the cause of WE was fasting or malnutrition in 10.2% of cases [33].

Brain MRI showed typical findings of WE, although this test is more sensitive for detecting WE lesions in non-alcoholic than in alcoholic patients [34]; clinical recovery was excellent with vitamin supplementation.

Regarding the pathophysiology of these symptoms, thiamine reserves were depleted in 2–3 weeks due to caloric restriction. In the event of thiamine depletion, the function of the thiamine-dependent enzyme systems deteriorates, and blood thiamine levels decrease. This damage occurs 4 days after the onset of thiamine deficiency and eventually progresses to programmed cell death. At 14 days, brain lesions develop [2]. It is probable that some subjects with genetically reduced transketolase activity require higher levels of thiamine and therefore present a higher risk of WE in situations of increased demand or lower absorption [34].

Additionally, the low level of magnesium (a thiamine cofactor) also contributed to the genesis of this clinical picture. Many cases of WE may also have magnesium (Mg) depletion, and it is known that in elderly people, Mg intake may be suboptimum. If a depletion of Mg reserve impedes the phosphorylation of thiamine, Mg depletion could have an effect on other enzymes hose activities depending on Mg [35]. Other vitamin deficiencies were vitamin B12 and vitamin D. It is recognised that long-term use of pantoprazole suppresses gastric acid production, which may lead to vitamin B12 malabsorption [36].

This case is special because being the clinical picture of several weeks of evolution, the first diagnostic hypothesis was vertebrobasilar stroke. WE was diagnosed in a context of severe malnutrition little evident in a nonalcoholic patient, despite symptoms (complete classic triad present) and neuroimaging findings being more typical (except alterations of cerebral cortex) of an alcoholic patient [34]. There was also no atrophy of the mammillary bodies, a very specific pathological finding in chronic EW and KS and present in up to 80% of alcoholic patients with a history of EW [37–39].

We propose that WE should be considered in elderly patients with mental status changes of unknown cause and risk for thiamine deficiency, even in nonalcoholic patients. Infusion of thiamine should be started immediately when the disorder is suspected, even in the absence of typical symptoms. With this case, we aim to raise awareness of the need to identify this preventable, treatable, and high-mortality disease.

#### **4.3 Future perspectives**

Nowadays, despite the caloric density, the diet is often of poor nutrition quality and does not meet recommended dietary guidelines for micronutrient intake, making this an at-risk population for micronutrient malnutrition [40].

#### *Malnutrition*

On the other hand, genetic factors may be involved in thiamine deficiency, i.e. pathogenic gene mutations in key regulators of the thiamine pathway, including thiamine pyrophosphokinase 1 (TPK1), thiamine diphosphate kinase (TDPK), thiamine triphosphatase (THTPA), and thiamine transporters (SLC25A19, SLC19A2/THTR1, and SLC19A3/THTR2) [40]. More recently, it has been defended that the organic cation transporter 1 (OCT1) plays a role as a hepatic thiamine transporter [41].

In addition, oxidative stress also is involved in this disease. In the near future, supplemental antioxidants will be incorporated for the prevention and treatment of the EW.

#### **5. Conclusion**

WE in elderly related to severe malnutrition is a little-recognised and underdiagnosed condition. Beyond an anamnesis of suspicion and a timely neurological semiology, nutrition education is necessary, and this information must be explicit in the clinical records. Parenteral thiamine should be given to all at-risk subjects admitted to the emergency room, and in every patient with WE, other nutritional deficiencies must be searched. It is necessary that a collaborative network of researchers in the field of malnutrition in older patients and clinicians should raise awareness of the need to identify this preventable, treatable, and high-mortality disease.

### **Conflict of interest**

There is no conflict of interest.

#### **Author details**

Francisco Javier Ros Forteza1,2

1 Neurology Service, Local Health Unit of Guarda, E.P.E., Guarda, Portugal

2 Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal

\*Address all correspondence to: javierros40@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**77**

*Wernicke Encephalopathy in Elderly Related to Severe Malnutrition*

south African public-sector hospitals. South African Journal of Clinical

[9] Bernard M, Rombeau J. Nutritional support for the elderly patient. In: Young E, editor. Nutrition, Ageing and Health. New York: Alan R. Liss Inc;

[11] Department of Health and Social Security. Dietary Reference Values for Food Energy and Nutrients for the United Kingdom. Report on Health and Social Subjects, no. 41.

[12] Smidt LJ, Cremin FM, Grivetti LE, Clifford AJ. Influence of thiamin supplementation on the health and general well-being of an elderly Irish population with marginal thiamin deficiency. Journal of Gerontology.

[13] O'Keeffe ST. Thiamine deficiency in elderly people. Age and Ageing.

In: Zarranz JJ, editor. Neurologia. 3nd ed. Madrid: Elsevier Science; 2003.

[15] Diop AG, Millogo A, Obot I, Thiam I, Tylleskar T. Neurological disorders associated with malnutrition. In: Aarli JA, Avanzini G, Bertolote JM, de Boer H, Breivik H, Dua T, et al., editors. Neurological Disorders: Public Health Challenges. World Health Organization,

[14] Zarranz JJ, Pérez-Concha T. Enfermedades carenciales.

Geneva. 2006. p. 111-126

[16] Tanphaichitr V. Thiamin. In: Shils ME, Olson JA, Shike M, Ross AC,

Nutrition. 2017;**32**(1):1-7

1986. pp. 229-258

2011;**39**:45-50

[10] Saunders J, Smith T, Stroud M. Malnutrition and undernutrition. Medicine.

London: HMSO; 1991

1991;**46**:M16-M22

2000;**29**:99-101

pp. 879-886

*DOI: http://dx.doi.org/10.5772/intechopen.89997*

[1] Victor M, Adams RA, Collins GH. The Wernicke-Korsakoff Syndrome and Related Disorders Due to Alcoholism and Malnutrition. Philadelphia: FA

[2] Hutcheon DA. Malnutrition-induced Wernicke's encephalopathy following a water-only fasting diet. Nutrition in Clinical Practice. 2015;**30**:92-99

Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex: A retrospective analysis of 131 cases diagnosed at necropsy. Journal of Neurology, Neurosurgery, and Psychiatry. 1986;**49**:341-345

[4] Caine D, Halliday GM, Kril JJ, Harper CG. Operational criteria for the classification of chronic alcoholics:

encephalopathy. Journal of Neurology,

Identification of Wernicke's

1997;**62**:51

Neurosurgery, and Psychiatry.

[5] Rauscher C. Canadian Family Physian. Malnutrition among the Elderly. 1993;**39**:1395-1403

[6] White JV, Guenter P, Jensen G, et al. Consensu statement: Academy of nutrition ans dietetics and American Society for Parenteral and Enteral Nutrition: Characteristics recommended for the identification and documentation of adult malnutrition (undernutrition). Journal of Parenteral and Enteral Nutrition. 2012;**36**:275

[7] Ritchie H, Roser M. Micronutrient Deficiency. 2018. Published online at OurWorldInData.org. Retrieved from: https://ourworldindata.org/

[8] van Tonder E, Gardner L, Cressey S, Tydeman-Edwards R, Gerber K. Adult malnutrition: Prevalence and use of nutrition-related quality indicators in

micronutrient-deficiency

**References**

Davis; 1989

[3] Harper CG, Giles M,

*Wernicke Encephalopathy in Elderly Related to Severe Malnutrition DOI: http://dx.doi.org/10.5772/intechopen.89997*

#### **References**

*Malnutrition*

the EW.

**5. Conclusion**

**Conflict of interest**

**Author details**

Francisco Javier Ros Forteza1,2

Interior, Covilhã, Portugal

There is no conflict of interest.

On the other hand, genetic factors may be involved in thiamine deficiency, i.e. pathogenic gene mutations in key regulators of the thiamine pathway, including thiamine pyrophosphokinase 1 (TPK1), thiamine diphosphate kinase (TDPK), thiamine triphosphatase (THTPA), and thiamine transporters (SLC25A19, SLC19A2/THTR1, and SLC19A3/THTR2) [40]. More recently, it has been defended that the organic cation transporter 1 (OCT1) plays a role as a hepatic thiamine transporter [41]. In addition, oxidative stress also is involved in this disease. In the near future, supplemental antioxidants will be incorporated for the prevention and treatment of

WE in elderly related to severe malnutrition is a little-recognised and underdiagnosed condition. Beyond an anamnesis of suspicion and a timely neurological semiology, nutrition education is necessary, and this information must be explicit in the clinical records. Parenteral thiamine should be given to all at-risk subjects admitted to the emergency room, and in every patient with WE, other nutritional deficiencies must be searched. It is necessary that a collaborative network of researchers in the field of malnutrition in older patients and clinicians should raise awareness of the need to identify this preventable, treatable, and high-mortality disease.

1 Neurology Service, Local Health Unit of Guarda, E.P.E., Guarda, Portugal

\*Address all correspondence to: javierros40@hotmail.com

provided the original work is properly cited.

2 Department of Medical Sciences, Faculty of Health Sciences, University of Beira

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

**76**

[1] Victor M, Adams RA, Collins GH. The Wernicke-Korsakoff Syndrome and Related Disorders Due to Alcoholism and Malnutrition. Philadelphia: FA Davis; 1989

[2] Hutcheon DA. Malnutrition-induced Wernicke's encephalopathy following a water-only fasting diet. Nutrition in Clinical Practice. 2015;**30**:92-99

[3] Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex: A retrospective analysis of 131 cases diagnosed at necropsy. Journal of Neurology, Neurosurgery, and Psychiatry. 1986;**49**:341-345

[4] Caine D, Halliday GM, Kril JJ, Harper CG. Operational criteria for the classification of chronic alcoholics: Identification of Wernicke's encephalopathy. Journal of Neurology, Neurosurgery, and Psychiatry. 1997;**62**:51

[5] Rauscher C. Canadian Family Physian. Malnutrition among the Elderly. 1993;**39**:1395-1403

[6] White JV, Guenter P, Jensen G, et al. Consensu statement: Academy of nutrition ans dietetics and American Society for Parenteral and Enteral Nutrition: Characteristics recommended for the identification and documentation of adult malnutrition (undernutrition). Journal of Parenteral and Enteral Nutrition. 2012;**36**:275

[7] Ritchie H, Roser M. Micronutrient Deficiency. 2018. Published online at OurWorldInData.org. Retrieved from: https://ourworldindata.org/ micronutrient-deficiency

[8] van Tonder E, Gardner L, Cressey S, Tydeman-Edwards R, Gerber K. Adult malnutrition: Prevalence and use of nutrition-related quality indicators in

south African public-sector hospitals. South African Journal of Clinical Nutrition. 2017;**32**(1):1-7

[9] Bernard M, Rombeau J. Nutritional support for the elderly patient. In: Young E, editor. Nutrition, Ageing and Health. New York: Alan R. Liss Inc; 1986. pp. 229-258

[10] Saunders J, Smith T, Stroud M. Malnutrition and undernutrition. Medicine. 2011;**39**:45-50

[11] Department of Health and Social Security. Dietary Reference Values for Food Energy and Nutrients for the United Kingdom. Report on Health and Social Subjects, no. 41. London: HMSO; 1991

[12] Smidt LJ, Cremin FM, Grivetti LE, Clifford AJ. Influence of thiamin supplementation on the health and general well-being of an elderly Irish population with marginal thiamin deficiency. Journal of Gerontology. 1991;**46**:M16-M22

[13] O'Keeffe ST. Thiamine deficiency in elderly people. Age and Ageing. 2000;**29**:99-101

[14] Zarranz JJ, Pérez-Concha T. Enfermedades carenciales. In: Zarranz JJ, editor. Neurologia. 3nd ed. Madrid: Elsevier Science; 2003. pp. 879-886

[15] Diop AG, Millogo A, Obot I, Thiam I, Tylleskar T. Neurological disorders associated with malnutrition. In: Aarli JA, Avanzini G, Bertolote JM, de Boer H, Breivik H, Dua T, et al., editors. Neurological Disorders: Public Health Challenges. World Health Organization, Geneva. 2006. p. 111-126

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editors. Modern Nutrition in Health and Disease. 9th ed. Baltimore: Williams and syndrome due to a bilateral anterior fornix infarction: A diffusion tensor tractography study. Archives of Neurology. 2008;**65**:1252

[26] Magalhães Scoralick F, Louzada LL, Toledo MA, Ruback M. Wernicke's encephalopathy as a complication of Chagas mega esophagus. Journal of Aging Research & Clinical Practice.

2012;**1**(2):178-180

2014;**71**:230-232

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[30] Nariai H, Mittelmann E,

[31] Yokote K, Yamanouchi H, Mizutani T, Shimada H. Clinical characteristics of Wernicke's

[32] Ros Forteza FJ, Cabrera H, Bousende M. Malnutrition and

encephalopathy in the elderly. Nihon Ronen Igakkai Zasshi. 1992;**29**:35-40

Wernicke encephalopathy in the elderly. Neurología. 2018;**34**:543-546. DOI: 10.1016/j.nrleng.2018.11.005

[33] Galvin R, Brathen G, Ivashynka A, Hillbom M, Tanasescu R, Leone MA.

[27] Chidlovskii E, Tahar A,

Deschasse G, Couturier P. Wernicke's encephalopathy associated with pellagra encephalopathy: Rare and unusual complication in an elderly hospitalized for aspiration pneumonia. La Revue de médicine interne. 2012;**33**:453-456

[28] Hata Y, Takeuchi Y, Kinoshita K, Nishida N. An autopsy case of acute and nonalcoholic thiamine-deficient encephalopathy. European Neurology.

[29] Terada N, Kinoshita K, Taguchi S, Tokuda Y. Wernicke encephalopathy and pellagra in an alcoholic and malnourished patient. BML Case Reports. 2015:Oct 21. DOI: 10.1136/

Farmakidis C, Zampolin RL, Robbins MS. Bithalamic dysfunction in Wernicke's encephalopathy. The Einstein Journal of Biology and Medicine. 2016;**31**:23-24

Wilkins; 1999. pp. 381-389

[17] Thomson AD, Cook CCH, Touquet R, Henry JA. The Royal College of Physicians report on alcohol: Guidelines for managing Wernicke's encephalopathy in the accident and emergency department. Alcohol and Alcoholism. Supplement.

[18] Martin PR, Singleton CK, Hiller-Sturmhöfel S. The role of thiamine deficiency in alcoholic brain disease. Alcohol Research & Health.

[19] McLean J, Manchip S. Wernicke's encephalopathy induced by magnesium depletion. Lancet. 1999;**353**:1768

[20] So YT, Aminoff MJ, Wilterdink JL. Wernicke encephalopathy. UpToDate

Kobold MJ. Electro-nystagmography for the diagnosis of vestibular dysfunction in the Wernicke-Korsakow syndrome. Clinical Neurology and Neurosurgery.

[22] Charness ME. Intracranial voyeurism: Revealing the mammillary bodies in alcoholism. Alcoholism, Clinical and Experimental Research. 1999;**23**:1941

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Jeon BS. Magnetic resonance reflects

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[24] Yoneoka Y, Takeda N, Inoue A, et al. Acute Korsakoff syndrome following mammillothalamic tract infarction.

[25] Renou P, Ducreux D, Batouche F, Denier C. Pure and acute Korsakoff

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[34] Gascón-Bayarri J, Campdelacreu J, García-Carreira MC, Estela J, Martínez-Yélamos S, Palasí A, et al. Encefalopatía de Wernicke en pacientes no alcohólicos: una serie de 8 casos. Neurología. 2011;**26**:540-547

[35] McLean J, Manchip S. Wernicke's encephalopathy induced by magnesium depletion. The Lancet. 1999;**353**:1768

[36] Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. Journal of the American Medical Association. 2013;**310**:2435-2442

[37] Skullerud K, Andersen SN, Lundevall J. Cerebral lesions and causes of death in male alcoholics. A forensic autopsy study. International Journal of Legal Medicine. 1991;**104**:209-213

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[39] Zuccoli G, Pipitone N. Neuroimaging findings in acute Wernicke's encephalopathy: Review of the literature. American Journal of Roentgenology. 2009;**192**:501-508

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**Chapter 6**

**Abstract**

lives.

**81**

**1. Introduction**

*Natisha Dukhi*

Global Prevalence of Malnutrition:

Malnutrition is a widespread problem, affecting the global population at some life stage. This public health epidemic targets everyone, but the most vulnerable groups are poverty-stricken people, young children, adolescents, older people, those who are with illness and have a compromised immune system, as well as lactating and pregnant women. Malnutrition includes both undernutrition (wasting, stunting, underweight, and mineral- and vitamin-related malnutrition) and overnutrition (overweight, obesity, and diet-related noncommunicable diseases). In combating malnutrition, healthcare costs increase, productivity is

reduced, and economic growth is staggered, thus perpetuating the cycle of ill health

1000 days of life as this window period is ideal for intervention implementation and tracking for the improvement of child growth and development. There is an unprecedented opportunity to address the various forms of malnutrition, especially the 2016–2025 Decade of Action on Nutrition set by the United Nation. This aims to achieve the relevant targets of the Sustainable Development Goals that aim to end hunger and improve nutrition, as well as promote well-being and ensure healthy

Malnutrition is a universal public health problem in both children and adults globally [1]. It is not only a public health concern but it is an impediment to global poverty eradication, productivity and economic growth. By eliminating malnutrition, it is estimated that 32% of the global disease burden would be removed [2]. As a widespread serious problem affecting children in developing countries, progress towards tackling the different forms of malnutrition remains relatively slow [3]. Malnutrition occurs due to an imbalance in the body, whereby the nutrients required by the body and the amount used by the body do not balance [1]. There are several forms of malnutrition and these include two broad categories namely undernutrition and over nutrition. Undernutrition manifests as wasting or low weight for height (acute malnutrition), stunting or low height for age (chronic malnutrition), underweight or low weight for age, and mineral and vitamin deficiencies or excessiveness. Over nutrition includes overweight, obesity and dietrelated non-communicable diseases (NCDs) such as diabetes mellitus, heart disease, some forms of cancer and stroke [1]. Malnutrition is an important global issue

and poverty. The best-targeted age for addressing malnutrition is the first

**Keywords:** malnutrition, children, wasting, stunting, obesity

Evidence from Literature

#### **Chapter 6**

## Global Prevalence of Malnutrition: Evidence from Literature

*Natisha Dukhi*

#### **Abstract**

Malnutrition is a widespread problem, affecting the global population at some life stage. This public health epidemic targets everyone, but the most vulnerable groups are poverty-stricken people, young children, adolescents, older people, those who are with illness and have a compromised immune system, as well as lactating and pregnant women. Malnutrition includes both undernutrition (wasting, stunting, underweight, and mineral- and vitamin-related malnutrition) and overnutrition (overweight, obesity, and diet-related noncommunicable diseases). In combating malnutrition, healthcare costs increase, productivity is reduced, and economic growth is staggered, thus perpetuating the cycle of ill health and poverty. The best-targeted age for addressing malnutrition is the first 1000 days of life as this window period is ideal for intervention implementation and tracking for the improvement of child growth and development. There is an unprecedented opportunity to address the various forms of malnutrition, especially the 2016–2025 Decade of Action on Nutrition set by the United Nation. This aims to achieve the relevant targets of the Sustainable Development Goals that aim to end hunger and improve nutrition, as well as promote well-being and ensure healthy lives.

