Scoping review of micronutrient imbalances, clinical manifestations, and interventions

Abstract

Micronutrients are fundamental to support and maintain normal physiological function. Deficiencies of these nutrients are a growing public health concern with potentially devastating consequences. An adequate diet of whole foods is the primary source of micronutrients; supplementation is sometimes necessary. Both deficiency and excess of these nutrients have adverse effects. Common deficiencies include iron, folate, iodine, zinc, and vitamin A, which can present clinically as a syndrome. Micronutrient deficiencies (MNDs) are common contributors to intellectual impairments, poor growth, perinatal complications, and increased risk for morbidity and mortality. Excess of a select few of these nutrients can result in conditions such as idiopathic intracranial hypertension and diarrhea. Interventions, including supplementation, fortification, and biofortification, can help combat MNDs. This article reviews some common micronutrient imbalances, their clinical manifestations, and treatment interventions.

Key Words: Micronutrient; Iron; Vitamin A; Vitamin B12; Fat-soluble vitamin; Water soluble vitamin; Vitamin C; Micronutrient deficiency

Core Tip: Micronutrient deficiency is an emerging public health concern affecting more than 2 billion people globally. These deficiencies can contribute to poor growth and intellectual disabilities, which increase the risk of morbidity and mortality, particularly in developing countries. Risk factors vary by micronutrient deficiency. Early recognition and intervention by clinicians drastically decrease global mortality. This article reviews various micronutrient deficiencies, their clinical features, and treatments in detail.

INTRODUCTION

Nutrition is a modifiable factor that can be targeted to promote optimal health and reduce disease risk throughout a lifetime[1]. A healthy diet contains all the resources needed to meet the body’s metabolic demands[1,2]. Nutrients (macronutrients and micronutrients) are essential molecules required to sustain a healthy and prolonged life[2,3]. Macronutrients (carbohydrates, lipids, and protein) are needed in significant amounts to facilitate hormone creation, synthesis of molecules, energy production, and regulation of metabolic pathways[4]. In smaller quantities, micronutrients such as minerals, vitamins, and antioxidants are needed to aid biochemical processes such as enzyme reactions, protection against oxidative stress, and gene transcription[5,6].

Micronutrient deficiencies (MNDs) occur when an individual, regardless of reason, does not consume an adequate amount of food to meet their energy requirements[5-7]. Patients at risk include older adults, individuals with alcohol use disorders, pregnant women, vegans or vegetarians, and persons with increased requirements due to medical conditions or long-term drug use that alters metabolism, absorption, and excretion[7-9]. A sufficient amount is needed to support physiological processes and metabolism[10]. However, inadequate and excessive intake can be harmful and should be avoided[8-10]. MNDs continue to affect more than 2 billion people worldwide despite advances in technology and science[11]. In this article, we provide a scoping review of MNDs with a particular focus on fat and water-soluble vitamins, their clinical manifestations, and treatment. A few micronutrients in excess were expanded upon.

EPIDEMIOLOGY

Micronutrients are vitamins and minerals needed by the body in small quantities to meet its daily metabolic needs[11,12]. Deficiency occurs with low dietary intake of these compounds, and it is particularly prevalent in the developing world, affecting an estimated 2 billion people worldwide[11,13]. A lack of iron, folate, and vitamin B₁₂ can result in anemia, which affects an estimated 42% of children under 5 years of age and approximately 40% of pregnant women[14,15]. Prevalence rates of MND are typically higher across South Asia and sub-Saharan Africa[16,17].

More than half of children under age five and more than two-thirds of women of reproductive age are deficient in at least one micronutrient[14-18]. Iron is the most common MND worldwide, which can result in anemia[19]. The World Health Organization (WHO) estimates that 25% of people worldwide have anemia and iron deficiency, the most common cause, is responsible for 50% of all cases[20,21]. Approximately 1.2 billion people worldwide suffer from iron deficiency anemia, with a higher prevalence in women and children[22,23].