**Keywords:** malnutrition, children, wasting, stunting, obesity

#### **1. Introduction**

Malnutrition is a universal public health problem in both children and adults globally [1]. It is not only a public health concern but it is an impediment to global poverty eradication, productivity and economic growth. By eliminating malnutrition, it is estimated that 32% of the global disease burden would be removed [2]. As a widespread serious problem affecting children in developing countries, progress towards tackling the different forms of malnutrition remains relatively slow [3]. Malnutrition occurs due to an imbalance in the body, whereby the nutrients required by the body and the amount used by the body do not balance [1]. There are several forms of malnutrition and these include two broad categories namely undernutrition and over nutrition. Undernutrition manifests as wasting or low weight for height (acute malnutrition), stunting or low height for age (chronic malnutrition), underweight or low weight for age, and mineral and vitamin deficiencies or excessiveness. Over nutrition includes overweight, obesity and dietrelated non-communicable diseases (NCDs) such as diabetes mellitus, heart disease, some forms of cancer and stroke [1]. Malnutrition is an important global issue

currently, as it affects all people despite the geography, socio-economic status, sex and gender, overlapping households, communities and countries. Anyone can experience malnutrition but the most vulnerable groups affected are children, adolescents, women, as well as people who are immune-compromised, or facing the challenges of poverty [3].

improvement of her feeding practices, enable her to make choices and have preference of health facilities available, increase her nutritional needs awareness, and give her the chance of changing her beliefs regarding medicine and disease [16]. Some of the nutritional interventions that have had some success in addressing malnutrition include exclusive breastfeeding for the first 6 months of life, vitamin A supplementation, deworming, zinc treatment and rehydration salts for diarrhea, food fortification, and folic acid/iron for lactating and pregnant women, improvement of access to piped water and hygiene [17]. These interventions have positively influenced the development, growth and survival of children [18]. Malnutrition is not a uniform condition and therefore groups and areas that experience high risk of malnutrition must be identified and targeted interventions available to assist [17]. To determine both over and undernutrition, assessment of the nutritional status is important. This identifies those individuals who are vulnerable and at risk, and how to guide a response [19]. In determining the nutritional status of a child, it must be referenced in comparison to a healthy child [20]. Most of the anthropometric indices are used with reference tables such as that of the National Center for Health Statistics (NCHS) and the currently widely recommended and used 2006 WHO child growth standards [21]. In expressing anthropometric indices relative to a reference population, the measurements are developed using the median and standard deviations of the reference populations, which are known as Z scores [22–24]. The Z score classification system interprets weight for age (W/A), weight for height (W/H) and height for age (H/A). Z scores describe a child's mid upper arm circumference (MUAC)/weight/height in comparison to the median and the mid upper arm circumference (MUAC)/weight/height of the child relative to the reference population [25]. The anthropometric value is expressed by the two score system as "a number of standard deviations or Z scores below or above the reference mean or median value" [26]. Thus, the Z score is calculated as follows:

*Global Prevalence of Malnutrition: Evidence from Literature*

*DOI: http://dx.doi.org/10.5772/intechopen.92006*

Z score <sup>¼</sup> observed value � median value of the reference population

As previously mentioned malnutrition consists of both over and undernutrition

Undernutrition does not only affect the health of individuals but impacts greatly

on the growth of the economy and productivity, as well as the eradication of poverty. To support their growth and development, infants and young children have increased nutritional needs and therefore are most affected by undernutrition [27, 28]. Prolonged malnourished status in children can lead to the development of

**Classification Z score values** Adequately nourished �2 < Z-score < +1 Moderately malnourished �3 < Z-score < �2 Severely malnourished Z-score < �3

**2. Classification of malnutrition**

*Malnutrition classification of children based on Z scores [20].*

(**Table 1**).

**Table 1.**

**83**

**2.1 Undernutrition**

standard deviation value of reference population (1)

According to the World Health Organization (WHO), 462 million adults are underweight, while 1.9 billion adults are overweight and/or obese. In children under 5 years of age, 155 million are stunted, 52 million are wasted, 17 million are severely wasted and 41 million are overweight and/or obese [1]. The manifestation of malnutrition is multifold, but the paths to addressing prevention are key and include exclusive breastfeeding for the first 2 years of life, diverse and nutritious foods during childhood, healthy environments, access to basic services such as water, hygiene, health and sanitation, as well as pregnant and lactating women having proper maternal nutrition before, during and after the respective phases (levels and trends) [3].

It is vital that malnutrition is addressed in children as malnutrition manifestations and symptoms begin to appear in the first 2 years of life [4]. Coinciding with the mental development and growth periods in children, protein energy malnutrition (PEM) is said to be a problem at ages 6 months to 2 years. Thus, this age period is considered a window period during which it is essential to prevent and/or manage acute and chronic malnutrition manifestations [4–6]. Child and maternal malnutrition together have contributed to 3.5 million annual deaths. Furthermore, children less than 5 years of age have a disease burden of 35% [7]. In 2008, 8.8 million global deaths in children less than 5 years old were due to underweight, of which 93% occurred in Africa and Asia. Approximately one in every seven children faces mortality before their fifth birthday in sub Saharan Africa (SSA) due to malnutrition [8].

Young malnourished children are affected by compromised immune systems by succumbing to infectious diseases and are prone to cognitive development delays, damaging long term psychological and intellectual development effects, as well as mental and physical development that is compromised due to stunting [7, 9–11]. A malnutrition cycle exists in populations experiencing chronic undernutrition and in this cycle, the nutritional requirements are not met in pregnant women. Thus, infants born to these mothers are of low birth weight, are unable to reach their full growth potential and may therefore be stunted, susceptible to infections, illness, and mortality early in life. The cycle is aggravated when low birth weight females grow into malnourished children and adults, and are therefore more likely to give birth to infants of low birth weight as well [9]. Malnutrition is not just a health issue but also affects the global burden of malnutrition socially, economically, developmentally and medically, affecting individuals, their families and communities with serious and long lasting consequences [1].

Studies in Sudan, Ethiopia, Bangladesh, and Haiti have indicated that the causes of malnutrition are multi-faceted, with both environmental and dietary factors contributing to malnutrition risk in young children [12]. Diet and disease have been identified as primary immediate determinants; with household food security, access to health facilities, healthy environment, and childcare practices influenced by socio-economic conditions [13]. Mother's antenatal visit and body mass index were also identified as risk factors for malnutrition [14]. In children under 3 years of age some of the main factors included poor nutrition, feeding practices, education and occupation of parent/caregiver, residence, household income, nutrition knowledge of mother [15]. These studies have suggested that nutrition education for the mother is important, as it is a resource that mothers can utilize for better care of their children. It can also provide the necessary skills required for childcare,

#### *Global Prevalence of Malnutrition: Evidence from Literature DOI: http://dx.doi.org/10.5772/intechopen.92006*

currently, as it affects all people despite the geography, socio-economic status, sex and gender, overlapping households, communities and countries. Anyone can experience malnutrition but the most vulnerable groups affected are children, adolescents, women, as well as people who are immune-compromised, or facing the

According to the World Health Organization (WHO), 462 million adults are underweight, while 1.9 billion adults are overweight and/or obese. In children under 5 years of age, 155 million are stunted, 52 million are wasted, 17 million are severely wasted and 41 million are overweight and/or obese [1]. The manifestation of malnutrition is multifold, but the paths to addressing prevention are key and include exclusive breastfeeding for the first 2 years of life, diverse and nutritious foods during childhood, healthy environments, access to basic services such as water, hygiene, health and sanitation, as well as pregnant and lactating women having proper maternal nutrition before, during and after the respective phases (levels and

It is vital that malnutrition is addressed in children as malnutrition manifestations and symptoms begin to appear in the first 2 years of life [4]. Coinciding with the mental development and growth periods in children, protein energy malnutrition (PEM) is said to be a problem at ages 6 months to 2 years. Thus, this age period is considered a window period during which it is essential to prevent and/or manage acute and chronic malnutrition manifestations [4–6]. Child and maternal malnutrition together have contributed to 3.5 million annual deaths. Furthermore, children less than 5 years of age have a disease burden of 35% [7]. In 2008, 8.8 million global deaths in children less than 5 years old were due to underweight, of which 93% occurred in Africa and Asia. Approximately one in every seven children faces mortality before their fifth birthday in sub Saharan Africa (SSA) due to

Young malnourished children are affected by compromised immune systems by succumbing to infectious diseases and are prone to cognitive development delays, damaging long term psychological and intellectual development effects, as well as mental and physical development that is compromised due to stunting [7, 9–11]. A malnutrition cycle exists in populations experiencing chronic undernutrition and in this cycle, the nutritional requirements are not met in pregnant women. Thus, infants born to these mothers are of low birth weight, are unable to reach their full growth potential and may therefore be stunted, susceptible to infections, illness, and mortality early in life. The cycle is aggravated when low birth weight females grow into malnourished children and adults, and are therefore more likely to give birth to infants of low birth weight as well [9]. Malnutrition is not just a health issue but also affects the global burden of malnutrition socially, economically, developmentally and medically, affecting individuals, their families and communities with

Studies in Sudan, Ethiopia, Bangladesh, and Haiti have indicated that the causes

of malnutrition are multi-faceted, with both environmental and dietary factors contributing to malnutrition risk in young children [12]. Diet and disease have been identified as primary immediate determinants; with household food security, access to health facilities, healthy environment, and childcare practices influenced by socio-economic conditions [13]. Mother's antenatal visit and body mass index were also identified as risk factors for malnutrition [14]. In children under 3 years of age some of the main factors included poor nutrition, feeding practices, education and occupation of parent/caregiver, residence, household income, nutrition knowledge of mother [15]. These studies have suggested that nutrition education for the mother is important, as it is a resource that mothers can utilize for better care of their children. It can also provide the necessary skills required for childcare,

challenges of poverty [3].

trends) [3].

*Malnutrition*

malnutrition [8].

**82**

serious and long lasting consequences [1].

improvement of her feeding practices, enable her to make choices and have preference of health facilities available, increase her nutritional needs awareness, and give her the chance of changing her beliefs regarding medicine and disease [16]. Some of the nutritional interventions that have had some success in addressing malnutrition include exclusive breastfeeding for the first 6 months of life, vitamin A supplementation, deworming, zinc treatment and rehydration salts for diarrhea, food fortification, and folic acid/iron for lactating and pregnant women, improvement of access to piped water and hygiene [17]. These interventions have positively influenced the development, growth and survival of children [18]. Malnutrition is not a uniform condition and therefore groups and areas that experience high risk of malnutrition must be identified and targeted interventions available to assist [17].

To determine both over and undernutrition, assessment of the nutritional status is important. This identifies those individuals who are vulnerable and at risk, and how to guide a response [19]. In determining the nutritional status of a child, it must be referenced in comparison to a healthy child [20]. Most of the anthropometric indices are used with reference tables such as that of the National Center for Health Statistics (NCHS) and the currently widely recommended and used 2006 WHO child growth standards [21]. In expressing anthropometric indices relative to a reference population, the measurements are developed using the median and standard deviations of the reference populations, which are known as Z scores [22–24]. The Z score classification system interprets weight for age (W/A), weight for height (W/H) and height for age (H/A). Z scores describe a child's mid upper arm circumference (MUAC)/weight/height in comparison to the median and the mid upper arm circumference (MUAC)/weight/height of the child relative to the reference population [25]. The anthropometric value is expressed by the two score system as "a number of standard deviations or Z scores below or above the reference mean or median value" [26]. Thus, the Z score is calculated as follows:

$$Z \text{ score} = \frac{\text{observed value} - \text{median value of the reference population}}{\text{standard deviation value of reference population}} \quad (1)$$

### **2. Classification of malnutrition**

As previously mentioned malnutrition consists of both over and undernutrition (**Table 1**).

#### **2.1 Undernutrition**

Undernutrition does not only affect the health of individuals but impacts greatly on the growth of the economy and productivity, as well as the eradication of poverty. To support their growth and development, infants and young children have increased nutritional needs and therefore are most affected by undernutrition [27, 28]. Prolonged malnourished status in children can lead to the development of


**Table 1.** *Malnutrition classification of children based on Z scores [20].* motor function and physical growth delays, lack of social skills, and low infection resistance, thus making them susceptible to common ailments and infections [28, 29]. Additionally, due to frequent infection, susceptible children become engaged in a negative cycle whereby infections lead to growth delays and their learning abilities are hindered, and infections in malnourished children may lead to childhood mortality [30].

**2.4 Stunting (height for age or H/A)**

*DOI: http://dx.doi.org/10.5772/intechopen.92006*

*Global Prevalence of Malnutrition: Evidence from Literature*

settlements within urban and rural areas [36–45].

capital development complications [40].

**2.5 Overweight and obesity**

**85**

Stunting is a major public health concern that begins in intrauterine life although children are only classified as stunted at approximately age 2 years. The detrimental effects of stunting include intrauterine growth retardation, as well as inadequate nutrition required for growth and development of children [41]. High frequency of infection and decreased disease resistance such as diarrhea and pneumonia are influenced by stunting. Childhood stunting may also lead to increased mortality, poor recovery from disease and is also an obesity risk factor in adulthood [41, 42]. Stunting causes growth impairment during childhood that is associated with increased cardio-metabolic disease and obesity risk and cognitive development delay in adulthood [43]. This creates both short and long term effects that indicate the importance of stunting being identified and monitored in early life [42]. In children the initial 1000 days of life are an important window period for intervention implementation and tracking for the improvement of child growth and development [7–44]. Often stunting is correlated with poor socio-economic status, as well as environmental conditions surveys in South Africa (SA) have identified an increased stunting prevalence in black people compared to their Indian or white counterparts [31]. Some surveys looked at a wider age range of children (0– 14 years) and higher stunting prevalence was found in children living informal

In stunting or low height for age the Z score is below 2 standard deviations [21]. It is prevalent usually in infants and children younger than 5 years [36], who are susceptible to infection and have an insufficient intake of nutrients over the long term. Low height for age is seen as the failure of an individual to reach full linear growth and if stunting occurs before age two then irreversible poor cognitive and motor developments may occur [41]. Severe stunting is indicated by a height for age that is lesser than the median by 85% to represent a standard deviation of �3SD [46]. In 2013 in children under 5 years of age, 161 million were identified as stunted globally. The trend of global decrease were evident from the period 2000–2013, during which figures declined from 199 million to 161 million (33–25%). However, one third of stunted children were still found in Africa [47]. During 2000–2018 the number and proportion of stunted children under age five rose by 6.5 million in Central and Western Africa and by 1.4 million in Southern and Eastern Africa. Thus, the stunting burden continues to escalate in Africa, creating serious human

In the last five decades overweight and obesity appears to be reaching epidemic levels in both developing and developed countries [48, 49]. Eclipsing infectious disease and under-nutrition as a significant mortality and ill-health contributor, overweight and obesity have presented as the most prevalent global nutritional problem over the last two decades. Globally an estimated 1 billion adults are overweight, with 300 million of them being obese [49]. An estimated 155 million obese children contribute to this epidemic [50]. Obese children tend to become obese adults. Obesity-related health problems occur in early years of life and progress into adulthood [51]. Several chronic disease conditions in later life are associated with childhood obesity. These chronic diseases include diabetes, stroke, high blood pressure, cancers and heart disease [52]. Despite the increased prevalence of overweight and obesity in children, research evaluating treatment in these age groups is minimal. Middle-income countries such as South Africa (SA), Brazil and China have increased

overweight and obesity rates across all age groups and economic levels [49].

Undernutrition is subdivided into two categories that include micronutrient malnutrition and growth failure. To differentiate between acute or chronic malnutrition, the nutritional status of an individual is assessed by using anthropometry [27]. According to Zere and McIntyre [31], anthropometry is advantageous over biochemical evaluation, as it is less invasive and cost effective; hence, in addressing child survival nutritional status anthropometry is one of the favored predictors [32]. To assess the growth status of children the most common indices used in anthropometry include low weight for height or wasting, stunting or low height for age, underweight or a low weight for age and waist/arm circumference.

#### **2.2 Undernutrition/protein energy malnutrition (PEM)**

In PEM the condition is characterized by the individual being susceptible to infection due to long-term consumption of protein and energy that is insufficient to meet the body's needs. While the body may first attempt to utilize the nutrients to meet the energy demands, if there is insufficient intake of energy then the consumed protein is used to meet the energy demands and does not address the functions of the protein in the body, hence leading to PEM. While PEM requires the measuring of growth parameters such as height and weight as it is not immediately obvious, in severe PEM children present with marasmus and kwashiorkor [33, 34]. Marasmus is characterized by a lack of protein and energy in the diet, while an inadequate intake of protein causes kwashiorkor. Marasmus or severe wasting (below �3SD) presents with a MUAC less than 115 mm in children under age five. Children with marasmus present with an "old man" appearance and are very thin [33]. In kwashiorkor, a child does not necessarily appear as undernourished but there is the presence of oedema. The children present with hair that is discolored and skin that is shiny and very tight. The weight for height is greater than or equal to �2SD. In marasmic-kwashiorkor bilateral oedema is present, with a weight for height less than �2SD [33–35].

#### **2.3 Underweight (weight for age or W/A)**

A common presentation of PEM in children is underweight. Underweight is seen as children having a weight for age with a Z score of �2SD, with severe underweight at �3SD [36, 37]. Since proteins and/or energy are insufficient in a diet, there is weight loss or failure to gain weight. This can be accompanied by a decline in linear height [38]. While the children may present with normal body proportions such as weight to height ratios, they will be undersized and underweight [39]. Through regular monitoring of growth indices such as height and weight, underweight can be identified at an early stage [26–39]. In 2013, 99 million children less than 5 years of age were underweight. Of this figure, one third of the children were from Africa and two-thirds present in Asia. An estimated 14.6% of newborns were with low birth weight in 2015, and approximately nine out of 10 of the newborns were from low and middle income countries (LMICs). Approximately 45% of deaths in LMICs in children under age five is due to underweight. In adolescent girls the underweight prevalence increased from 5.5% in 2000 to 5.7% in 2016 [40].