These deficiencies are particularly prevalent in low-income countries, suggesting that poor sanitation, poor diet, and inadequate health care are major contributory factors[11,13,16,18]. Anemia and iodine deficiency disorders separately affect approximately 2 billion people in both developed and developing countries, and vitamin A deficiency is prevalent in up to 12% of low-income nations[13-19]. Muthayya et al[24] defined the hidden hunger index based on the national estimates of the prevalence of stunting, anemia due to iron deficiency, and low serum retinol concentration. Hot spots were found in South Asia and sub-Saharan Africa, where the highest prevalence of exists. MNDs are more common in developing countries, and clinical outcomes are more severe, given the lack of resources, including the quality of healthcare within these areas[12,14,16,18,20,22].

SOURCES AND CLINICAL MANIFESTATIONS OF FAT-SOLUBLE VITAMIN DEFICIENCIES/EXCESS

Fat-soluble vitamins, including A, D, E, and K, are energy-independent molecules that are essential to maintain adequate bodily function[25]. Their intake is almost exclusively from diet[26]. As such, deficiencies in fat-soluble vitamins are more likely seen in developing countries with limited resources than in industrialized nations[27]. These vitamins are classically absorption dependent on bile emulsification, pancreatic secretions, and a functional ileum[28]. Due to this fact, certain patient groups are at a higher risk for deficiencies, including those with liver disease, malabsorption syndromes with steatorrhea (i.e., celiac disease and cystic fibrosis) intensive care unit patients, and patients with chronic mineral oil intake[29-31]. Toxicity is less common for fat-soluble vitamins compared to water-soluble as fat-soluble molecules accumulate in fat[32]. The clinical manifestations of fat-soluble vitamin deficiencies and their dietary sources can be seen below.

Vitamin A

Vitamin A is a general term for a group of fat-soluble compounds consisting primarily of retinol and retinyl esters[33]. This class of molecules are responsible for immune function, reproductive growth, and cellular signaling and differentiation[33,34]. Vitamin A is essential for the differentiation of epithelial cells into specialized tissues (mucus-secreting and pancreatic cells), playing a crucial role in the normal formation and maintenance of organs such as the lungs, heart, and eye[33-35]. It is also critical for vision, as it serves as an essential component of rhodopsin, the light-sensitive protein found in the rod cells of the retina that plays a pivotal role in the process of visual transduction[36,37].

Dietary vitamin A can be found in animal products, including kidney, liver, dairy products, and eggs[38]. They additionally can be seen as provitamin A (β-carotene) in plant sources, such as fruits and leafy vegetables[38,39]. Patients with vitamin A deficiency may present clinically with reduced night vision, dry eyes, keratomalacia, hyperkeratotic papular lesions, immunosuppression with recurrent infections, and dry skin[38-41]. Ophthalmological examination reveals conjunctival lesions with triangular perilimbal debris[41,42]. In healthy adults, vitamin A's recommended dietary allowance (RDA) is 700 mcg per day for women and 900 mcg per day for men. In pregnant women, the RDA is 770 mcg per day, while in children, it ranges between 300 to 900 mcg per day.

Toxicity: Excessive consumption of vitamin A can lead to acute and chronic toxicity[43]. This is characterized by elevated levels of > 80 mcg/dL in the body, known as hypervitaminosis A[43,44]. Acute vitamin A toxicity leads to nausea, vomiting, and elevated intracranial pressure, which can present clinically with blurred vision and vertigo[45]. Patients with chronic toxicity, in contrast, present clinically with alopecia, xerosis cutis, idiopathic intracranial hypertension, and hepatomegaly/hepatoxicity[45,46].

Vitamin D

Vitamin D is a fat-soluble entity that plays a vital role in calcium regulation and bone metabolism[47]. It has also been shown to play a key part in muscle, cardiovascular, immune, and nervous system functions[47-49]. Vitamin D is known as an immunomodulatory hormone, as experimental studies have shown that the active form [1,25-dihydroxyvitamin D₃ = 1,25(OH)2 D₃] exerts immunological activities on components of the adaptive and innate immune system[50]. There have been observed associations between low levels of serum 25-hydroxyvitamin D [25(OH)D] and the development of autoimmune disorders such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and others[51].