#### **2.4 Stunting (height for age or H/A)**

motor function and physical growth delays, lack of social skills, and low infection resistance, thus making them susceptible to common ailments and infections [28, 29]. Additionally, due to frequent infection, susceptible children become engaged in a negative cycle whereby infections lead to growth delays and their learning abilities are hindered, and infections in malnourished children may lead to

Undernutrition is subdivided into two categories that include micronutrient malnutrition and growth failure. To differentiate between acute or chronic malnutrition, the nutritional status of an individual is assessed by using anthropometry [27]. According to Zere and McIntyre [31], anthropometry is advantageous over biochemical evaluation, as it is less invasive and cost effective; hence, in addressing child survival nutritional status anthropometry is one of the favored predictors [32]. To assess the growth status of children the most common indices used in anthropometry include low weight for height or wasting, stunting or low height for age,

In PEM the condition is characterized by the individual being susceptible to infection due to long-term consumption of protein and energy that is insufficient to meet the body's needs. While the body may first attempt to utilize the nutrients to meet the energy demands, if there is insufficient intake of energy then the consumed protein is used to meet the energy demands and does not address the functions of the protein in the body, hence leading to PEM. While PEM requires the measuring of growth parameters such as height and weight as it is not immediately obvious, in severe PEM children present with marasmus and kwashiorkor [33, 34]. Marasmus is characterized by a lack of protein and energy in the diet, while an inadequate intake of protein causes kwashiorkor. Marasmus or severe wasting (below �3SD) presents with a MUAC less than 115 mm in children under age five. Children with marasmus present with an "old man" appearance and are very thin [33]. In kwashiorkor, a child does not necessarily appear as undernourished but there is the presence of oedema. The children present with hair that is discolored and skin that is shiny and very tight. The weight for height is greater than or equal to �2SD. In marasmic-kwashiorkor bilateral oedema is present, with a weight for

A common presentation of PEM in children is underweight. Underweight is seen

as children having a weight for age with a Z score of �2SD, with severe underweight at �3SD [36, 37]. Since proteins and/or energy are insufficient in a diet, there is weight loss or failure to gain weight. This can be accompanied by a decline in linear height [38]. While the children may present with normal body proportions such as weight to height ratios, they will be undersized and underweight [39]. Through regular monitoring of growth indices such as height and weight, underweight can be identified at an early stage [26–39]. In 2013, 99 million children less than 5 years of age were underweight. Of this figure, one third of the children were from Africa and two-thirds present in Asia. An estimated 14.6% of newborns were with low birth weight in 2015, and approximately nine out of 10 of the newborns were from low and middle income countries (LMICs). Approximately 45% of deaths in LMICs in children under age five is due to underweight. In adolescent girls the underweight prevalence increased from 5.5% in 2000 to 5.7% in 2016 [40].

underweight or a low weight for age and waist/arm circumference.

**2.2 Undernutrition/protein energy malnutrition (PEM)**

childhood mortality [30].

*Malnutrition*

height less than �2SD [33–35].

**84**

**2.3 Underweight (weight for age or W/A)**

Stunting is a major public health concern that begins in intrauterine life although children are only classified as stunted at approximately age 2 years. The detrimental effects of stunting include intrauterine growth retardation, as well as inadequate nutrition required for growth and development of children [41]. High frequency of infection and decreased disease resistance such as diarrhea and pneumonia are influenced by stunting. Childhood stunting may also lead to increased mortality, poor recovery from disease and is also an obesity risk factor in adulthood [41, 42]. Stunting causes growth impairment during childhood that is associated with increased cardio-metabolic disease and obesity risk and cognitive development delay in adulthood [43]. This creates both short and long term effects that indicate the importance of stunting being identified and monitored in early life [42].

In children the initial 1000 days of life are an important window period for intervention implementation and tracking for the improvement of child growth and development [7–44]. Often stunting is correlated with poor socio-economic status, as well as environmental conditions surveys in South Africa (SA) have identified an increased stunting prevalence in black people compared to their Indian or white counterparts [31]. Some surveys looked at a wider age range of children (0– 14 years) and higher stunting prevalence was found in children living informal settlements within urban and rural areas [36–45].

In stunting or low height for age the Z score is below 2 standard deviations [21]. It is prevalent usually in infants and children younger than 5 years [36], who are susceptible to infection and have an insufficient intake of nutrients over the long term. Low height for age is seen as the failure of an individual to reach full linear growth and if stunting occurs before age two then irreversible poor cognitive and motor developments may occur [41]. Severe stunting is indicated by a height for age that is lesser than the median by 85% to represent a standard deviation of �3SD [46]. In 2013 in children under 5 years of age, 161 million were identified as stunted globally. The trend of global decrease were evident from the period 2000–2013, during which figures declined from 199 million to 161 million (33–25%). However, one third of stunted children were still found in Africa [47]. During 2000–2018 the number and proportion of stunted children under age five rose by 6.5 million in Central and Western Africa and by 1.4 million in Southern and Eastern Africa. Thus, the stunting burden continues to escalate in Africa, creating serious human capital development complications [40].

#### **2.5 Overweight and obesity**

In the last five decades overweight and obesity appears to be reaching epidemic levels in both developing and developed countries [48, 49]. Eclipsing infectious disease and under-nutrition as a significant mortality and ill-health contributor, overweight and obesity have presented as the most prevalent global nutritional problem over the last two decades. Globally an estimated 1 billion adults are overweight, with 300 million of them being obese [49]. An estimated 155 million obese children contribute to this epidemic [50]. Obese children tend to become obese adults. Obesity-related health problems occur in early years of life and progress into adulthood [51]. Several chronic disease conditions in later life are associated with childhood obesity. These chronic diseases include diabetes, stroke, high blood pressure, cancers and heart disease [52]. Despite the increased prevalence of overweight and obesity in children, research evaluating treatment in these age groups is minimal. Middle-income countries such as South Africa (SA), Brazil and China have increased overweight and obesity rates across all age groups and economic levels [49].

However, over the last few years overweight has increased in every continent. It has been postulated that the number of overweight children under age five will rise from over 40 million to approximately 43 million by 2025 [53]. As of 2018, approximately half of the overweight under five children were in Asia, with a quarter in Africa. Between 2000 and 2018 in Africa, the number of overweight under five children rose by just under 44%. In children and adolescents aged 5–19 years old, the proportion of overweight in 2000 rose from one in 10 (10.3%) to just under one in five (18.4%) in 2016 [40].

2018 [62]. Children left untreated with severe acute malnutrition (SAM) are at least 12 times more likely to die than healthy children [63]. South Asia is the global wasting epicenter as 15.2% of children under five are wasted. Together with other hotspots such as Oceania, Southeast Asia and SSA, improvements regarding wasting

**Wasting Overweight Stunting Underweight**

2013–2014 8.1 4.4 42.7 23.4

**survey**

Angola 2015–2016 4.9 3.4 37.6 19.0 Benin 2017–2018 5.0 1.9 32.2 16.8 Botswana 2007–2008 7.2 11.2 31.4 11.2 Burkina Faso 2017 8.6 1.7 21.1 16.2 Burundi 2016–2017 5.1 1.4 55.9 29.3 Cabo Verde 1994 6.9 — 21.4 11.8 Cameroon 2014 5.2 6.7 31.7 14.8 Central African Republic 2012 7.6 1.9 39.6 24.6 Chad 2014–2015 13.3 2.8 39.8 29.4 Comoros 2012 11.3 10.6 31.1 16.9 The Congo 2014–2015 8.2 5.9 21.2 12.3 Cote d'Ivoire 2016 6.1 1.5 21.6 12.8

Djibouti 2012 21.6 8.1 33.5 29.9 Equatorial Guinea 2011 3.1 9.7 26.2 5.6 Eritrea 2010 15.3 2.0 52.0 39.4 Eswatini (former Swaziland) 2014 2.0 9.0 25.5 5.8 Ethiopia 2016 10.0 2.9 38.4 23.6 Gabon 2012 3.4 7.7 17.0 6.4 The Gambia 2013 11.0 3.2 24.6 16.5 Ghana 2014 4.7 2.6 18.8 11.2 Guinea 2016 8.1 4.0 32.4 18.3 Guinea—Bissau 2014 6.0 2.3 27.6 17.0 Kenya 2014 4.2 4.1 26.2 11.2 Lesotho 2014 2.8 7.5 33.4 10.5 Liberia 2013 5.6 3.2 32.1 15.3 Madagascar 2012–2013 7.9 1.1 48.9 32.9 Malawi 2015–2016 2.8 4.6 37.4 11.8 Mali 2015 13.5 1.9 30.4 25.0 Mauritania 2015 14.8 1.3 27.9 24.9 Mauritius 1995 15.7 6.5 13.6 13.0 Mozambique 2011 6.1 7.8 42.9 15.6 Namibia 2013 7.1 4.0 22.7 13.2

are minimal [64] (**Table 2**).

Democratic Republic of

Congo

**87**

**Country Year of last**

*Global Prevalence of Malnutrition: Evidence from Literature*

*DOI: http://dx.doi.org/10.5772/intechopen.92006*

#### **2.6 Stunting versus overweight/obesity**

Some developing countries such as SA are currently facing a nutrition transition with the dual burden of over and undernutrition. This nutrition transition is the replacement of traditional home cooked balanced diet meals by energy-dense foods, as well as sedentary lifestyles due to technology and urbanization. A review study highlighted the dual burden in SA in children aged 0–20 years. The prevalence of wasting and stunting was higher in younger male children and predominant in rural areas, whereas overweight/obesity prevalence was highest in females and children in urban settings. It is important for tracking of over and undernutrition in children at a district level that can also be used to prioritize, monitor and evaluate government policies regarding malnutrition [54]. More recent years have seen the double burden of malnutrition being accompanied by a triple burden of malnutrition, affecting families, communities and countries. In countries such as India and Egypt, the problem is increasing and therefore highlights the urgent need to consider child malnutrition in the greater familial and household contexts [40–55]. A study in Ghana addressed the concurrent occurrence of obesity and stunting in children aged under 5 years, providing data for the first time on such an occurrence. The study reported a stunting prevalence of 27.5%, overweight prevalence of 2.4% and an overall concurrent stunting and overweight prevalence of 1.2% [56]. A study in South Africa, with children aged 6–12 years old, reported that 9.1% were stunted, while 14.9% were overweight/obese [57]. This highlights the need for urgent targeted interventions in children to address this double burden to prevent these malnutrition issues as they transition into adulthood.

#### **2.7 Wasting (weight for length/height or W/H)**

In wasting or low weight for height the Z score is below 2 standard deviations [21]. Wasting is reflective of a body mass that is low in comparison to the age and may be due to disease or starvation. Weight loss and retardation of growth occur due to inadequate intake of food and long term it leads to wasting and becomes more severe with emaciation [58]. A child falls behind another child who is growing actively when his/her own growth is affected acutely [38], and the body height and weight become less than ideal for the age of the child [59]. Severe wasting occurs when the weight for height is less than the median by 70% to represent a standard deviation of �3SD [46]. According to the national Department of Health (DoH) height measurements in all children should be conducted at least every 3 months [60]. In measuring overall growth to compare growth standards, both height and weight measurements are essential. Globally, in 2013, in children less than 5 years of age, 51 million were wasted and 17 million severely wasted. Global wasting prevalence in 2013 approximated 8%, of which 3% accounted for severe wasting. A postulated third of wasted children were present in Africa and an estimate of the children severely wasted in Africa followed the same trend [61]. As of 2018–2019 52 million children are wasted, with an estimated 16.6 suffering from severe wasting in However, over the last few years overweight has increased in every continent. It has been postulated that the number of overweight children under age five will rise from over 40 million to approximately 43 million by 2025 [53]. As of 2018, approximately half of the overweight under five children were in Asia, with a quarter in Africa. Between 2000 and 2018 in Africa, the number of overweight under five children rose by just under 44%. In children and adolescents aged 5–19 years old, the proportion of overweight in 2000 rose from one in 10 (10.3%) to just under one in five (18.4%) in

Some developing countries such as SA are currently facing a nutrition transition with the dual burden of over and undernutrition. This nutrition transition is the replacement of traditional home cooked balanced diet meals by energy-dense foods, as well as sedentary lifestyles due to technology and urbanization. A review study highlighted the dual burden in SA in children aged 0–20 years. The prevalence of wasting and stunting was higher in younger male children and predominant in rural areas, whereas overweight/obesity prevalence was highest in females and children in urban settings. It is important for tracking of over and undernutrition in children at a district level that can also be used to prioritize, monitor and evaluate government policies regarding malnutrition [54]. More recent years have seen the double burden of malnutrition being accompanied by a triple burden of malnutrition, affecting families, communities and countries. In countries such as India and Egypt, the problem is increasing and therefore highlights the urgent need to consider child malnutrition in the greater familial and household contexts [40–55]. A study in Ghana addressed the concurrent occurrence of obesity and stunting in children aged under 5 years, providing data for the first time on such an occurrence. The study reported a stunting prevalence of 27.5%, overweight prevalence of 2.4% and an overall concurrent stunting and overweight prevalence of 1.2% [56]. A study in South Africa, with children aged 6–12 years old, reported that 9.1% were stunted, while 14.9% were overweight/obese [57]. This highlights the need for urgent targeted interventions in children to address this double burden to prevent these

In wasting or low weight for height the Z score is below 2 standard deviations [21]. Wasting is reflective of a body mass that is low in comparison to the age and may be due to disease or starvation. Weight loss and retardation of growth occur due to inadequate intake of food and long term it leads to wasting and becomes more severe with emaciation [58]. A child falls behind another child who is growing actively when his/her own growth is affected acutely [38], and the body height and weight become less than ideal for the age of the child [59]. Severe wasting occurs when the weight for height is less than the median by 70% to represent a standard deviation of �3SD [46]. According to the national Department of Health (DoH) height measurements in all children should be conducted at least every 3 months [60]. In measuring overall growth to compare growth standards, both height and weight measurements are essential. Globally, in 2013, in children less than 5 years of age, 51 million were wasted and 17 million severely wasted. Global wasting prevalence in 2013 approximated 8%, of which 3% accounted for severe wasting. A postulated third of wasted children were present in Africa and an estimate of the children severely wasted in Africa followed the same trend [61]. As of 2018–2019 52 million children are wasted, with an estimated 16.6 suffering from severe wasting in

2016 [40].

*Malnutrition*

**86**

**2.6 Stunting versus overweight/obesity**

malnutrition issues as they transition into adulthood.

**2.7 Wasting (weight for length/height or W/H)**

2018 [62]. Children left untreated with severe acute malnutrition (SAM) are at least 12 times more likely to die than healthy children [63]. South Asia is the global wasting epicenter as 15.2% of children under five are wasted. Together with other hotspots such as Oceania, Southeast Asia and SSA, improvements regarding wasting are minimal [64] (**Table 2**).


#### *Malnutrition*


National Food Consumption Survey-Fortification Baseline (NFCS-FB) reported that of children aged 1–9 years old, 20% were affected by stunting, 9.3% were underweight, wasting was found in 4.5%, and 14% were overweight or obese [72].

(SANHANES) conducted in 2012 reported that in children aged 0–14 years stunting prevalence was 15.4%, with 3.8% having severe stunting. Wasting was reported at 2.9%, with severe wasting at 0.8%. Underweight was reported at 5.8%, with severe underweight at 1.1%. Regarding over nutrition, SANHANES identified 18.1% of children as overweight and 4.6% as obese [36]. The prevalence of overweight and obesity was significantly greater in females (25% and 40.1%) compared to males (19.6% and 11.6%) respectively. Underweight was significantly higher in males (13.1%) in comparison to females (4.0%) [36]. Thus, it is evident that SA is facing the malnutrition epidemic at a young age and context-specific and targeted interventions are required to prevent child malnutrition before it progresses into

During 2012–2013, WHO member states recognized the seriousness of malnutrition and its effect on global health [3]. Thus, at the United Nation's General Assembly in 2016, the United Nations Decade of Action on Nutrition 2016–2025 was announced. This set a time frame for all forms of malnutrition to be addressed and for diet-related and nutrition targets to be met by 2025. This also set the time frame for the Sustainable Development Goals (SGDs) to be achieved before 2030, particularly SDG 2 that aims to improve nutrition, achieve food security and end hunger, as well as SDG 3 that aims to ensure healthy living and promote well-being for all [1]. To tackle the malnutrition epidemic food fortification is important to ensure that children with good weight do not risk becoming overweight or obese [73]. All malnutrition indicators must be included in interventions, and more importantly treated together rather than stand-alone issues [74]. As part of the health system strengthening and with the goal of combatting malnutrition, existing policies on child malnutrition must be evaluated. The coexistence of stunting and overweight/obesity remains a challenge in LMICs that requires multi-sectoral action. During infancy and early childhood optimal nutrition is vital to ensure that, development and rapid growth demands are met. In the efforts to tackle the nutrition disparities, the first 1000 days of life are an important window period, presenting the opportunity to prevent both stunting and overweight/obesity [75]. Interventions must be inclusive of both linear growth and appropriate weight, beginning in early life and preferably during this important window period. To further tackle the double and triple burdens of malnutrition, early screening and identification of at risk children, including those already with malnutrition, is essential at healthcare facilities [76]. Thus, a more holistic, context-specific approach is required, whereby interventions not only take into consideration the risk factors, but also consider the inclusion of nutritionists and educating mothers on self and childcare regarding nutrition [77]. Furthermore, child malnutrition research and interventions must be up-scaled from community level to provincial and national levels so that it informs policy on the intervention strategies that can address the burden of child malnutrition. This is vital as children left untreated transition into malnourished adulthood, increasing the healthcare costs and needs, weakening the healthcare systems, and perpetuating the vicious malnutrition cycle.

The South African National Health and Nutrition Examination Survey

*Global Prevalence of Malnutrition: Evidence from Literature*

*DOI: http://dx.doi.org/10.5772/intechopen.92006*

adulthood.

**89**

**4. Conclusion**

**Table 2.**

*Joint malnutrition country estimates of anthropometric indicators in children aged 0–59 months [65].*

#### **3. Malnutrition in South Africa**

As a developing or middle-income country, SA is still undergoing major transitions socially, economically and in the population's health. The country is currently facing a quadruple disease burden, with non-communicable diseases linked to diet and lifestyle; the burden of Human Immunodeficiency Virus/Acquired immunodeficiency syndrome (HIV/AIDS); infectious diseases and poverty linked to under nutrition; and deaths due to injuries [66]. As a developing country SA is in a nutrition transition where both over and undernutrition coexist [67]. The first 2 years of life are a vulnerable time frame as it is during this period that malnutrition begins. According to Faber and Wenhold [68], chronic malnutrition or stunting is more prevalent in children in SA compared to wasting. Since the post-apartheid era in 1994, SA has faced great challenges in addressing the nutritional status of infants, young children and adults [69]. However, large-scale nationwide surveys were conducted to trace the progress, failures and successes in addressing malnutrition. In 1994 the South African Vitamin A Consultative Group (SAVACG) conducted a national survey on the nutritional status of children aged 6–71 months [70]. Anthropometric results revealed that approximately 10% or 660,000 children were underweight, with one in every four children (1.5 million) affected by stunting. Severe wasting was only recorded in 0.4% of children. KwaZulu-Natal (KZN), Eastern Cape and Northern Province revealed the greatest prevalence of malnutrition [70]. In 1999 the National Food Consumption Survey (NFCS) was conducted in children aged 1–9 years [71], collecting a larger set of data in comparison to the SAVACG survey. The NFCS reported 10% underweight in children, with 20% affected by stunting and 17.1% as overweight and/or obese. The NFCS secondary analysis, focusing on children aged 1–5 years, reported underweight at 6.8%, stunting at 20.1%, overweight at 20.6% and obesity at 9.5% [69]. In 2005, the

*Global Prevalence of Malnutrition: Evidence from Literature DOI: http://dx.doi.org/10.5772/intechopen.92006*

National Food Consumption Survey-Fortification Baseline (NFCS-FB) reported that of children aged 1–9 years old, 20% were affected by stunting, 9.3% were underweight, wasting was found in 4.5%, and 14% were overweight or obese [72]. The South African National Health and Nutrition Examination Survey (SANHANES) conducted in 2012 reported that in children aged 0–14 years stunting prevalence was 15.4%, with 3.8% having severe stunting. Wasting was reported at 2.9%, with severe wasting at 0.8%. Underweight was reported at 5.8%, with severe underweight at 1.1%. Regarding over nutrition, SANHANES identified 18.1% of children as overweight and 4.6% as obese [36]. The prevalence of overweight and obesity was significantly greater in females (25% and 40.1%) compared to males (19.6% and 11.6%) respectively. Underweight was significantly higher in males (13.1%) in comparison to females (4.0%) [36]. Thus, it is evident that SA is facing the malnutrition epidemic at a young age and context-specific and targeted interventions are required to prevent child malnutrition before it progresses into adulthood.