Vitamin D is obtained primarily from diet in the form of fish, milk, plants, fungi, and yeast [ergocalciferol (D₂) and cholecalciferol (D₃)][52]. Cholecalciferol can additionally be synthesized from skin exposure to the sun[53]. Both forms are converted to the storage form [25(OH)D] of vitamin D in the liver and then subsequently to the active form, 1,25(OH)2 D₃ (calcitriol) in the kidney that increases intestinal absorption of calcium, promotes bone resorption, and decreases renal excretion of calcium and phosphate (Figure 1)[54,55]. Deficiency of vitamin D can be caused by malabsorption, reduced sun exposure, chronic kidney disease, poor diet, and advanced liver disease[56]. In children, deficiency can lead to rickets, a condition characterized by a defect in mineralization of the epiphyseal plates, which can present clinically with craniotabes, rickety rosary, spinal column deformity, genu varum, and other musculoskeletal findings (i.e., bone softening, gait disturbance, and growth retardation)[57,58]. In adults, it may lead to osteomalacia, characterized by abnormal bone mineralization, which may present clinically with bone pain, muscle weakness, and hypocalcemic tetany[59].

Figure 1 Diagram depicting the activation of vitamin D. Vitamin D from diet and the skin forms pre-vitamin D₃, which is converted to the storage form of vitamin D (25-hydroxyvitamin D) in the liver via 25-hydroxylase. Low serum calcium and phosphorous concentrations activate the kidney, converting 25(OH)D to activated 1,25(OH)2 D₃via 1α-hydroxylase. This activated form subsequently promotes calcium and phosphorus reabsorption in the kidneys and intestines and increases the release of both minerals from the bone.

Recommendations regarding daily vitamin D intake vary by age. The Endocrine Society defines vitamin D [25(OH)D] deficiency as less than 30 ng/mL[60]. To maintain levels within the preferred range of 40 to 60 ng/mL, the organization recommends an intake of 400 to 1000 international units (IU) daily for infants below 1 year old, 600 to 1000 IU per day for children and adolescents up to 18 years old, and 1500 to 2000 IU for all adults. Oral vitamin D should be given to breastfed infants[61]. Darker skin and prematurity notably predispose to deficiency[62].

Toxicity: Elevated levels of vitamin D, also known as hypervitaminosis D, are related to excessive long-term intake, disruptions in the metabolic pathway, or concurrent disease that produces the active vitamin D metabolite[63]. This condition presents a range of clinical symptoms[63]. These include abdominal pain, polyuria, polydipsia, confusion, apathy, and loss of appetite[32,63]. Laboratory assessment typically shows hypercalcemia, hypercalciuria, and 25(OH)D concentrations > 150 ng/mL (> 375 nmol/L)[32,63,64]. Hypervitaminosis D can also be seen in granulomatous diseases that increase vitamin D levels by activating epithelioid macrophages[65].

Vitamin E

Vitamin E is the combined name for a group of fat-soluble vitamins with distinct antioxidant properties[66]. They act as antioxidants that protect red blood cells (RBCs) and neuronal membranes from free radical damage[66,67]. Naturally occurring vitamin E exists in several chemical forms that possess different levels of biological activity[68]. The α-tocopherol is the only form recognized to meet human metabolic needs[69]. Vitamin E is found in avocadoes, soybeans, nuts, olive oil, and leafy vegetables[68,69].

Clinical manifestations of Vitamin E deficiency include acanthocytosis, muscle weakness, ataxia, decreased proprioception and vibration, and hemolytic anemia[70]. Demyelination of the spinocerebellar tract and the posterior columns is responsible for ataxia and loss of proprioception and vibration, respectively[71,72]. These neurological symptoms may appear similar to those of patients with vitamin B₁₂ deficiency. However, megaloblastic anemia and elevated serum methylmalonic acid levels are absent[69-72]. The RDA for patients aged 14 years and older is 15 mg of α-tocopherol.

Toxicity: Vitamin E toxicity is associated with an elevated bleeding risk[73]. High-dose supplementation is known to alter the metabolism of vitamin K, which can enhance the anticoagulation effect in patients on warfarin[74]. In infants, toxicity is associated with the risk of enterocolitis[75].

Vitamin K

Vitamin K is a group of molecules, including phylloquinone (vitamin K₁) and a series of menaquinones (vitamin K₂), that are naturally present in some foods[76]. Menaquinones are designated as MK-4 through MK-13 based on the length of their unsaturated isoprenyl side chains, with MK-4, MK-7, and MK-9 being the most well-studied menaquinones[77]. Phylloquinone is found in green leafy vegetables and is the primary dietary source of vitamin K[78]. Menaquinone is primarily synthesized in the human gut by bacteria[77,79]. Vitamin K is activated by epoxide reductase to the reduced form, which serves as a cofactor for the γ-carboxylation of glutamic acid residues, that is essential for the maturation of clotting factors II, VII, IX, X, protein C and S[77-81].

Clinical manifestations of vitamin K deficiency include neonatal hemorrhage, as neonates possess sterile intestines and are unable to synthesize vitamin K[82]. Labs commonly show elevated prothrombin, activated partial thromboplastin, and normal bleeding time[82,83]. The absence of vitamin K in the human body can result in a range of complications, including impaired bone development, bleeding disorders, and elevated risk for cardiovascular disease[82-85]. For adult men and women, the RDA of vitamin K is 120 and 90 mcg per day, respectively.

SOURCES AND CLINICAL MANIFESTATIONS OF WATER-SOLUBLE VITAMIN DEFICIENCIES/EXCESS

Water-soluble vitamins are a group of organic compounds that are required in small amounts by the human body to prevent disorders of metabolism[86]. Given their chemical properties, regular intake is required to avoid nutritional deficiency. The water-soluble vitamins include vitamin C and vitamin B complex (thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folate, cobalamin, and ascorbic acid). These vitamins are readily excreted from the body except cobalamin (B₁₂) and folate (B₉)[87]. B₁₂ is stored in the liver for approximately 3-4 years, while B₉ is stored in the same organ for 3-4 months[88]. B-complex deficiencies often result in dermatitis, glossitis, and diarrhea[88,89]. These compounds can also be coenzymes (i.e., ascorbic acid) or precursors to coenzymes [i.e., flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide+ (NAD+)][88-90]. The clinical manifestations of water-soluble vitamin deficiencies and their dietary sources can be seen below.

B₁ (thiamine)

Vitamin B₁, or thiamine, is a water-soluble compound that is a cofactor for various enzymes important in energy metabolism and glucose breakdown[91]. As such, it plays a critical role in cell growth, development, and function[91,92]. Approximately 80% of thiamin in the adult human body is thiamine pyrophosphate, the main metabolically active form of thiamine[91-93]. It can be found in nuts, poultry, soybeans, fortified foods, and peas[92-94]. Thiamine status is often measured indirectly by assaying transketolase activity following B₁ administration[95]. An increase in RBC transketolase activity following thiamine administration suggests deficiency[93-95].

Inadequate levels of thiamine results in impaired glucose breakdown, which leads to adenosine triphosphate (ATP) depletion[91-94]. As such, highly aerobic tissues (i.e., the heart and brain) are affected more acutely[91-95]. Risk factors for deficiency include malnutrition and chronic alcohol overuse[96]. Insufficient levels of this vitamin can lead to several notable disorders, including Wernicke encephalopathy, Korsakoff syndrome, Wernicke-Korsakoff syndrome, and dry and wet beriberi[91-96].

Wernicke encephalopathy is an acute reversible life-threatening neurological condition due to B₁ deficiency in the setting of alcohol use that may present clinically with confusion, ophthalmoplegia/nystagmus, and ataxia[97]. Thiamine deficiency can also lead to Korsakoff syndrome, which is an amnestic disorder due to chronic alcohol use that presents clinically with confabulations, memory loss, and personality changes[97,98]. Wernicke-Korsakoff syndrome appears clinically as a combination of both disorders due to damage to the mammillary bodies and the medial dorsal nucleus of the thalamus[99]. Inadequate thiamine levels can also cause dry beriberi syndrome, which presents clinically with polyneuropathy and symmetric muscle wasting, as well as wet beriberi, which causes high-output heart failure due to systemic vasodilation[100,101]. The RDA for adult males and females is 1.2 and 1.0 mg per day, respectively.