#### **4. Conclusion**

**3. Malnutrition in South Africa**

**Table 2.**

*Malnutrition*

**88**

**Country Year of last**

**survey**

Niger 2016 10.1 1.1 40.6 31.4 Nigeria 2016–2017 10.8 1.5 43.6 31.5 Rwanda 2014–2015 2.3 7.9 38.2 9.6 Sao Tome and Principe 2014 4.0 2.4 17.2 8.8 Senegal 2017 9.0 0.9 16.5 14.4 Seychelles 2012 4.3 10.2 7.9 3.6 Sierra Leone 2013 9.5 8.8 37.8 18.2 Somalia 2009 15.0 3.0 25.3 23.0 South Africa 2016 2.5 13.3 27.4 5.9 South Sudan 2010 24.3 5.8 31.3 29.1 Togo 2013–2014 6.6 2.0 27.6 16.1 Uganda 2016 3.5 3.7 28.9 10.4 United Republic of Tanzania 2015–16 4.5 3.7 34.5 13.7 Zambia 2013–14 6.2 6.2 40.0 14.9 Zimbabwe 2015 3.3 5.6 27.1 8.5

**Wasting Overweight Stunting Underweight**

As a developing or middle-income country, SA is still undergoing major transitions socially, economically and in the population's health. The country is currently facing a quadruple disease burden, with non-communicable diseases linked to diet and lifestyle; the burden of Human Immunodeficiency Virus/Acquired immunodeficiency syndrome (HIV/AIDS); infectious diseases and poverty linked to under nutrition; and deaths due to injuries [66]. As a developing country SA is in a nutrition transition where both over and undernutrition coexist [67]. The first 2 years of life are a vulnerable time frame as it is during this period that malnutrition begins. According to Faber and Wenhold [68], chronic malnutrition or stunting is more prevalent in children in SA compared to wasting. Since the post-apartheid era in 1994, SA has faced great challenges in addressing the nutritional status of infants, young children and adults [69]. However, large-scale nationwide surveys were conducted to trace the progress, failures and successes in addressing malnutrition. In 1994 the South African Vitamin A Consultative Group (SAVACG) conducted a national survey on the nutritional status of children aged 6–71 months [70].

*Joint malnutrition country estimates of anthropometric indicators in children aged 0–59 months [65].*

Anthropometric results revealed that approximately 10% or 660,000 children were underweight, with one in every four children (1.5 million) affected by stunting. Severe wasting was only recorded in 0.4% of children. KwaZulu-Natal (KZN), Eastern Cape and Northern Province revealed the greatest prevalence of malnutrition [70]. In 1999 the National Food Consumption Survey (NFCS) was conducted in children aged 1–9 years [71], collecting a larger set of data in comparison to the SAVACG survey. The NFCS reported 10% underweight in children, with 20% affected by stunting and 17.1% as overweight and/or obese. The NFCS secondary analysis, focusing on children aged 1–5 years, reported underweight at 6.8%, stunting at 20.1%, overweight at 20.6% and obesity at 9.5% [69]. In 2005, the

During 2012–2013, WHO member states recognized the seriousness of malnutrition and its effect on global health [3]. Thus, at the United Nation's General Assembly in 2016, the United Nations Decade of Action on Nutrition 2016–2025 was announced. This set a time frame for all forms of malnutrition to be addressed and for diet-related and nutrition targets to be met by 2025. This also set the time frame for the Sustainable Development Goals (SGDs) to be achieved before 2030, particularly SDG 2 that aims to improve nutrition, achieve food security and end hunger, as well as SDG 3 that aims to ensure healthy living and promote well-being for all [1]. To tackle the malnutrition epidemic food fortification is important to ensure that children with good weight do not risk becoming overweight or obese [73]. All malnutrition indicators must be included in interventions, and more importantly treated together rather than stand-alone issues [74]. As part of the health system strengthening and with the goal of combatting malnutrition, existing policies on child malnutrition must be evaluated. The coexistence of stunting and overweight/obesity remains a challenge in LMICs that requires multi-sectoral action. During infancy and early childhood optimal nutrition is vital to ensure that, development and rapid growth demands are met. In the efforts to tackle the nutrition disparities, the first 1000 days of life are an important window period, presenting the opportunity to prevent both stunting and overweight/obesity [75]. Interventions must be inclusive of both linear growth and appropriate weight, beginning in early life and preferably during this important window period. To further tackle the double and triple burdens of malnutrition, early screening and identification of at risk children, including those already with malnutrition, is essential at healthcare facilities [76]. Thus, a more holistic, context-specific approach is required, whereby interventions not only take into consideration the risk factors, but also consider the inclusion of nutritionists and educating mothers on self and childcare regarding nutrition [77]. Furthermore, child malnutrition research and interventions must be up-scaled from community level to provincial and national levels so that it informs policy on the intervention strategies that can address the burden of child malnutrition. This is vital as children left untreated transition into malnourished adulthood, increasing the healthcare costs and needs, weakening the healthcare systems, and perpetuating the vicious malnutrition cycle. *Malnutrition*

#### **Author details**

Natisha Dukhi Human Sciences Research Council, Cape Town, South Africa

\*Address all correspondence to: doctordukhi@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**References**

[1] World Health Organization (WHO). Malnutrition [Internet] 2019. Available from: https://www.who.int/newsroom/fact-sheets/detail/malnutrition

*DOI: http://dx.doi.org/10.5772/intechopen.92006*

*Global Prevalence of Malnutrition: Evidence from Literature*

[9] Nutrition and South Africa's Children [Internet]. nd. Available from: http:// www.soulcity.org.za/projects/soulbuddyz/soul-buddyz-series-3/literaturereview/nutrition-literature-review

[10] Blössner M, DeOnis M.

43120

2238S

Malnutrition: Quantifying the health impact at national and local levels. In: Environmental Burden of Disease Series [Internet]. 2005. p. 12. Available from: https://apps.who.int/iris/handle/10665/

[11] Grantham-McGregor S. A review of

[12] De Onis M, Monteiro C, Akre J, et al. The worldwide magnitude of protein energy malnutrition; an overview from the WHO global database on child growth. Bulletin of the World Health Organization. 1993;**71**:703-712

Malnutrition and health in developing countries. CMAJ. 2005;**173**:279-286.

[14] Siddiqi NA, Haque N, Goni MA. Malnutrition of under-five children: Evidence from Bangladesh. Asian Journal of Medical Sciences. 2001;**2**: 113-118. DOI: 10.3126/ajms.v2i2.3662

Kushel MB. Food insecurity is associated with chronic disease among low-income NHANES participants. The Journal of Nutrition. 2010;**140**:304-310. DOI:

[16] Tesfaye M. Bayesian approach to identify predictors of children Nutritional status in Ethiopia [thesis] [Internet]. 2009. Available from: http://localhost:80/

xmlui/handle/123456789/4465

malnutrition on mental development. Journal of Nutrition. 1995;**125**(8):2233S-

studies of the effect of severe

[13] Müller O, Krawinkel M.

DOI: 10.1503/cmaj.050342

[15] Seligman HK, Laraia BA,

10.3945/jn.109.112573

[2] World Health Organization (WHO). Nutrition [Internet] 2020. Available from: https://www.who.int/nutrition/ topics/2\_background/en/index1.html

[Internet]. 2018. Available from: https:// globalnutritionreport.org/reports/ global-nutrition-report-2018/

[3] Global Nutrition Report 2018

[4] Shrimpton R, Victora CG, De Onis M, Lima RC, Blossner M, Clugston G. Worldwide timing of growth faltering: Implications for nutritional interventions. Paediatrics. 2001;**107**(5):75-81. DOI: 10.1542/

[5] Bern C, Nathanail L. Is mid-upperarm circumference a useful tool for screening in emergency settings? Lancet. 1995;**345**:631-633. DOI: 10.1016/

[6] Benson T. Improving Nutrition as a Development Priority: Addressing Undernutrition in National Policy Processes in Sub-Saharan Africa [Internet]. Washington DC: International Food Policy Research Institute; 2008. Available from: http:// www.ifpri.org/sites/default/files/

peds.107.5.e75

s0140-6736(95)90527-8

publications/rr156.pdf

61690-0

**91**

[7] Black RE, Allen LH, Bhutta ZA, Caulfield LE, de Onis M, Ezzati M. Maternal and child undernutrition: Global and regional exposures and health consequences. Lancet. 2008;**371**: 243-260. DOI: 10.1016/S0140-6736(07)

[8] Walton E, Allen S. Malnutrition in developing countries. Paediatrics and Child Health. 2011;**21**(9):418-424. DOI:

10.1016/j.paed.2011.04.004

*Global Prevalence of Malnutrition: Evidence from Literature DOI: http://dx.doi.org/10.5772/intechopen.92006*

#### **References**

[1] World Health Organization (WHO). Malnutrition [Internet] 2019. Available from: https://www.who.int/newsroom/fact-sheets/detail/malnutrition

[2] World Health Organization (WHO). Nutrition [Internet] 2020. Available from: https://www.who.int/nutrition/ topics/2\_background/en/index1.html

[3] Global Nutrition Report 2018 [Internet]. 2018. Available from: https:// globalnutritionreport.org/reports/ global-nutrition-report-2018/

[4] Shrimpton R, Victora CG, De Onis M, Lima RC, Blossner M, Clugston G. Worldwide timing of growth faltering: Implications for nutritional interventions. Paediatrics. 2001;**107**(5):75-81. DOI: 10.1542/ peds.107.5.e75

[5] Bern C, Nathanail L. Is mid-upperarm circumference a useful tool for screening in emergency settings? Lancet. 1995;**345**:631-633. DOI: 10.1016/ s0140-6736(95)90527-8

[6] Benson T. Improving Nutrition as a Development Priority: Addressing Undernutrition in National Policy Processes in Sub-Saharan Africa [Internet]. Washington DC: International Food Policy Research Institute; 2008. Available from: http:// www.ifpri.org/sites/default/files/ publications/rr156.pdf

[7] Black RE, Allen LH, Bhutta ZA, Caulfield LE, de Onis M, Ezzati M. Maternal and child undernutrition: Global and regional exposures and health consequences. Lancet. 2008;**371**: 243-260. DOI: 10.1016/S0140-6736(07) 61690-0

[8] Walton E, Allen S. Malnutrition in developing countries. Paediatrics and Child Health. 2011;**21**(9):418-424. DOI: 10.1016/j.paed.2011.04.004

[9] Nutrition and South Africa's Children [Internet]. nd. Available from: http:// www.soulcity.org.za/projects/soulbuddyz/soul-buddyz-series-3/literaturereview/nutrition-literature-review

[10] Blössner M, DeOnis M. Malnutrition: Quantifying the health impact at national and local levels. In: Environmental Burden of Disease Series [Internet]. 2005. p. 12. Available from: https://apps.who.int/iris/handle/10665/ 43120

[11] Grantham-McGregor S. A review of studies of the effect of severe malnutrition on mental development. Journal of Nutrition. 1995;**125**(8):2233S-2238S

[12] De Onis M, Monteiro C, Akre J, et al. The worldwide magnitude of protein energy malnutrition; an overview from the WHO global database on child growth. Bulletin of the World Health Organization. 1993;**71**:703-712

[13] Müller O, Krawinkel M. Malnutrition and health in developing countries. CMAJ. 2005;**173**:279-286. DOI: 10.1503/cmaj.050342

[14] Siddiqi NA, Haque N, Goni MA. Malnutrition of under-five children: Evidence from Bangladesh. Asian Journal of Medical Sciences. 2001;**2**: 113-118. DOI: 10.3126/ajms.v2i2.3662

[15] Seligman HK, Laraia BA, Kushel MB. Food insecurity is associated with chronic disease among low-income NHANES participants. The Journal of Nutrition. 2010;**140**:304-310. DOI: 10.3945/jn.109.112573

[16] Tesfaye M. Bayesian approach to identify predictors of children Nutritional status in Ethiopia [thesis] [Internet]. 2009. Available from: http://localhost:80/ xmlui/handle/123456789/4465

**Author details**

Human Sciences Research Council, Cape Town, South Africa

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: doctordukhi@gmail.com

provided the original work is properly cited.

Natisha Dukhi

*Malnutrition*

**90**

[17] Ayoya AM, Heidkamp R, Ngnie, Teta I, Pierre JM, Stoltzfus RJ. Child malnutrition in Haiti: Progress despite disasters. Global Health: Science and Practice. 2013;**1**(3):389-396. DOI: 10.9745/GHSP-D-13-00069

[18] Bhutta ZA, Das JK, Rizvi A, Gaffey MF, Walker N, Horton S, et al. Evidence-based interventions for improvement of maternal and child nutrition: What can be done and at what cost? Lancet. 2013;**382**(9890):452-477. DOI: 10.1016/S0140-6736(13)60996-4

[19] Pan American Health Organization. Understanding Malnutrition [Internet]. 2013. Available from: https://cursos. campusvirtualsp.org/pluginfile.php/ 73101/mod\_resource/content/6/Unit% 202%20–%20Understanding%20 malnutrition.pdf

[20] Webb P and Bhatia RA. A Manual: Measuring and Interpreting Malnutrition and Mortality [Internet]. 2005. Available from: http://www. unhcr.org/45f6abc92.html

[21] World Health Organization (WHO). WHO Child Growth Standards: Length/Height-for-Age, Weight-for-Age, Weight-for-Length, Weight-for-Height and Body Mass Index-for-Age: Methods and Development [Internet]. Geneva: World Health Organization; 2006. Available from: https://www.who. int/childgrowth/standards/technical\_ report/en/

[22] Jellife DB. The assessment of the nutritional status of the community. In: WHO Monographs [Internet]. 1966. p. 53. Available from: https://apps.who. int/iris/handle/10665/41780

[23] Sachdev HPS. Assessment of nutritional status. Bulletin of the World Health Organization. 1977;**55**(1): 489-498

[24] Waterlow JC, Buzina RKW, Lane JM, Nichaman MZ, Tanner JM. The presentation and use of height and weight data for comparing the nutritional status of children under the age of 10 years. Bulletin of the World Health Organization. 1977;**55**(4):489-498 Africa. International Journal for Equity in Health. 2003;**2**(7). DOI: 10.1186/

*DOI: http://dx.doi.org/10.5772/intechopen.92006*

*Global Prevalence of Malnutrition: Evidence from Literature*

www.childinfo.org/files/MICS3\_

of-worlds-children-2019

[41] Mzumara B, Bwembya P, Halwiindi H, Mugode R, Banda J. Factors associated with stunting among children below five years of age in Zambia: Evidence from the 2014

10.1186/s40795-018-0260-9

443-448

61692-4

[42] Pelletier DL, Frongillo EA Jr, Schroeder DG, Habicht JP. The effects of malnutrition on child mortality in developing counties. Bulletin of the World Health Organization. 1995;**73**:

[43] Victora CG, Adair L, Fall C, Hallal PC, Martorell R, Richter L, et al. Maternal and child undernutrition: Consequences for adult health and human capital. Lancet. 2008;**371**: 340-357. DOI: 10.1016/S0140-6736(07)

[44] Prentice AM, Ward KA,

DOI: 10.3945/ajcn.112.052332

609589fa6148f2c20db1.pdf

[45] Ardington C, Case A. Health: Analysis of the National Income Dynamics Study (NIDS) Wave 1 Dataset. Cape Town: Southern Africa Labour and Development Research Unit, School of Economics, University of Cape Town [Internet]; 2009. Available from: https://pdfs.semantic scholar.org/f693/a6d90fb4a895c84f

Goldberg GR, Jarjou LM, Moore SE, Fulford AJ, et al. Critical windows for nutritional interventions against stunting. The American Journal of Clinical Nutrition. 2013;**97**(5):911-918.

Zambia demographic and health survey. BMC Nutrition. 2018;**4**(51):1-8. DOI:

Chapter\_0- Title\_Page\_and\_Contents.pdf

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[33] Taking Action, Nutrition for Survival, Growth & Development ACF International White Paper [Internet]. 2010. Available from: http://www. actionagainsthunger.org.uk/resourcecentre/online-library/detail/media/acf-

international-white-paper/

[34] Sisodia U, Desai N, Akerkar S. Protein energy malnutrition severe acute malnutrition, LRTI with KOCH'S. Acta Scientific Nutritional Health. 2018;

[35] Save the Children. Emergency Health and Nutrition [Internet]. 2014.

[36] Shisana O, Labadarios D, Rehle T, Simbayi L, Zuma K, Dhansay A, et al. South African National Health and Nutrition Examination Survey

(SANHANES-1): Edition. Cape Town:

[38] Golden MHN, Golden BE. Severe Malnutrition in Human Nutrition and Dietetics. United Kingdom: Churchill

[39] United Nations Children's Fund (UNICEF). CHILDINFO: Monitoring the Situation of Children and Women. United Nations Children's Fund

[Internet]. 2009. Available from: http://

[37] Wittenberg DF. Nutritional Disorders. Oxford: South Africa; 2004

HSRC Press; 2014

Livingstone; 2000

**93**

Available from: https://www. savethechildren.org/us/what-we-do/ global-programs/health/healthand-nutrition-emergencies

1475-9276-2-7

inp/status.html

**2**(5):19-20

[25] Pederson D, Gore C. Anthropometry Measurement Error. Sydney, Australia: University of New South Wales Press; 1996

[26] World Health Organization (WHO). WHO global database on child growth and malnutrition. In:World Health Organization/Programme of Nutrition [Internet]. 2004. Available from: http:// www.who.int/nutgrowthdb/en/

[27] Torún B. Protein-Energy Malnutrition in, Modern Nutrition in Health and Disease. United States of America: Lippincott Williams & Wilkins; 2006

[28] Fentahun W, Wubshet M, Tariku A. Undernutrition and associated factorsamong children aged 6-59 months in east Belesa District, Northwest Ethiopia: A community based cross-sectional study. BMC Public Health. 2016;**16**(506):1-10. DOI: 10.1186/s12889-016-3180-0

[29] Kandala NB, Madungu TP, Emina JBO, Nzita KPD, Cappuccio FP. Malnutrition among children under the age of five in the Democratic Republic of Congo (DRC): Does geographic location matter? BMC Public Health. 2011;**11**(261):1-15. DOI: 10.1186/ 1471-2458-11-261

[30] Mengistu K, Alemu K, Destaw B. Prevalence of malnutrition and associated factors among children aged 6-59 months at Hidabu Abote District, North Shewa Oromia Regional State. Journal of Nutritional Disorders and Therapy. 2013;**1**(1):1-15. DOI: 10.4172/ 2161-0509.1000T1-001

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Africa. International Journal for Equity in Health. 2003;**2**(7). DOI: 10.1186/ 1475-9276-2-7

[17] Ayoya AM, Heidkamp R, Ngnie, Teta I, Pierre JM, Stoltzfus RJ. Child malnutrition in Haiti: Progress despite disasters. Global Health: Science and Practice. 2013;**1**(3):389-396. DOI: 10.9745/GHSP-D-13-00069

*Malnutrition*

presentation and use of height and weight data for comparing the

[25] Pederson D, Gore C.