B₂ (riboflavin)

Riboflavin is a water-soluble vitamin that serves as an essential component of two major coenzymes, FAD and flavin mononucleotide[102,103]. These enzymes play a significant part in energy production, cellular function, and growth[102-104]. FAD and flavin mononucleotide are used as cofactors in redox reactions (i.e., succinate dehydrogenase reaction in the Krebs cycle)[105]. Riboflavin also plays a role as an antioxidant, as it helps in the regeneration of glutathione[106]. It can be found in fortified grains, dairy products, and certain fruits and vegetables[102-106].

Riboflavin deficiency can cause cheilosis and corneal vascularization. The RDA for women and men is 0.9 to 1.1 and 1.1 to 1.3 mg per day, respectively.

B₃ (niacin)

Niacin is a water-soluble B vitamin that is naturally present in many foods[107]. Body tissues convert niacin to its metabolically active form, NAD, which serves as a catalyst for more than 400 enzymes in the body[107]. NAD is also converted into another active form, nicotinamide adenine dinucleotide phosphate (NADP), which facilitates reactions in all tissues except skeletal muscle[108]. NAD is primarily involved in catabolic reactions that transform potential energy in proteins, fats, and carbohydrates to ATP[109]. NADP, in contrast, facilitates anabolic reactions such as fatty acid and cholesterol synthesis and plays a role in maintaining cellular antioxidant function[110]. Both are used in redox reactions and are cofactors for many dehydrogenases[107-110]. Niacin can be found in milk, meat, legumes, and fish[108,109]. Tryptophan is also a precursor for niacin to create NAD, so tryptophan is considered a dietary source of niacin[111].

Deficiencies are more common in developing countries due to insufficient dietary intake[108-112]. The lack of niacin and its precursor tryptophan leads to the manifestation of pellagra, which may be due to inadequate intake, Hartnup disease, malignant carcinoid syndrome, or isoniazid deficiency[113-115]. Symptoms of niacin deficiency include diarrhea, dementia (also hallucinations), and dermatitis (C3/C4 dermatome circumferential rash and hyperpigmentation on sun-exposed limbs)[108,110,113,115]. Hartnup disease is a rare autosomal recessive disorder due to a deficiency of neutral amino acid transporters in the proximal renal tubular cells and enterocytes[116]. This leads to neutral aminoaciduria and decreased absorption from the gut, resulting in little or no tryptophan for conversion to niacin, ultimately leading to pellagra-like symptoms. The RDA of niacin is 14 mg per day for women and 16 mg per day for men.

Toxicity: If niacin is consumed at high doses through supplements, it can lead to niacin toxicity. High doses of nicotinic acid may present clinically with facial flushing, hyperglycemia, hepatotoxicity, and hyperuricemia[117].

B₅ (pantothenic acid)

Pantothenic acid is a water-soluble compound that is naturally present in some foods and available as a dietary supplement[118]. The main function of vitamin B₅ is in the synthesis of coenzyme A (CoA) and acyl carrier protein[118,119]. It also serves as a component of fatty acid synthase[119]. Pantothenic acid is found in milk, vegetables, eggs, chicken, and others[118-120].

Deficiency of B₅ may lead to dermatitis, enteritis, alopecia, and adrenal insufficiency, which may lead to burning feet syndrome, distal paresthesias, and dysesthesia[119-121]. The RDA for adult men and women is 5 mg per day.

B₆ (pyridoxine)

Pyridoxine is a group of water-soluble vitamins that are naturally present in many foods[122]. Pyridoxal 5’ phosphate and pyridoxamine 5’ phosphate are the active coenzyme forms of B₆[123]. Pyridoxal 5’ phosphate is a cofactor that is used in several metabolic processes, including transamination, decarboxylation, and phosphorylation reactions[124]. It also plays a vital role in protein, carbohydrate, lipid metabolism, and the creation of RBCs[122-124]. Pyridoxine can be found in liver, poultry, and fortified cereals[122,123].

Patients with pyridoxine deficiency may present clinically with convulsions, hyperirritability, and peripheral neuropathy[125]. Some patients may appear with sideroblastic anemia due to impaired hemoglobin synthesis and iron excess[126]. The RDA for adults is 1.75 mg per day.

B₇ (biotin)

Biotin is a water-soluble compound that plays a role in energy metabolism and the regulation of oxidative stress[127]. It serves as a cofactor for several carboxylation enzymes, including pyruvate carboxylase, acetyl-CoA carboxylase, and propionyl-CoA carboxylase[127,128]. The vitamin can be found in many foods, such as egg yolk, liver, wheat, dairy, rice, and spinach[127,128].

Biotin deficiency is relatively rare[129]. It is commonly caused by long-term antibiotic use or excessive ingestion of raw egg whites, as raw egg whites contain a large volume of avidin, which binds to biotin[129,130]. Patients with a deficiency in this vitamin may clinically present with dermatitis, enteritis, and alopecia[127-130]. Intake recommendations range between 5 and 35 mcg per day.

B₉ (Folate)

Folate is a water-soluble B molecule that is present in multiple foods and is available as a dietary supplement[131]. Folate in foods is in the tetrahydrofolate form and usually possesses additional glutamate residues, making them polyglutamates[131,132]. Folic acid is the completely oxidized monoglutamate form of the vitamin that is used in most dietary supplements and fortified foods[133]. Folate plays a crucial role in the methylation/1-carbon transfer reactions necessary for deoxyribonucleic acid (DNA) and ribonucleic acid synthesis and metabolism of amino acids[131-133]. One of the most important folate-dependent reactions is the methylation of deoxyuridylate to thymidylate in the formation of DNA, which is required for proper cell division[134]. Impairment in this reaction initiates several steps that can lead to megaloblastic anemia, one of the hallmarks of folate deficiency[135]. Folate can be found in leafy green vegetables, eggs, and milk[132-136]. It is also produced by the guy microbiota, and a small, reserved pool is stored primarily in the liver[131-135].

Risk factors for folate deficiency include pregnancy, chronic alcohol use, digestive disorders such as Crohn’s disease, and several medications (i.e., phenytoin, trimethoprim, and methotrexate)[131,136,137]. These patients may clinically present with glossitis, megaloblastic anemia, and oral ulcers[134-137]. Folate deficiency before and during pregnancy increases the risk of neural tube defects[138]. A healthy adult requires 400 mcg per day, with higher intakes recommended during pregnancy to prevent neural tube defects.

B₁₂ (cobalamin)

Vitamin B₁₂ is a water-soluble vitamin that is required for the development, myelination, and function of the central nervous system[139]. Cobalamin is also essential for RBC formation and DNA synthesis[139,140]. It serves as a cofactor for methionine synthase and L-methylmalonyl-CoA mutase[141]. Methionine synthase catalyzes the conversion of homocysteine to methionine[142]. Methionine is needed for the creation of S-adenosylmethionine, which is a universal methyl donor for several substrates, including ribonucleic acid, DNA, proteins, and lipids[141,142]. L-methylmalonyl-CoA mutase converts L-methylmalonyl-CoA to succinyl-CoA in the metabolism of propionate. B₁₂ is found in animal products (i.e., meat, dairy, eggs) and is synthesized only by intestinal microbiota[141-143]. The site of synthesis in humans is distal to the site of absorption[144]. Thus, B₁₂ must be consumed via animal products[143,144].

Humans possess a very large reserve pool of B₁₂ that is primarily stored in the liver[145]. Deficiency can be caused by a lack of intrinsic factor (i.e., pernicious anemia, gastric bypass surgery), malabsorption (i.e., enteritis, sprue, achlorhydria, alcohol overuse, bacterial overgrowth, Diphyllobothrium latum), insufficient intake (i.e., veganism), absence of ileum (surgical resection, i.e., Crohn’s) and certain medications (i.e., metformin)[146-149]. Patients with deficiency may present with megaloblastic anemia, paresthesias, and subacute combined degeneration in severe cases (degeneration of dorsal columns, lateral corticospinal tracts, and spinocerebellar tracts) due to abnormal myelin[141,143,144,148-150]. B₁₂ deficiency is associated with elevated serum homocysteine and methylmalonic acid levels and secondary folate deficiency[146-151]. A prolonged state of insufficiency can lead to irreversible nerve damage. The RDA of cobalamin for adults is 2.4 mcg per day.