South Wales Press; 1996

[27] Torún B. Protein-Energy

Undernutrition and associated factorsamong children aged 6-59 months in east Belesa District, Northwest Ethiopia: A community based cross-sectional study. BMC Public

Health. 2016;**16**(506):1-10. DOI: 10.1186/s12889-016-3180-0

[29] Kandala NB, Madungu TP,

1471-2458-11-261

2161-0509.1000T1-001

Emina JBO, Nzita KPD, Cappuccio FP. Malnutrition among children under the age of five in the Democratic Republic of Congo (DRC): Does geographic location matter? BMC Public Health. 2011;**11**(261):1-15. DOI: 10.1186/

[30] Mengistu K, Alemu K, Destaw B. Prevalence of malnutrition and

associated factors among children aged 6-59 months at Hidabu Abote District, North Shewa Oromia Regional State. Journal of Nutritional Disorders and Therapy. 2013;**1**(1):1-15. DOI: 10.4172/

[31] Zere E, McIntyre D. Inequities in under-five child malnutrition in South

Wilkins; 2006

Malnutrition in, Modern Nutrition in Health and Disease. United States of America: Lippincott Williams &

[28] Fentahun W, Wubshet M, Tariku A.

nutritional status of children under the age of 10 years. Bulletin of the World Health Organization. 1977;**55**(4):489-498

Anthropometry Measurement Error. Sydney, Australia: University of New

[26] World Health Organization (WHO). WHO global database on child growth and malnutrition. In:World Health Organization/Programme of Nutrition [Internet]. 2004. Available from: http:// www.who.int/nutgrowthdb/en/

[18] Bhutta ZA, Das JK, Rizvi A, Gaffey MF, Walker N, Horton S, et al. Evidence-based interventions for improvement of maternal and child nutrition: What can be done and at what cost? Lancet. 2013;**382**(9890):452-477. DOI: 10.1016/S0140-6736(13)60996-4

[19] Pan American Health Organization. Understanding Malnutrition [Internet]. 2013. Available from: https://cursos. campusvirtualsp.org/pluginfile.php/ 73101/mod\_resource/content/6/Unit% 202%20–%20Understanding%20

[20] Webb P and Bhatia RA. A Manual:

Malnutrition and Mortality [Internet]. 2005. Available from: http://www.

[21] World Health Organization (WHO).

[22] Jellife DB. The assessment of the nutritional status of the community. In: WHO Monographs [Internet]. 1966. p. 53. Available from: https://apps.who.

int/iris/handle/10665/41780

[23] Sachdev HPS. Assessment of nutritional status. Bulletin of the World Health Organization. 1977;**55**(1):

[24] Waterlow JC, Buzina RKW,

Lane JM, Nichaman MZ, Tanner JM. The

Measuring and Interpreting

unhcr.org/45f6abc92.html

WHO Child Growth Standards: Length/Height-for-Age, Weight-for-Age, Weight-for-Length, Weight-for-Height and Body Mass Index-for-Age: Methods and Development [Internet]. Geneva: World Health Organization; 2006. Available from: https://www.who. int/childgrowth/standards/technical\_

malnutrition.pdf

report/en/

489-498

**92**

[32] National Department of Health: Directorate Nutrition. The Integrated Nutrition Programme—Nutritional Status [Internet]. 2005. Available from: http://www.doh.gov.za/programmes/ inp/status.html

[33] Taking Action, Nutrition for Survival, Growth & Development ACF International White Paper [Internet]. 2010. Available from: http://www. actionagainsthunger.org.uk/resourcecentre/online-library/detail/media/acfinternational-white-paper/

[34] Sisodia U, Desai N, Akerkar S. Protein energy malnutrition severe acute malnutrition, LRTI with KOCH'S. Acta Scientific Nutritional Health. 2018; **2**(5):19-20

[35] Save the Children. Emergency Health and Nutrition [Internet]. 2014. Available from: https://www. savethechildren.org/us/what-we-do/ global-programs/health/healthand-nutrition-emergencies

[36] Shisana O, Labadarios D, Rehle T, Simbayi L, Zuma K, Dhansay A, et al. South African National Health and Nutrition Examination Survey (SANHANES-1): Edition. Cape Town: HSRC Press; 2014

[37] Wittenberg DF. Nutritional Disorders. Oxford: South Africa; 2004

[38] Golden MHN, Golden BE. Severe Malnutrition in Human Nutrition and Dietetics. United Kingdom: Churchill Livingstone; 2000

[39] United Nations Children's Fund (UNICEF). CHILDINFO: Monitoring the Situation of Children and Women. United Nations Children's Fund [Internet]. 2009. Available from: http:// www.childinfo.org/files/MICS3\_ Chapter\_0- Title\_Page\_and\_Contents.pdf

[40] United Nations Children's Fund (UNICEF). The State of the World's Children 2019. Children, Food and Nutrition: Growing Well in a Changing World [Internet]. 2019. Available from: https://www.unicef.org/reports/stateof-worlds-children-2019

[41] Mzumara B, Bwembya P, Halwiindi H, Mugode R, Banda J. Factors associated with stunting among children below five years of age in Zambia: Evidence from the 2014 Zambia demographic and health survey. BMC Nutrition. 2018;**4**(51):1-8. DOI: 10.1186/s40795-018-0260-9

[42] Pelletier DL, Frongillo EA Jr, Schroeder DG, Habicht JP. The effects of malnutrition on child mortality in developing counties. Bulletin of the World Health Organization. 1995;**73**: 443-448

[43] Victora CG, Adair L, Fall C, Hallal PC, Martorell R, Richter L, et al. Maternal and child undernutrition: Consequences for adult health and human capital. Lancet. 2008;**371**: 340-357. DOI: 10.1016/S0140-6736(07) 61692-4

[44] Prentice AM, Ward KA, Goldberg GR, Jarjou LM, Moore SE, Fulford AJ, et al. Critical windows for nutritional interventions against stunting. The American Journal of Clinical Nutrition. 2013;**97**(5):911-918. DOI: 10.3945/ajcn.112.052332

[45] Ardington C, Case A. Health: Analysis of the National Income Dynamics Study (NIDS) Wave 1 Dataset. Cape Town: Southern Africa Labour and Development Research Unit, School of Economics, University of Cape Town [Internet]; 2009. Available from: https://pdfs.semantic scholar.org/f693/a6d90fb4a895c84f 609589fa6148f2c20db1.pdf

[46] Picot J, Hartwell D, Harris P, Mendes D, Clegg AJ, Takeda A. The effectiveness of interventions to treat severe acute malnutrition in young children: A systematic review. Health Technology Assessment. 2012;**16**(19). DOI: 10.3310/hta16190

[47] United Nations Children's Fund (UNICEF). State of the World's Children. Maternal and Newborn Health [Internet]. 2009. Available from: http:// www.unicef.org/sowc09/

[48] Müller MJ, Asbeck I, Mast M, Largnäse K, Grund A. Prevention of obesity—more than an intention. Concept and first results of the Kiel Obesity Prevention Study (KOPS). International Journal of Obesity. 2001;**25**(1):S66-S74. DOI: 10.1038/sj.ijo.0801703

[49] Kruger HS, Puoane T, Senekal M, van der Merwe MT. Obesity in South Africa: Challenges for government and health professionals. Public Health Nutrition. 2005;**8**(5):491-500. DOI: 10.1079/PHN2005785

[50] Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world—A growing challenge. The New England Journal of Medicine. 2007;**356**: 3. DOI: 10.1056/NEJMp068177

[51] Lau DCW, Douketis JD, Morrison KM, Hramiak IM, Sharma AM, Ur E. 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children (summary). Canadian Medical Association Journal. 2007;**176**(8):S1-S13. DOI: 10.1503/ cmaj.061409

[52] Brennan L, Walkley J, Fraser SF, Greenway K, Wilks R. Motivational interviewing and cognitive behaviour therapy in the treatment of adolescent overweight and obesity: Study design and methodology. Contemporary Clinical Trials. 2008;**29**:359-375. DOI: 10.1016/j.cct.2007.09.001

[53] UNICEF, WHO, International Bank for Reconstruction and Development and World Bank. Levels and Trends in Child Malnutrition: Key Findings of the 2019 Edition of the Joint Child Malnutrition Estimates [Internet]. Geneva: WHO; 2019. Available from: https://www.who.int/nutgrowthdb/ estimates2018/en/

[60] National Department of Health. National Guidelines on Nutrition for People Living with HIV, AIDS, TB and Other Chronic Debilitating Conditions. South Africa: Department of Health; 2007

*DOI: http://dx.doi.org/10.5772/intechopen.92006*

*Global Prevalence of Malnutrition: Evidence from Literature*

[Internet] 2008. Available from: http://

[68] Faber M, Wenhold F. Nutrition in contemporary South Africa. Water South Africa. 2007;**33**(3):393-399. DOI:

[69] Iversen PO, du Plessis L, Marais D, Morseth M, Høisæther EA. Nutritional health of young children in South Africa over the first 16 years of democracy. SAJCH. 2011;**5**(3):72-77. DOI: http://hdl.

[70] Labadarios D, Van Middelkoop A,

[71] Labadarios D, Steyn NP, Maunder E, et al. The National Food Consumption Survey (NFCS): South Africa, 1999. Public Health Nutrition. 2005;**8**:533-543

[72] Labadarios D. National Food Consumption Survey-Fortification Baseline (NFCS-FB): South Africa 2005 [Internet]. Pretoria: Directorate: Nutrition, Department of Health; 2007. Available from: http://www.sajcn.co.za/ index.php/SAJCN/article/view/286

[73] Rachmi CN, Agho KE, Li M, Baur LA. Stunting, underweight and overweight in children aged 2.0–4.9 years in Indonesia: Prevalence trends and associated risk factors. PLoS One. 2016;**11**(5):e0154756. DOI: 10.1371/

[74] Shrimpton R, Rokx C. The Double Burden of Malnutrition in Indonesia. Jakarta, Indonesia: World Bank Jakarta.

[Internet]; 2013. Available from: http:// documents.worldbank.org/curated/en/

Contract No.: Report 76192-ID

journal.pone.0154756

www.dbsa.org/EN/AboutUs/ Publications/Documents/South%20 Africa%20Nutrition\_%20input%20

paper\_roadmap.pdf

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handle.net/10019.1/19087

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[62] No Wasted Lives Coalition

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[57] Graham L, Hochfeld T, Stuart L. Double trouble: Addressing stunting and obesity via school nutrition. South African journal of child health. 2018; **12**(3):90-94. DOI: 10.7196/SAJCH.2018. v12i3.1455

[58] Briend, Khara T, Dolan C. Wasting and stunting—Similarities and differences: Policy and programmatic implications. Food and Nutrition Bulletin. 2015;**36**(1):S15-S23

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[60] National Department of Health. National Guidelines on Nutrition for People Living with HIV, AIDS, TB and Other Chronic Debilitating Conditions. South Africa: Department of Health; 2007

[46] Picot J, Hartwell D, Harris P, Mendes D, Clegg AJ, Takeda A. The effectiveness of interventions to treat severe acute malnutrition in young children: A systematic review. Health Technology Assessment. 2012;**16**(19). [53] UNICEF, WHO, International Bank for Reconstruction and Development and World Bank. Levels and Trends in Child Malnutrition: Key Findings of the

[54] Stevens G, Finucane M, Paciorek C, Flaxman S, White R, Donner A, et al. Nutrition Impact Model Study Group. Trends in mild, moderate, and severe stunting and underweight, and progress towards MDG 1 in 141 developing countries: A systematic analysis of population representative data. Lancet. 2012;**380**:824-834. DOI: 10.1016/

2019 Edition of the Joint Child Malnutrition Estimates [Internet]. Geneva: WHO; 2019. Available from: https://www.who.int/nutgrowthdb/

estimates2018/en/

S0140-6736(12)60647-3

[55] Dang A, Meenakshi JV. The nutrition transition and the intrahousehold double burden of

[56] Atsu BK, Guure C, Laar AK. Determinants of overweight with concurrent stunting among Ghanaian children. BMC Pediatrics. 2017;**17**(177): 1-12. DOI: 10.1186/s12887-017-0928-3

[57] Graham L, Hochfeld T, Stuart L. Double trouble: Addressing stunting and obesity via school nutrition. South African journal of child health. 2018; **12**(3):90-94. DOI: 10.7196/SAJCH.2018.

[58] Briend, Khara T, Dolan C. Wasting

[59] Shetty P. Food and Nutrition: The Global Challenge. United Kingdom:

and stunting—Similarities and differences: Policy and programmatic implications. Food and Nutrition Bulletin. 2015;**36**(1):S15-S23

Blackwell Publishing; 2002

v12i3.1455

malnutrition in India. In: ADBI Working Paper 725 [Internet]. Tokyo: Asian Development Bank Institute; 2017. Available from: https://www.adb.org/ publications/nutrition-transitionhousehold-malnutrition-india

[47] United Nations Children's Fund (UNICEF). State of the World's

Children. Maternal and Newborn Health [Internet]. 2009. Available from: http://

DOI: 10.3310/hta16190

*Malnutrition*

www.unicef.org/sowc09/

DOI: 10.1038/sj.ijo.0801703

10.1079/PHN2005785

[49] Kruger HS, Puoane T, Senekal M, van der Merwe MT. Obesity in South Africa: Challenges for government and health professionals. Public Health Nutrition. 2005;**8**(5):491-500. DOI:

[50] Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world—A growing challenge. The New England Journal of Medicine. 2007;**356**:

[52] Brennan L, Walkley J, Fraser SF, Greenway K, Wilks R. Motivational interviewing and cognitive behaviour therapy in the treatment of adolescent overweight and obesity: Study design and methodology. Contemporary Clinical Trials. 2008;**29**:359-375. DOI:

10.1016/j.cct.2007.09.001

3. DOI: 10.1056/NEJMp068177

[51] Lau DCW, Douketis JD, Morrison KM, Hramiak IM, Sharma AM, Ur E. 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children (summary). Canadian Medical Association Journal. 2007;**176**(8):S1-S13. DOI: 10.1503/

cmaj.061409

**94**

[48] Müller MJ, Asbeck I, Mast M, Largnäse K, Grund A. Prevention of obesity—more than an intention. Concept and first results of the Kiel Obesity Prevention Study (KOPS). International Journal of Obesity. 2001;**25**(1):S66-S74.

[61] United Nations Children's Fund, World Health Organization, The World Bank. UNICEFWHO-World Bank Joint Child Malnutrition Estimates [Internet]. New York; Geneva; Washington, DC: UNICEF; WHO; The World Bank; 2012. Available from: http://www.who.int/ nutgrowthdb/jme\_unicef\_who\_wb.pdf

[62] No Wasted Lives Coalition (undated). State of acute malnutrition. In: UNICEF, WHO and World Bank Group. Joint Child Malnutrition Estimates [Internet]. Geneva: WHO; 2019. Available from: https://www. acutemalnutrition.org/en/countries

[63] Olofin I et al. Associations of suboptimal growth with all-cause and cause specific mortality in children under five years: A pooled analysis of ten prospective studies'. PLoS One. 2013;**8**(5):e64636. DOI: 10.1371/journal. pone.0064636

[64] Harding KL, Aguayo VM, Webb P. Factors associated with wasting among children under five years old in South Asia: Implications for action. PLoS One. 2018;**13**(7):e0198749

[65] United Nations Children's Fund (UNICEF). Malnutrition [Internet]. 2019. Available from: https://data.unicef .org/topic/nutrition/malnutrition/

[66] Steyn NP, Bradshaw D, Norman R, Joubert J, Schneider M, Steyn K. Dietary Changes and The Health Transition in South Africa: Implications for Health Policy [Internet]. Cape Town: South African Medical Research Council; 2006. Available from: http://www.fao. org/docrep/009/a0442e/a0442e0v.html

[67] Combating malnutrition in South Africa. Input Paper for Health Roadmap [Internet] 2008. Available from: http:// www.dbsa.org/EN/AboutUs/ Publications/Documents/South%20 Africa%20Nutrition\_%20input%20 paper\_roadmap.pdf

[68] Faber M, Wenhold F. Nutrition in contemporary South Africa. Water South Africa. 2007;**33**(3):393-399. DOI: 10.4314/wsa.v33i3.49122

[69] Iversen PO, du Plessis L, Marais D, Morseth M, Høisæther EA. Nutritional health of young children in South Africa over the first 16 years of democracy. SAJCH. 2011;**5**(3):72-77. DOI: http://hdl. handle.net/10019.1/19087

[70] Labadarios D, Van Middelkoop A, The South African Vitamin A Consultative Group (SAVACG). Children Aged 6 to 71 Months in South Africa, 1994: Their Anthropometric, Vitamin a, Iron and Immunisation Coverage Status. Isando: SAVACG. 1995

[71] Labadarios D, Steyn NP, Maunder E, et al. The National Food Consumption Survey (NFCS): South Africa, 1999. Public Health Nutrition. 2005;**8**:533-543

[72] Labadarios D. National Food Consumption Survey-Fortification Baseline (NFCS-FB): South Africa 2005 [Internet]. Pretoria: Directorate: Nutrition, Department of Health; 2007. Available from: http://www.sajcn.co.za/ index.php/SAJCN/article/view/286

[73] Rachmi CN, Agho KE, Li M, Baur LA. Stunting, underweight and overweight in children aged 2.0–4.9 years in Indonesia: Prevalence trends and associated risk factors. PLoS One. 2016;**11**(5):e0154756. DOI: 10.1371/ journal.pone.0154756

[74] Shrimpton R, Rokx C. The Double Burden of Malnutrition in Indonesia. Jakarta, Indonesia: World Bank Jakarta. Contract No.: Report 76192-ID [Internet]; 2013. Available from: http:// documents.worldbank.org/curated/en/

955671468049836790/The-doubleburden-of-malnutrition-in-Indonesia

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[76] Steenkamp L, Lategan R, Raubenheimer J. Moderate malnutrition in children aged five years and younger in South Africa: Are wasting or stunting being treated? South African Journal of Clinical Nutrition. 2016;**29**(1):27-31 Available from: http://www.sajcn.co.za/ index.php/SAJCN/article/view/1030

[77] Modjadji P, Madiba S. The double burden of malnutrition in a rural health and demographic surveillance system site in South Africa: A study of primary schoolchildren and their mothers. BMC Public Health. 2019;**19**(1087):1-11 . Available from. DOI: 10.1186/ s12889-019-7412-y

**97**

**Chapter 7**

Risk

**Abstract**

Detection of Nutrient-Related SNP

Malnutrition is a result of complicated reasons from diet and food behavior and also related to genetic background which has been revealed by studies in recent decades. Traditionally, nutrition status are measured and expressed with indexes of anthropometric, diet survey, clinical symptom, biochemistry, behavior, etc. These measurement has been used in national nutrition monitoring, clinic nutrition therapy, mother and children nutrition care, nutrition intervention projects, and scientific studies. However, genetic and epigenetic information on nutrition explain malnutrition in a genetic view that would supply additional new theory and methodology for the growing requirement in terms of personalized and precise nutrition. In this chapter, an introduction on the detection of nutrient-related SNP

Malnutrition is a state of disordered nutrition, in which a combination of varying degrees of over- or undernutrition and inflammatory activity has led to a change in body composition, diminished function, and outcome [1]. Malnutrition, including undernutrition, micronutrient deficiencies, and overweight and obesity, not only affects the people's health and well-being by impacting negatively on human physical and cognitive development, compromising the immune system, increasing susceptibility to communicable and noncommunicable diseases, restricting the attainment of human potential, and reducing productivity but also poses a high burden in the form of negative social and economic consequences to individu-

Currently, more than 810 million people worldwide are hungry, mainly in poor,

natural disaster-destroyed and war-torn countries. About 2 billion people are suffering from micronutrient deficiencies, which is called hidden hunger, and about 2 billion adults are affected by overweight and obesity, with one in 12 adults suffering from diabetes and one in two with cardiovascular diseases [3]. Developmental Origins of Health and Disease (DoHaD theory) considers that adult disease stems from malnutrition in the fetus and early childhood. More evidence accumulated that malnutrition would result in adverse consequences to the later life cycle and

to Reveal Individual Malnutrition

*Junsheng Huo and Chunhong Zhang*

to reveal individual malnutrition risk is discussed.

**Keywords:** SNP, nutrients, malnutrition

als, families, communities, and states [2].

should be addressed in the whole life cycle [4].

**1. Introduction**

#### **Chapter 7**

955671468049836790/The-doubleburden-of-malnutrition-in-Indonesia

[75] Perez-Escamilla R, Bermudez O, Buccini GS, Kumanyika S, Lutter CK, Monsivais P, et al. Nutrition disparities and the global burden of malnutrition. BMJ. 2018;**361**:1-8. DOI: 10.1136/bmj.

[76] Steenkamp L, Lategan R,

Raubenheimer J. Moderate malnutrition in children aged five years and younger in South Africa: Are wasting or stunting being treated? South African Journal of Clinical Nutrition. 2016;**29**(1):27-31 Available from: http://www.sajcn.co.za/ index.php/SAJCN/article/view/1030

[77] Modjadji P, Madiba S. The double burden of malnutrition in a rural health and demographic surveillance system site in South Africa: A study of primary schoolchildren and their mothers. BMC Public Health. 2019;**19**(1087):1-11 . Available from. DOI: 10.1186/

s12889-019-7412-y

**96**

k2252

*Malnutrition*

## Detection of Nutrient-Related SNP to Reveal Individual Malnutrition Risk

*Junsheng Huo and Chunhong Zhang*

#### **Abstract**

Malnutrition is a result of complicated reasons from diet and food behavior and also related to genetic background which has been revealed by studies in recent decades. Traditionally, nutrition status are measured and expressed with indexes of anthropometric, diet survey, clinical symptom, biochemistry, behavior, etc. These measurement has been used in national nutrition monitoring, clinic nutrition therapy, mother and children nutrition care, nutrition intervention projects, and scientific studies. However, genetic and epigenetic information on nutrition explain malnutrition in a genetic view that would supply additional new theory and methodology for the growing requirement in terms of personalized and precise nutrition. In this chapter, an introduction on the detection of nutrient-related SNP to reveal individual malnutrition risk is discussed.

**Keywords:** SNP, nutrients, malnutrition

#### **1. Introduction**

Malnutrition is a state of disordered nutrition, in which a combination of varying degrees of over- or undernutrition and inflammatory activity has led to a change in body composition, diminished function, and outcome [1]. Malnutrition, including undernutrition, micronutrient deficiencies, and overweight and obesity, not only affects the people's health and well-being by impacting negatively on human physical and cognitive development, compromising the immune system, increasing susceptibility to communicable and noncommunicable diseases, restricting the attainment of human potential, and reducing productivity but also poses a high burden in the form of negative social and economic consequences to individuals, families, communities, and states [2].

Currently, more than 810 million people worldwide are hungry, mainly in poor, natural disaster-destroyed and war-torn countries. About 2 billion people are suffering from micronutrient deficiencies, which is called hidden hunger, and about 2 billion adults are affected by overweight and obesity, with one in 12 adults suffering from diabetes and one in two with cardiovascular diseases [3]. Developmental Origins of Health and Disease (DoHaD theory) considers that adult disease stems from malnutrition in the fetus and early childhood. More evidence accumulated that malnutrition would result in adverse consequences to the later life cycle and should be addressed in the whole life cycle [4].

#### *Malnutrition*

Malnutrition is a result of complicated reasons from diet and food behavior and also related to genetic background which has been revealed by studies in recent decades. Traditionally, nutrition status are measured and expressed with indexes of anthropometric, diet survey, clinical symptom, biochemistry, behavior, etc. [5]. These measurement has been used in national nutrition monitoring, clinic nutrition therapy, mother and children nutrition care, nutrition intervention projects, and scientific studies. However, genetic and epigenetic information on nutrition explain malnutrition in a genetic view that would supply additional new theory and methodology for the growing requirement in terms of personalized and precise nutrition. In this chapter, an introduction on detection of nutrient-related SNP to reveal individual malnutrition risk is discussed.

#### **2. Malnutrition related to inheritance**

Following the restrictive enzyme cut technology on fragment length polymorphisms and short series repeat sequences, single nucleotide polymorphisms (SNP) became the third-generation polymorphism marker with the characteristics of high genetic marker density, high stability, and high feasibility of automation detection, which showed a strong application prospect in human genomics research, such as genetic diagnosis, genetic risk assessment, chain imbalance map, and genetic association analysis. Severe malnutrition such as iron deficiency anemia, xerophthalmia and nyctalopia, pellagra, scurvy, rickets, beriberi, and other nutrient deficiency diseases was caused by the combined impact of environment and genetic factors. And the Human Genome Project study showed that 99.9% of DNA sequences were consistent among different individuals, with only small genetic differences in the sequence. 0.1% of DNA sequence differences may vary the level of risk of malnutrition and diseases such as non-chronic diseases. Single nucleotide polymorphism could be measureable markers to reveal the genetic differences.

#### **2.1 Iron deficiency-related genes**

The discovery of polymorphisms on DNA sequences associated with common diseases was an important way to understand the risk of nutritional deficiency from genetic perspective. Iron deficiency was one of the most important nutritional problems in the world, especially in developing countries. Iron deficiency not only leads to anemia but also causes the body's immune function, work performance, and damage of adolescent's psychological behavior and mental development. With the deepening of research on nutritional genomics, genetic polymorphisms associated with iron nutrition status have been found. A study reported by Mclaren et al. [6] showed that rs2111833 and rs1121312 in TMPRSS6 gene with iron biochemical indicators showed that rs2111833 is associated with serum iron and log-to-ferritin saturation in the Caucasian population and shows total iron binding force, unsaturated iron binding force, and serum iron in the Asian population. Rs1421312 sites were associated with serum iron and log-to-ferritin saturation in the Caucasian population and serum iron and log-ferritin saturation in the Afro-American population. The study found that rs2111833 and rs1421312 had an impact on iron nutrition in different races.

#### **3. Folic acid deficiency genes**

Folic acid was a cofactor that interacted with a variety of enzymes in many intercellular reactions, with methionine enzymes acting as coenzymes when isocysteine

**99**

*Detection of Nutrient-Related SNP to Reveal Individual Malnutrition Risk*

was converted to cystic thiopental. The extent to which the body absorbed folic acid and vitamin B6 and B12 is influenced by environmental and genetic factors. In 1964, Smithells et al. [7] showed that women with reproductive neural tube malformations (neural tube defect, NTD) had micronutrient deficiencies, especially folic acid. NTDs were congenital malformations of the brain and spinal cord that occurred within pregnancy from 21 to 28 days, including spina bifida, anencephaly, and brain bulging, which could lead to infant death and child disability. NTDs had the epidemiological characteristics of environmental and genetic factors. In 1995, a variant of MTHFR enzyme was identified which causes a substitution of C to T at nucleotide 677 [8]. The MTHFR C677T homozygous variant (TT genotype) is thermolabile, and its activity is reduced by 70% compared to the wild type (CC genotype). This reduced enzyme activity causes an accumulation of plasma homocysteine and higher rates of thymidylate synthesis. It is well established that B vitamin status is affected by genotype, particularly the C677T polymorphism in MTHFR, with the T allele being associated with higher circulating concentrations of homocysteine and lower circulating concentrations of plasma and erythrocyte folate. In 2018, Zhang et al. [9, 10] explored the association between maternal methylenetetrahydrofolate reductase (*MTHFR*) C677T, methionine synthase reductase (*MTRR*) A66G, and methionine synthase (*MTR*) A2756G which effects on absorption and utilization of folate, B6 and B12, and neural tube defects in offspring through metaanalysis, which showed that these SNPs were significantly associated with NTDs in offspring. A cross-sectional study of dietary and genetic predictors of blood folate levels in a large racial healthy young adults group by Daniel et al. in 2017 [11] showed that the interactive effect of the genotype with naturally occurring food folate intake on RBC folate levels occurred in the anticipated stronger individuals that is homozygous for the T allele. This pattern suggests that polyglutamated folic acid (naturally occurring food folate) is less well absorbed among C allele carriers. This interpretation is consistent with the results from previous research, which found that those with hypofunctional *FOLH1* 484 variants had lower RBC folate levels despite equivalent dietary folate intake. Understanding why circulating folate levels vary from person to person is critical to ensuring adequate bioavailability,

*DOI: http://dx.doi.org/10.5772/intechopen.92458*

especially among women of childbearing age.

**3.2 Measurement of malnutrition-related SNPs**

In recent years, the levels of folic acid; vitamin B2, B3, B6, and B12; and homocysteine (HCY) in pregnant women, as well as enzymes in folic acid and HCY pathways such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), and gene polymorphism sites associated with methionine synostic ingendraase (MTR) have been explored as potential causes of NTDs. Wilcken et al. [12] showed that the frequency of the homozygous C677T genotype (TT) was highest among individuals of Hispanic ethnicity, followed by whites, with the lowest frequency found in blacks. There were geographical and racial differences in gene polymorphisms, so future studies should conduct large samples and cross-regional surveys and established a database of gene polymorphisms in different regions and populations to provide a scientific basis for precise nutrition

Nutrigenomics studies have sufficiently accumulated data in the last two decades to reveal phenotypes of SNPs between health and micronutrient deficiency population [13]. Zhang et al. [9, 10] explored that the genes of MTHFR C677T,

**3.1 Genes of other nutrients deficiency**

guidance and intervention.

#### *Detection of Nutrient-Related SNP to Reveal Individual Malnutrition Risk DOI: http://dx.doi.org/10.5772/intechopen.92458*

*Malnutrition*

Malnutrition is a result of complicated reasons from diet and food behavior and also related to genetic background which has been revealed by studies in recent decades. Traditionally, nutrition status are measured and expressed with indexes of anthropometric, diet survey, clinical symptom, biochemistry, behavior, etc. [5]. These measurement has been used in national nutrition monitoring, clinic nutrition therapy, mother and children nutrition care, nutrition intervention projects, and scientific studies. However, genetic and epigenetic information on nutrition explain malnutrition in a genetic view that would supply additional new theory and methodology for the growing requirement in terms of personalized and precise nutrition. In this chapter, an introduction on detection of nutrient-related SNP to

Following the restrictive enzyme cut technology on fragment length polymorphisms and short series repeat sequences, single nucleotide polymorphisms (SNP) became the third-generation polymorphism marker with the characteristics of high genetic marker density, high stability, and high feasibility of automation detection, which showed a strong application prospect in human genomics research, such as genetic diagnosis, genetic risk assessment, chain imbalance map, and genetic association analysis. Severe malnutrition such as iron deficiency anemia, xerophthalmia and nyctalopia, pellagra, scurvy, rickets, beriberi, and other nutrient deficiency diseases was caused by the combined impact of environment and genetic factors. And the Human Genome Project study showed that 99.9% of DNA sequences were consistent among different individuals, with only small genetic differences in the sequence. 0.1% of DNA sequence differences may vary the level of risk of malnutrition and diseases such as non-chronic diseases. Single nucleotide polymorphism

The discovery of polymorphisms on DNA sequences associated with common diseases was an important way to understand the risk of nutritional deficiency from genetic perspective. Iron deficiency was one of the most important nutritional problems in the world, especially in developing countries. Iron deficiency not only leads to anemia but also causes the body's immune function, work performance, and damage of adolescent's psychological behavior and mental development. With the deepening of research on nutritional genomics, genetic polymorphisms associated with iron nutrition status have been found. A study reported by Mclaren et al. [6] showed that rs2111833 and rs1121312 in TMPRSS6 gene with iron biochemical indicators showed that rs2111833 is associated with serum iron and log-to-ferritin saturation in the Caucasian population and shows total iron binding force, unsaturated iron binding force, and serum iron in the Asian population. Rs1421312 sites were associated with serum iron and log-to-ferritin saturation in the Caucasian population and serum iron and log-ferritin saturation in the Afro-American population. The study found that

rs2111833 and rs1421312 had an impact on iron nutrition in different races.

Folic acid was a cofactor that interacted with a variety of enzymes in many intercellular reactions, with methionine enzymes acting as coenzymes when isocysteine

reveal individual malnutrition risk is discussed.

could be measureable markers to reveal the genetic differences.

**2. Malnutrition related to inheritance**

**2.1 Iron deficiency-related genes**

**3. Folic acid deficiency genes**

**98**

was converted to cystic thiopental. The extent to which the body absorbed folic acid and vitamin B6 and B12 is influenced by environmental and genetic factors. In 1964, Smithells et al. [7] showed that women with reproductive neural tube malformations (neural tube defect, NTD) had micronutrient deficiencies, especially folic acid. NTDs were congenital malformations of the brain and spinal cord that occurred within pregnancy from 21 to 28 days, including spina bifida, anencephaly, and brain bulging, which could lead to infant death and child disability. NTDs had the epidemiological characteristics of environmental and genetic factors. In 1995, a variant of MTHFR enzyme was identified which causes a substitution of C to T at nucleotide 677 [8]. The MTHFR C677T homozygous variant (TT genotype) is thermolabile, and its activity is reduced by 70% compared to the wild type (CC genotype). This reduced enzyme activity causes an accumulation of plasma homocysteine and higher rates of thymidylate synthesis. It is well established that B vitamin status is affected by genotype, particularly the C677T polymorphism in MTHFR, with the T allele being associated with higher circulating concentrations of homocysteine and lower circulating concentrations of plasma and erythrocyte folate. In 2018, Zhang et al. [9, 10] explored the association between maternal methylenetetrahydrofolate reductase (*MTHFR*) C677T, methionine synthase reductase (*MTRR*) A66G, and methionine synthase (*MTR*) A2756G which effects on absorption and utilization of folate, B6 and B12, and neural tube defects in offspring through metaanalysis, which showed that these SNPs were significantly associated with NTDs in offspring. A cross-sectional study of dietary and genetic predictors of blood folate levels in a large racial healthy young adults group by Daniel et al. in 2017 [11] showed that the interactive effect of the genotype with naturally occurring food folate intake on RBC folate levels occurred in the anticipated stronger individuals that is homozygous for the T allele. This pattern suggests that polyglutamated folic acid (naturally occurring food folate) is less well absorbed among C allele carriers. This interpretation is consistent with the results from previous research, which found that those with hypofunctional *FOLH1* 484 variants had lower RBC folate levels despite equivalent dietary folate intake. Understanding why circulating folate levels vary from person to person is critical to ensuring adequate bioavailability, especially among women of childbearing age.

#### **3.1 Genes of other nutrients deficiency**

In recent years, the levels of folic acid; vitamin B2, B3, B6, and B12; and homocysteine (HCY) in pregnant women, as well as enzymes in folic acid and HCY pathways such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), and gene polymorphism sites associated with methionine synostic ingendraase (MTR) have been explored as potential causes of NTDs. Wilcken et al. [12] showed that the frequency of the homozygous C677T genotype (TT) was highest among individuals of Hispanic ethnicity, followed by whites, with the lowest frequency found in blacks. There were geographical and racial differences in gene polymorphisms, so future studies should conduct large samples and cross-regional surveys and established a database of gene polymorphisms in different regions and populations to provide a scientific basis for precise nutrition guidance and intervention.

#### **3.2 Measurement of malnutrition-related SNPs**

Nutrigenomics studies have sufficiently accumulated data in the last two decades to reveal phenotypes of SNPs between health and micronutrient deficiency population [13]. Zhang et al. [9, 10] explored that the genes of MTHFR C677T,

MTRR A66G, and MTR A2756G were genetic factors for low absorption and bioavailability of folate, B6, B12, etc. Those nutrients are closely related with the prevalence of neural tube defects (NTDs) in newborn infants. Daniel et al. [11] reported that mutant genotype of a C allele SNP of individuals predicted lower RBC folate concentration than that of T allele SNP of individuals with the same diet folate intake level. Studies have reported numbers of micronutrient deficiencyrelated SNPs (MD-SNPs) of vitamins A, D, E, B6, and B12, folate, calcium, iron, zinc, selenium, etc. [14–22]. It is assumed that MD-SNPs based on high -quality observations in large population could be used as biomarkers for assessing genetic potential risk of micronutrient deficiency. The sequencing of the human genome has catalyzed efforts to search for disease genes by the strategy of associating sequence variants with measurable phenotypes. In particular, the Human Genome Project and follow-on efforts to characterize genetic variation have resulted in the discovery of millions of SNPs, which have emerged as genetic markers of choice because of their high-density and relatively even distribution in the human genomes**.** When one nutrient deficiency risk-related gene has been mapped to a chromosomal region, a high-density SNP mapping or candidate gene association studies are logical steps to follow.

#### **3.3 Gene sequencing**

The first-generation sequencing technology, also known as Sanger sequencing method, is based on the sequencing of DNA polymerase synthesis reaction. The basic principle is that the test DNA template, desired DNA synthase, deoxynucleoside triphosphates (dNTPs), reaction buffer, primers, and other components of DNA synthesis reaction and a small amount of four kinds of radioisotope dideoxynucleoside triphosphates (ddATP, ddTTP, ddCTP, and ddGTP) were added to the reaction system. Because the ddNTP dideoxyribose connected on the 3-carbon atom is not a hydroxyl group (-OH) but the hydrogen (H) after deoxidation, the ddNTP is added to the DNA strand being synthesized, the system subsequent to dNTP no longer be bound to this DNA strand, and the synthesis of this DNA strand was randomly terminated at the base of the ddNTP. Thus, after several cycles, a group is formed from short to long DNA fragments; these fragments can be directly length difference of one nucleotide, and the 3'end nucleotide is radiolabelled with A, T, C, or G. The product was divided into A, T, C, and G, the four electrophoresis lanes; the base can be read in the order to be synthesized, thereby obtaining the DNA sequence to be tested. Thereafter, on the basis of "the Sanger sequencing method," the automatic detection and fluorescence techniques, isotopically labeled with a fluorescent label in place of the four fluorophores, four bases were replaced and automatically detected by imaging techniques, no longer subjected to electrophoresis separately read sequences, greatly improving the speed and accuracy of DNA sequencing. Generation sequencing technology to ensure smooth implementation of Human Genome Project can be obtained secret of human health and disease at the molecular level. However, first-generation sequencing technology has considerable limitations, namely, low throughput, high cost, and long time. Further, since test DNA Sanger sequencing is applied to the support, and cloned in *E. coli* and other bacteria, therefore, it could not be cloned fragments of harmful bacteria, and, in some regions of the genome, such as the centromere and terminal area around the particles is difficult to be cloned, leading to deletion of part of gene sequence. Additionally, the method of analysis is limited ability alleles, SNP detection is very difficult, which facilitates the birth of a new generation of genome sequencing technology.

**101**

*Detection of Nutrient-Related SNP to Reveal Individual Malnutrition Risk*

Some technologies such as mass spectrometry, electrophoresis, and microarray hybridization are much more dependent on PCR multiplexing than others to reach their throughput potential [23–25]. However, the efficiency of these technologies was constricted by cross impact in the PCR of primers and DNA samples in one reaction tube. It is evidenced that less than 20 primer pairs could be amplified together that could not support large numbers of SNP measurement. And when multiple SNPs are amplified together in a reaction chamber, only 50–70% SNPs can be amplified successfully, and the amount of products varies greatly from 10 to 1000 folds, what leads to the cooling rate for samples which decreases dramatically—some SNPs that are scored for sample A may not be scored for sample B or C [26–28]. Single-base extension based on multiplexing PCR like mass spectrometry assay is expensive and requires well-trained personnel for performing the various steps of the analysis with a lengthy protocol. For most homogenous detection formats like fluorescence resonance energy transfer and fluorescent polarization, because their testing equipment have very limited capacity of multiplex recently, some technologies such as TaqMan 5′-nuclease assay, DNA hybridization, could not rely on multiplexing PCR to increase their throughput. Genotyping technologies have become a significant bottleneck for these applications despite rapid progress in the field. Exploring fast, accurate, highthroughput SNP genotyping, new technology is particularly urgent. Microfluidics chip is composed of microdroplets, microchannels, and microchambers [29–34]. Each microchamber could be used to amplify only one primer pair. A number of microchambers can be designed to meet the requirement. The physical isolation of different primer pairs is a simple and effective strategy to avoid the drawbacks of conventional multiplex PCR. In order to overcome the SNP genotyping error @ caused by different amplification efficiency, chambers and channels with special structures have also been designed for primer storage and allocation of reaction mixtures. The characteristics of smaller reaction volumes, high-throughput capacity, ease of integration, and portability compared to traditional PCR endow microfluidics (microdroplets, microchannels, and microchambers) with the potential to be a powerful technology to meet SNP genotyping demands. For example, 116-plex PCR designed by Li et al. can be accomplished using a hydrophobically patterned microarray [35]. However, it requires precise operations, and the amplification is performed in an open environment, which risks contamination. Microdroplets (e.g., digital PCR) are also a potential technology for multiplex PCR, but barcoding technology is essential but challenging for multiplex digital PCR. The OpenArray® platform from Applied Biosystems, which was the commercial products for multiplex PCR, is rather expensive and sophisticated, and costly instruments are also required. In brief, these methods for multiplex PCR are effective, but complications

in chip processing and/or their high associated costs hinder their wide use.

SNP genotype measurement has been widely studied in the risk screen and diagnosis for genetic diseases and chronic diseases, but few studies for nutrient deficiency risk determination. It is agreed that the body micronutrient diagnosis or evaluation is the bottleneck technology barrier since there are numbers of indexes for varieties of micronutrients; in addition, there seems even difficulty to know the genetic information related with micronutrient deficiency. Nutritional genotype studies have facilitated to use MD-SNPs (malnutrition-related SNPs) as risk biomarkers, i.e., vitamins A, D, E, and B12, folate, calcium, iron, zinc, and selenium.

**3.5 Measurement malnutrition-related SNPs and their genotypes**

*DOI: http://dx.doi.org/10.5772/intechopen.92458*

**3.4 Methods detecting SNP**

#### **3.4 Methods detecting SNP**

*Malnutrition*

studies are logical steps to follow.

**3.3 Gene sequencing**

MTRR A66G, and MTR A2756G were genetic factors for low absorption and bioavailability of folate, B6, B12, etc. Those nutrients are closely related with the prevalence of neural tube defects (NTDs) in newborn infants. Daniel et al. [11] reported that mutant genotype of a C allele SNP of individuals predicted lower RBC folate concentration than that of T allele SNP of individuals with the same diet folate intake level. Studies have reported numbers of micronutrient deficiencyrelated SNPs (MD-SNPs) of vitamins A, D, E, B6, and B12, folate, calcium, iron, zinc, selenium, etc. [14–22]. It is assumed that MD-SNPs based on high -quality observations in large population could be used as biomarkers for assessing genetic potential risk of micronutrient deficiency. The sequencing of the human genome has catalyzed efforts to search for disease genes by the strategy of associating sequence variants with measurable phenotypes. In particular, the Human Genome Project and follow-on efforts to characterize genetic variation have resulted in the discovery of millions of SNPs, which have emerged as genetic markers of choice because of their high-density and relatively even distribution in the human genomes**.** When one nutrient deficiency risk-related gene has been mapped to a chromosomal region, a high-density SNP mapping or candidate gene association

The first-generation sequencing technology, also known as Sanger sequencing method, is based on the sequencing of DNA polymerase synthesis reaction. The basic principle is that the test DNA template, desired DNA synthase, deoxynucleoside triphosphates (dNTPs), reaction buffer, primers, and other components of DNA synthesis reaction and a small amount of four kinds of radioisotope dideoxynucleoside triphosphates (ddATP, ddTTP, ddCTP, and ddGTP) were added to the reaction system. Because the ddNTP dideoxyribose connected on the 3-carbon atom is not a hydroxyl group (-OH) but the hydrogen (H) after deoxidation, the ddNTP is added to the DNA strand being synthesized, the system subsequent to dNTP no longer be bound to this DNA strand, and the synthesis of this DNA strand was randomly terminated at the base of the ddNTP. Thus, after several cycles, a group is formed from short to long DNA fragments; these fragments can be directly length difference of one nucleotide, and the 3'end nucleotide is radiolabelled with A, T, C, or G. The product was divided into A, T, C, and G, the four electrophoresis lanes; the base can be read in the order to be synthesized, thereby obtaining the DNA sequence to be tested. Thereafter, on the basis of "the Sanger sequencing method," the automatic detection and fluorescence techniques, isotopically labeled with a fluorescent label in place of the four fluorophores, four bases were replaced and automatically detected by imaging techniques, no longer subjected to electrophoresis separately read sequences, greatly improving the speed and accuracy of DNA sequencing. Generation sequencing technology to ensure smooth implementation of Human Genome Project can be obtained secret of human health and disease at the molecular level. However, first-generation sequencing technology has considerable limitations, namely, low throughput, high cost, and long time. Further, since test DNA Sanger sequencing is applied to the support, and cloned in *E. coli* and other bacteria, therefore, it could not be cloned fragments of harmful bacteria, and, in some regions of the genome, such as the centromere and terminal area around the particles is difficult to be cloned, leading to deletion of part of gene sequence. Additionally, the method of analysis is limited ability alleles, SNP detection is very difficult, which facilitates the birth of a new generation of genome sequencing

**100**

technology.

Some technologies such as mass spectrometry, electrophoresis, and microarray hybridization are much more dependent on PCR multiplexing than others to reach their throughput potential [23–25]. However, the efficiency of these technologies was constricted by cross impact in the PCR of primers and DNA samples in one reaction tube. It is evidenced that less than 20 primer pairs could be amplified together that could not support large numbers of SNP measurement. And when multiple SNPs are amplified together in a reaction chamber, only 50–70% SNPs can be amplified successfully, and the amount of products varies greatly from 10 to 1000 folds, what leads to the cooling rate for samples which decreases dramatically—some SNPs that are scored for sample A may not be scored for sample B or C [26–28]. Single-base extension based on multiplexing PCR like mass spectrometry assay is expensive and requires well-trained personnel for performing the various steps of the analysis with a lengthy protocol. For most homogenous detection formats like fluorescence resonance energy transfer and fluorescent polarization, because their testing equipment have very limited capacity of multiplex recently, some technologies such as TaqMan 5′-nuclease assay, DNA hybridization, could not rely on multiplexing PCR to increase their throughput. Genotyping technologies have become a significant bottleneck for these applications despite rapid progress in the field. Exploring fast, accurate, highthroughput SNP genotyping, new technology is particularly urgent. Microfluidics chip is composed of microdroplets, microchannels, and microchambers [29–34]. Each microchamber could be used to amplify only one primer pair. A number of microchambers can be designed to meet the requirement. The physical isolation of different primer pairs is a simple and effective strategy to avoid the drawbacks of conventional multiplex PCR. In order to overcome the SNP genotyping error @ caused by different amplification efficiency, chambers and channels with special structures have also been designed for primer storage and allocation of reaction mixtures. The characteristics of smaller reaction volumes, high-throughput capacity, ease of integration, and portability compared to traditional PCR endow microfluidics (microdroplets, microchannels, and microchambers) with the potential to be a powerful technology to meet SNP genotyping demands. For example, 116-plex PCR designed by Li et al. can be accomplished using a hydrophobically patterned microarray [35]. However, it requires precise operations, and the amplification is performed in an open environment, which risks contamination. Microdroplets (e.g., digital PCR) are also a potential technology for multiplex PCR, but barcoding technology is essential but challenging for multiplex digital PCR. The OpenArray® platform from Applied Biosystems, which was the commercial products for multiplex PCR, is rather expensive and sophisticated, and costly instruments are also required. In brief, these methods for multiplex PCR are effective, but complications in chip processing and/or their high associated costs hinder their wide use.

#### **3.5 Measurement malnutrition-related SNPs and their genotypes**

SNP genotype measurement has been widely studied in the risk screen and diagnosis for genetic diseases and chronic diseases, but few studies for nutrient deficiency risk determination. It is agreed that the body micronutrient diagnosis or evaluation is the bottleneck technology barrier since there are numbers of indexes for varieties of micronutrients; in addition, there seems even difficulty to know the genetic information related with micronutrient deficiency. Nutritional genotype studies have facilitated to use MD-SNPs (malnutrition-related SNPs) as risk biomarkers, i.e., vitamins A, D, E, and B12, folate, calcium, iron, zinc, and selenium.

#### *3.5.1 Microfluidic chip designed for malnutrition-related SNPs*

Microfluidic chip as high-throughput technology could amplify large numbers of target DNA fragments at the same time in a chip, and the physical isolation of different primer pairs is a simple and effective strategy to avoid the drawbacks of conventional multiplex PCR. Xu et al. took this advantage to reduce the mutual interference and competition among different primers in one tube for multiple PCR [36]. They adopted a modified method with a blocking step, which had showed less contamination than that without blocking method. A study reported by Zhang et al. showed that MD-SNPs were extracted from published studies of GWAS, reviews, and meta-analysis, which epidemically related with micronutrient deficiency, and a method was established by modified microfluidic chip for MD-SNPs measurement by Xu et al. The study would explore possibility to describe MD potential risk from genetic point of view for an individual.

#### *3.5.2 Primer design of nutrition-related SNPs*

Primer mix contained three primers, common reverse primer, tailed allele primer 1 and tailed allele primer 2, in a ratio of 5:2:2. Primer mix (0.14 μl, 2 μM for each forward and reverse primers) was preloaded in a reaction chamber. Master mix containing FRET cassette plus enzymes with high-fidelity activity in an optimized buffer solution was stored at −20°C in the refrigerator, kept cool with ice when taken out from refrigerator, and vortex shocked before use (**Figure 1**).

#### *3.5.3 MD-SNP measurement process*

The material of the chip was polymethylmethacrylate (PMMA) and was fabricated by machining to final dimensions of 7.5 cm (length) × 2.5 cm (width) × 2 mm (thickness). There were 28 microchambers in a column and 4 parallel columns in a chip that supported for simultaneously testing of 112 SNPs in 3 genotypes of wild type, hybrid type, and mutant type. Each column consisted of a circular inlet and outlet, a "sine-shaped" sample infusing channel, 28 linking channels, and 28 circular reaction chambers. A modified method has been established to prepare the microfluidic chip. Prior to use, the chip was washed with ethanol and ultrapure water and dried with nitrogen gas. Then, the primer pairs were pipetted into different reaction chambers and allowed to dry at room temperature for 30 min. A piece of single-sided, PCR-compatible adhesive tape was used to seal the top side of the chip at 175°C for 1 min. After sealing, the primer-loaded chip was stored at 4°C before use. An aqueous PCR mixture containing PCR master mix and DNA template was loaded into infusing channels by pipetting from the inlets. Outlets and inlets on the bottom side were sealed with adhesive tape to achieve a fully hermetic system. Then, the chip was centrifuged at 4000 rpm for 1 min so that the PCR mixture was uniformly transferred into reaction chambers and thoroughly mixed with the preloaded primers mix, and the final reaction volume was 0.8 μl. Each linking channel was blocked at 150°C for 1 min. Then, the chip was placed on a MasterCycler Nexus flat and pressed with a PMMA block to ensure tight contact and avoid distortion of the chip under high temperature (**Figure 2**).

The temperature program of PCR in the chip was set as follows (**Figure 2**): hot-start activation at 94°C for 15 min, followed by 10 touchdown cycles (94°C for 20 s; touchdown 61–55°C, dropping 0.6°C per cycle), and then followed by 26 cycles of amplification (94°C 20 s; 55°C 60 s). After thermal cycling for 100 min, the amplified products were detected by LuxScan-10 K/A scanner at 40°C or below for

**103**

*Detection of Nutrient-Related SNP to Reveal Individual Malnutrition Risk*

15 min. The fluorescence intensity values (FIVs) were used to identify three distinct

*Steps and principle of allele-specific extension on primer arrays. (A), primer pairs mix containing two different, allele-specific, competing forward primers with unique tail sequences and one reverse primer. Master mix containing FRET cassette plus enzymes with high-fidelity activity in an optimized buffer solution. Test DNA with the SNP of interest. (B), in the first round of PCR, one of the allele-specific primers matches the target SNP and, with the common reverse primer, amplifies the target region; (C), in the second round of PCR, reverse primer binds, elongates, and makes a complement copy of allele-1 tail; (D), in the third round of PCR, FAM-labeled oligo binds to new complementary tail sequence and is no longer quenched; in further rounds of PCR, the levels of allele-specific tail increase. The fluorescent substance-labeled part of the FRET cassette is complementary to new tail sequences and binds, releasing the fluorescent substance from the quencher to* 

Odd-numbered chambers in a column of a chip were preloaded primer mix, while even-numbered chambers were not. In addition, gel electrophoresis was observed with solutions from the corresponding reaction chambers. For specificity of primer mix and accuracy, each primer pair preloaded chamber loaded different template DNAs in a concentration of 10 ng/μl with master mix pipetted into infusing channels. The results were compared with the expected results obtained by next-generation sequencing (NGS). For the selection of appropriate DNA reaction concentration, 52 difficult DNA templates were diluted to 1 ng/μl, 5 ng/μl, 10 ng/μl, and 15 ng/μl to test appropriate DNA reaction concentration, respectively. The repeatability of multiplexed SNPs is observed with four repeats of 52 MD-SNPs in one DNA template. All these experiments were repeated six times. The established method was used to measure DNA templates from six

genotypes of wild type, hybrid type, and mutant type.

*3.5.4 Cross-contamination test*

*generate a fluorescent signal.*

**Figure 1.**

*DOI: http://dx.doi.org/10.5772/intechopen.92458*

*Detection of Nutrient-Related SNP to Reveal Individual Malnutrition Risk DOI: http://dx.doi.org/10.5772/intechopen.92458*

#### **Figure 1.**

*Malnutrition*

*3.5.1 Microfluidic chip designed for malnutrition-related SNPs*

genetic point of view for an individual.

*3.5.3 MD-SNP measurement process*

*3.5.2 Primer design of nutrition-related SNPs*

Microfluidic chip as high-throughput technology could amplify large numbers of target DNA fragments at the same time in a chip, and the physical isolation of different primer pairs is a simple and effective strategy to avoid the drawbacks of conventional multiplex PCR. Xu et al. took this advantage to reduce the mutual interference and competition among different primers in one tube for multiple PCR [36]. They adopted a modified method with a blocking step, which had showed less contamination than that without blocking method. A study reported by Zhang et al. showed that MD-SNPs were extracted from published studies of GWAS, reviews, and meta-analysis, which epidemically related with micronutrient deficiency, and a method was established by modified microfluidic chip for MD-SNPs measurement by Xu et al. The study would explore possibility to describe MD potential risk from

Primer mix contained three primers, common reverse primer, tailed allele primer 1 and tailed allele primer 2, in a ratio of 5:2:2. Primer mix (0.14 μl, 2 μM for each forward and reverse primers) was preloaded in a reaction chamber. Master mix containing FRET cassette plus enzymes with high-fidelity activity in an optimized buffer solution was stored at −20°C in the refrigerator, kept cool with ice when

The material of the chip was polymethylmethacrylate (PMMA) and was fabricated by machining to final dimensions of 7.5 cm (length) × 2.5 cm (width) × 2 mm (thickness). There were 28 microchambers in a column and 4 parallel columns in a chip that supported for simultaneously testing of 112 SNPs in 3 genotypes of wild type, hybrid type, and mutant type. Each column consisted of a circular inlet and outlet, a "sine-shaped" sample infusing channel, 28 linking channels, and 28 circular reaction chambers. A modified method has been established to prepare the microfluidic chip. Prior to use, the chip was washed with ethanol and ultrapure water and dried with nitrogen gas. Then, the primer pairs were pipetted into different reaction chambers and allowed to dry at room temperature for 30 min. A piece of single-sided, PCR-compatible adhesive tape was used to seal the top side of the chip at 175°C for 1 min. After sealing, the primer-loaded chip was stored at 4°C before use. An aqueous PCR mixture containing PCR master mix and DNA template was loaded into infusing channels by pipetting from the inlets. Outlets and inlets on the bottom side were sealed with adhesive tape to achieve a fully hermetic system. Then, the chip was centrifuged at 4000 rpm for 1 min so that the PCR mixture was uniformly transferred into reaction chambers and thoroughly mixed with the preloaded primers mix, and the final reaction volume was 0.8 μl. Each linking channel was blocked at 150°C for 1 min. Then, the chip was placed on a MasterCycler Nexus flat and pressed with a PMMA block to ensure tight contact

taken out from refrigerator, and vortex shocked before use (**Figure 1**).

and avoid distortion of the chip under high temperature (**Figure 2**).

The temperature program of PCR in the chip was set as follows (**Figure 2**): hot-start activation at 94°C for 15 min, followed by 10 touchdown cycles (94°C for 20 s; touchdown 61–55°C, dropping 0.6°C per cycle), and then followed by 26 cycles of amplification (94°C 20 s; 55°C 60 s). After thermal cycling for 100 min, the amplified products were detected by LuxScan-10 K/A scanner at 40°C or below for

**102**

*Steps and principle of allele-specific extension on primer arrays. (A), primer pairs mix containing two different, allele-specific, competing forward primers with unique tail sequences and one reverse primer. Master mix containing FRET cassette plus enzymes with high-fidelity activity in an optimized buffer solution. Test DNA with the SNP of interest. (B), in the first round of PCR, one of the allele-specific primers matches the target SNP and, with the common reverse primer, amplifies the target region; (C), in the second round of PCR, reverse primer binds, elongates, and makes a complement copy of allele-1 tail; (D), in the third round of PCR, FAM-labeled oligo binds to new complementary tail sequence and is no longer quenched; in further rounds of PCR, the levels of allele-specific tail increase. The fluorescent substance-labeled part of the FRET cassette is complementary to new tail sequences and binds, releasing the fluorescent substance from the quencher to generate a fluorescent signal.*

15 min. The fluorescence intensity values (FIVs) were used to identify three distinct genotypes of wild type, hybrid type, and mutant type.

#### *3.5.4 Cross-contamination test*

Odd-numbered chambers in a column of a chip were preloaded primer mix, while even-numbered chambers were not. In addition, gel electrophoresis was observed with solutions from the corresponding reaction chambers. For specificity of primer mix and accuracy, each primer pair preloaded chamber loaded different template DNAs in a concentration of 10 ng/μl with master mix pipetted into infusing channels. The results were compared with the expected results obtained by next-generation sequencing (NGS). For the selection of appropriate DNA reaction concentration, 52 difficult DNA templates were diluted to 1 ng/μl, 5 ng/μl, 10 ng/μl, and 15 ng/μl to test appropriate DNA reaction concentration, respectively. The repeatability of multiplexed SNPs is observed with four repeats of 52 MD-SNPs in one DNA template. All these experiments were repeated six times. The established method was used to measure DNA templates from six

different samples to evaluate the possible MD risk of vitamin A, D, E, and B12, folate, calcium, iron, zinc, and selenium (**Figure 3**).

#### *3.5.5 Multiplex PCR in MD-SNP measurement*

Multiplex PCR is a promising method for multiple nucleic acid analysis and detection. Several primers involved in a single tube behaves as multiplex PCR, in which one allele sequence is often preferentially amplified, resulting in the scarcity of other allele sequences, so it is very tedious to establish an optimized multiplex PCR protocol. Most chip-based multiplexed genotyping platforms are suitable for large-scale studies requiring genotypic data with thousands of SNPs. Although

**Figure 2.** *Workflow protocol of the chip.*

#### **Figure 3.**

*The cross-contamination testing of adjacent reaction chambers. Odd number and even number represented reaction chambers with and without preloaded primers, respectively. (A) is the fluorescence pseudo-color image; (B) is the corresponding gray scale image; (C) is the electrophoretogram of the amplicons in each reaction chamber which corresponded to the product in the chamber of (A) or (B) above. The lane marked with M represents the DNA marker. The molecular weights of the bands from the top to bottom were 1200, 900, 700, 500, 300, and 100 bps.*

**105**

*Detection of Nutrient-Related SNP to Reveal Individual Malnutrition Risk*

multiplexing offers greater throughput with less reagent consumption, it restricts the use which require low to medium marker density, for example, Illumina company requires a minimum number of plates ordered in order to develop specific assays, and this requirement was much higher than individual needs. So Xu et al. developed an innovative microfluidic chip to be the most convenient and cost-effective option for genotyping various individuals, which physically isolates the primer pairs in a reaction chamber. Fifty-two SNPs demonstrated the effectiveness of our strategy by multiplex PCRs and further illustrated its clinical applicability with blood and saliva samples. As a qualitative method, primer pairs of MD-SNPs designed in this study could be successfully amplified in the given conditions and replicated target DNA fragments with additional florescence carriers of FAM and HEX. Three genotypes of mutant type, hybrid type, and wild type could be identified specifically and accurately by the measurement. The sample chambers showed averagely at least two times higher FIV than that of NTCs. 5 ng/μl or higher suggested the suitable DNA concentration for the selected 52 MD-SNPs, although the optimal concentration for each primer pair may be different. The method showed high repeatability in both inner chips and among chips. The results of 52 MD-SNPs determined by MD-chips and NGS were completely the same, suggesting a high accuracy of the method.

There are several advantages of the microfluidic chip multiplex PCR: (1) the generality of the primer design principle which was adopted by this microfluidic chip assays. The principle is developed for common use in all genotyping assays to stringently target the two alleles with standard PCR conditions and similar amplification efficiencies and significantly decreases the cost in PCR reagents and labors. (2) It is more specific. The microfluidic chip genotyping results were completely coincident with next-generation sequencing results. (3) It is easier. All the primer pairs are physically isolated; deleting or adding one or a few primer pairs from a multiplex PCR primer panel will not alter the performance of the other primer pairs with standard PCR conditions; almost no additional optimization is required. So, the universal protocol is viable for developing diverse multiplex PCR applications. (4) Its throughput is flexible. The selection of a technique has to weigh factors of instrument, throughput, technical support, and cost. Because of its unprecedented specificity, simplicity, and flexibility of throughout, the chip could serve as a powerful tool in clinical individual nutriment deficiency risk diagnostics for multiplexed detection of nutriments. The results of the analysis performed using the chip may provide early and crucial information for physicians to prevent nutriment deficiency risk and conduct appropriate nutritional intervention.

The MD-SNP chip method was used to measure MD risk of six students which showed distinguished differences of genetic potentials. The MD risk of six students was shown in a colored image in a pattern of SNP genotypes in three colors. The wild type was in red, hybrid type in orange, and mutant type in green. The risk of individuals in a micronutrient deficiency could be identified by the differences of red color areas. The genotype for each SNP of micronutrients in a person could be

The combination of this method with present laboratory measurement might comprehensively explain individual MD risk in both genetic and diet environmental

**4. Malnutrition risk evaluated by personal SNPs**

**4.1 Expression of malnutrition risk with MD-SNPs**

presented with the image (**Figure 4**).

**4.2 Guiding on nutrient intake with MD-SNP**

*DOI: http://dx.doi.org/10.5772/intechopen.92458*

#### *Detection of Nutrient-Related SNP to Reveal Individual Malnutrition Risk DOI: http://dx.doi.org/10.5772/intechopen.92458*

*Malnutrition*

different samples to evaluate the possible MD risk of vitamin A, D, E, and B12,

Multiplex PCR is a promising method for multiple nucleic acid analysis and detection. Several primers involved in a single tube behaves as multiplex PCR, in which one allele sequence is often preferentially amplified, resulting in the scarcity of other allele sequences, so it is very tedious to establish an optimized multiplex PCR protocol. Most chip-based multiplexed genotyping platforms are suitable for large-scale studies requiring genotypic data with thousands of SNPs. Although

*The cross-contamination testing of adjacent reaction chambers. Odd number and even number represented reaction chambers with and without preloaded primers, respectively. (A) is the fluorescence pseudo-color image; (B) is the corresponding gray scale image; (C) is the electrophoretogram of the amplicons in each reaction chamber which corresponded to the product in the chamber of (A) or (B) above. The lane marked with M represents the DNA marker. The molecular weights of the bands from the top to bottom were 1200, 900,* 

folate, calcium, iron, zinc, and selenium (**Figure 3**).

*3.5.5 Multiplex PCR in MD-SNP measurement*

**104**

**Figure 3.**

*700, 500, 300, and 100 bps.*

**Figure 2.**

*Workflow protocol of the chip.*

multiplexing offers greater throughput with less reagent consumption, it restricts the use which require low to medium marker density, for example, Illumina company requires a minimum number of plates ordered in order to develop specific assays, and this requirement was much higher than individual needs. So Xu et al. developed an innovative microfluidic chip to be the most convenient and cost-effective option for genotyping various individuals, which physically isolates the primer pairs in a reaction chamber. Fifty-two SNPs demonstrated the effectiveness of our strategy by multiplex PCRs and further illustrated its clinical applicability with blood and saliva samples. As a qualitative method, primer pairs of MD-SNPs designed in this study could be successfully amplified in the given conditions and replicated target DNA fragments with additional florescence carriers of FAM and HEX. Three genotypes of mutant type, hybrid type, and wild type could be identified specifically and accurately by the measurement. The sample chambers showed averagely at least two times higher FIV than that of NTCs. 5 ng/μl or higher suggested the suitable DNA concentration for the selected 52 MD-SNPs, although the optimal concentration for each primer pair may be different. The method showed high repeatability in both inner chips and among chips. The results of 52 MD-SNPs determined by MD-chips and NGS were completely the same, suggesting a high accuracy of the method.

There are several advantages of the microfluidic chip multiplex PCR: (1) the generality of the primer design principle which was adopted by this microfluidic chip assays. The principle is developed for common use in all genotyping assays to stringently target the two alleles with standard PCR conditions and similar amplification efficiencies and significantly decreases the cost in PCR reagents and labors. (2) It is more specific. The microfluidic chip genotyping results were completely coincident with next-generation sequencing results. (3) It is easier. All the primer pairs are physically isolated; deleting or adding one or a few primer pairs from a multiplex PCR primer panel will not alter the performance of the other primer pairs with standard PCR conditions; almost no additional optimization is required. So, the universal protocol is viable for developing diverse multiplex PCR applications. (4) Its throughput is flexible. The selection of a technique has to weigh factors of instrument, throughput, technical support, and cost. Because of its unprecedented specificity, simplicity, and flexibility of throughout, the chip could serve as a powerful tool in clinical individual nutriment deficiency risk diagnostics for multiplexed detection of nutriments. The results of the analysis performed using the chip may provide early and crucial information for physicians to prevent nutriment deficiency risk and conduct appropriate nutritional intervention.

#### **4. Malnutrition risk evaluated by personal SNPs**

#### **4.1 Expression of malnutrition risk with MD-SNPs**

The MD-SNP chip method was used to measure MD risk of six students which showed distinguished differences of genetic potentials. The MD risk of six students was shown in a colored image in a pattern of SNP genotypes in three colors. The wild type was in red, hybrid type in orange, and mutant type in green. The risk of individuals in a micronutrient deficiency could be identified by the differences of red color areas. The genotype for each SNP of micronutrients in a person could be presented with the image (**Figure 4**).

#### **4.2 Guiding on nutrient intake with MD-SNP**

The combination of this method with present laboratory measurement might comprehensively explain individual MD risk in both genetic and diet environmental

**Figure 4.**

conditions, thus facilitating with precise nutrition intervention. For example, MTHFR-C677T polymorphism has been extensively studied, and the association between the TT genotype and low folate status is well documented. Individuals with the TT genotype seem to be particularly susceptible to insufficient status of several B vitamins, and they may need to consume more folate to maintain serum folate levels similar to those found in individuals with the CC/CT genotypes. A study by Crider et al. reported that daily 0.8 mg folic acid may be necessary to lower homocysteine concentration for Chinese hypertensive subjects with CT or TT genotype, which have important clinical and public health implications [37]. The Centers for Disease Control and Prevention in the United States showed in 1992 that women who have previously suffered a NTD-affected pregnancy are advised to take 4 mg of folic acid daily before conception and during the first months of pregnancy [38]. Then we could calculate the required amount of an individual micronutrients according to SNPs.

In the real world, the body's nutritional status is regulated by multiple genes and nutrients. For example, homocysteine (Hcy) is a precursor of methionine and cysteine. Methionine converts into S-adenosyl methionine, which acts as a universal methyl donor. These multistep reactions involve various enzymes and cofactors in the form of essential micronutrients, which include vitamin B complex family (B2, B6, B9, and B12). Therefore, in measuring tHcy, folic acid and vitamin B12, vis-a`-vis the genotypes of the Hcy-pathway genes, Zhang et al. evaluated contribution of the individual variables (SNPs of Hcy-pathway genes) in the development of the phenotype (Hcy level) and get an estimate of the relative contribution of the environment (vitamins) in modulating the effect of genotypes in this region. Hyperhomocysteinemia is a result of either reduced enzymatic activity in the enzymes that participate in homocysteine metabolism and/or a reduction in the concentrations of plasma B vitamins, particularly, folate. Dietary intake of folate or folic acid supplementation can lower the concentration of p-tHcy. The establishment of gender and age as covariates is associated with SNP HCY polygenic risk score model (PRS), PRS = −0.024802rs2274976 + 0.025011rs1801131 + 0.205567rs1801133– 0.025646rs1805087–0.025047rs2118981 + 0.340703rs492602– 0.448651rs602662 + 0.067954sex + 0.060073 age+1.553543; sex, female 0, male 1; age, Year (R2 = 0.4084, *p* < 2.2e-16).

The incidence of early detection, prevention, and intervention was the fundamental goal of promoting human health; predicting the probability of an

**107**

**Author details**

Prevention, China

Junsheng Huo\* and Chunhong Zhang

provided the original work is properly cited.

Institute of Nutrition and Health of China's Center for Disease Control and

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: huojs@ninh.chinacdc.cn

*Detection of Nutrient-Related SNP to Reveal Individual Malnutrition Risk*

individual assessment of the risk of susceptibility to disease was the core clinical decision-making, especially for the detection and prevention of common diseases. The current clinical data for common adult disease risk often relied on basic human indicators, such as age, gender and ethnicity, lifestyle, and basic health indicators, such as body mass index, smoking status, alcohol use, and physical activity habits; suffering disease relevant to the biomarkers like blood pressure level and biochemical indexes; analysis of environmental exposure, such as air pollution, heavy metals, and other environmental toxins; and family history. Many recent studies have begun to demonstrate the utility of gene association analysis and access to individual genetic susceptibility to a disease useful for the guidance of information from the probability of large population data. In theory, gene mapping could be

*DOI: http://dx.doi.org/10.5772/intechopen.92458*

considered a useful part of a healthy management.

#### *Detection of Nutrient-Related SNP to Reveal Individual Malnutrition Risk DOI: http://dx.doi.org/10.5772/intechopen.92458*

individual assessment of the risk of susceptibility to disease was the core clinical decision-making, especially for the detection and prevention of common diseases. The current clinical data for common adult disease risk often relied on basic human indicators, such as age, gender and ethnicity, lifestyle, and basic health indicators, such as body mass index, smoking status, alcohol use, and physical activity habits; suffering disease relevant to the biomarkers like blood pressure level and biochemical indexes; analysis of environmental exposure, such as air pollution, heavy metals, and other environmental toxins; and family history. Many recent studies have begun to demonstrate the utility of gene association analysis and access to individual genetic susceptibility to a disease useful for the guidance of information from the probability of large population data. In theory, gene mapping could be considered a useful part of a healthy management.

### **Author details**

*Malnutrition*

**Figure 4.**

conditions, thus facilitating with precise nutrition intervention. For example, MTHFR-C677T polymorphism has been extensively studied, and the association between the TT genotype and low folate status is well documented. Individuals with the TT genotype seem to be particularly susceptible to insufficient status of several B vitamins, and they may need to consume more folate to maintain serum folate levels similar to those found in individuals with the CC/CT genotypes. A study by Crider et al. reported that daily 0.8 mg folic acid may be necessary to lower homocysteine concentration for Chinese hypertensive subjects with CT or TT genotype, which have important clinical and public health implications [37]. The Centers for Disease Control and Prevention in the United States showed in 1992 that women who have previously suffered a NTD-affected pregnancy are advised to take 4 mg of folic acid daily before conception and during the first months of pregnancy [38]. Then we could calculate the required amount of an individual micronutrients

*The color grade of nine MD-SNPs in six measured individual samples. S, sample.*

In the real world, the body's nutritional status is regulated by multiple genes and nutrients. For example, homocysteine (Hcy) is a precursor of methionine and cysteine. Methionine converts into S-adenosyl methionine, which acts as a universal methyl donor. These multistep reactions involve various enzymes and cofactors in the form of essential micronutrients, which include vitamin B complex family (B2, B6, B9, and B12). Therefore, in measuring tHcy, folic acid and vitamin B12, vis-a`-vis the genotypes of the Hcy-pathway genes, Zhang et al. evaluated contribution of the individual variables (SNPs of Hcy-pathway genes) in the development of the phenotype (Hcy level) and get an estimate of the relative contribution of the environment (vitamins) in modulating the effect of genotypes in this region. Hyperhomocysteinemia is a result of either reduced enzymatic activity in the enzymes that participate in homocysteine metabolism and/or a reduction in the concentrations of plasma B vitamins, particularly, folate. Dietary intake of folate or folic acid supplementation can lower the concentration of p-tHcy. The establishment of gender and age as covariates is associated with SNP HCY polygenic risk score model (PRS), PRS = −0.024802rs2274976 + 0.025011rs1801131 + 0.205567rs1801133–

0.448651rs602662 + 0.067954sex + 0.060073 age+1.553543; sex, female 0, male 1;

The incidence of early detection, prevention, and intervention was the fundamental goal of promoting human health; predicting the probability of an

0.025646rs1805087–0.025047rs2118981 + 0.340703rs492602–

= 0.4084, *p* < 2.2e-16).

**106**

age, Year (R2

according to SNPs.

Junsheng Huo\* and Chunhong Zhang Institute of Nutrition and Health of China's Center for Disease Control and Prevention, China

\*Address all correspondence to: huojs@ninh.chinacdc.cn

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### *Edited by Muhammad Imran and Ali Imran*

Malnutrition is a major threat faced by the developing nations and it has caused a severe health care and economic burden. This menace causes severe structural and functional abnormalities that hinders the growth of the individual and nation. This book provides complete insight of the problem, pathophysiology, impact and rectifying strategies. Moreover, this book encompasses the different sections that highlight the problem in a sequential manner. Hopefully, this book will prove to be an aid for the reader to enlighten their knowledge regarding malnutrition and its tackling strategies.

Published in London, UK © 2020 IntechOpen © Jezperklauzen / iStock

Malnutrition

Malnutrition

*Edited by Muhammad Imran and Ali Imran*