Vitamin C (ascorbic acid)

Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that is present in certain foods[152]. Unlike most animals, humans cannot produce endogenous vitamin C, so it is essentially a dietary component[153]. Vitamin C is required for the biosynthesis of L-carnitine, collagen, and certain neurotransmitters[154]. It is necessary for the hydroxylation of lysine and proline in collagen synthesis, which plays a vital role in wound healing[152-154]. The vitamin is also necessary for dopamine β-hydroxylase, which converts dopamine to norepinephrine[155]. It additionally serves as an antioxidant and has been shown to regenerate other antioxidants within the body, including vitamin E[156,157]. In addition to its synthetic and antioxidant properties, vitamin C facilitates iron absorption and plays an important role in immune function[158]. It is primarily found in fruits and vegetables, such as citrus, potatoes, berries, and green leafy vegetables[155-159].

Severe vitamin C deficiency can result in scurvy, a disorder characterized by swollen gums, easy bruising, petechiae, anemia, hemarthrosis, poor wound healing, corkscrew hair, and perifollicular and subperiosteal hemorrhages[160]. This simultaneously results in a weakened immune system[160,161]. The recommended intake may vary based on age and gender but typically falls between 40 and 120 mg per day.

Toxicity: Excess vitamin C intake can lead to nausea, vomiting, fatigue, diarrhea, and calcium oxalate stones[162,163]. Elevated levels can also increase iron toxicity in predisposed individuals by increasing dietary iron absorption (i.e., it can worsen transfusion-related iron overload or hemochromatosis)[164,165].

DIAGNOSIS AND TREATMENT OF FAT/WATER-SOLUBLE VITAMIN DEFICIENCIES

Before treatment, a practitioner must obtain a diagnosis. This begins with attaining a good clinical history from the patient, including their surgical past and dietary habits. Based on clinical suspicion, the provider should perform a complete physical examination to look for the clinical signs described above. The next step includes a series of direct and indirect assays performed on the blood to determine vitamin levels, as seen in Table 1. Some deficiencies are clinically diagnosed, and laboratory assessment further confirms suspicion[166-168]. Biomarker limitations in a lab setting stem from elements such as cost, assay standardization, variability in measurement, and sampling handling. These host of factors can ultimately affect biomarker reliability and accuracy, especially in low-income countries that may not have adequate resources. Due to this fact, clinicians should not diagnose MND, or excess solely based on laboratory values.

Table 1 Laboratory testing for diagnostic evaluation of several micronutrient deficiencies.

Vitamin	Diagnostic test	Specimen type	Diagnostic values
A	Vitamin A (retinol) level	Serum	Low
D	Total 25-hydroxyvitamin D level	Serum	Low
E	Vitamin E (α-tocopherol) level	Serum	Low
K1	PT/INR	Serum	Prolonged/elevated
Thiamine2	Thiamine, whole blood	Whole blood EDTA	Low
Riboflavin	Riboflavin level or urinary excretion rate	Plasma or urine	Low
Niacin	Niacin level or urinary excretion of N1-methylnicotinamide	Serum or urine	Low
Pantothenic acid	Pantothenic acid level	Serum	Low
Pyridoxine3	Pyridoxal phosphate	Serum	Low
Biotin	Biotin level	Serum	Low
Folate	Vitamin B12 and folate levels	Serum	Low
Cobalamin4	Vitamin B12 and folate levels	Serum	Low
Ascorbic acid5	Ascorbic acid level	Serum	Low

¹If phytonadione (Vitamin K1) 1 mg IV dramatically decreases PT within 2-6 hours, a liver disorder is unlikely, and the diagnosis of vitamin K deficiency is confirmed.

²This assay measures the concentration of the primary active form of vitamin B1 (thiamine diphosphate). Approximately 90 percent of B₁ present in whole blood is thiamine diphosphate. Thiamine monophosphate and thiamine, which comprise the remaining 10 percent, are not measured. Values less than 70-180 nmol/L are considered diagnostic for thiamine deficiency. The United States Food and Drug Administration has not cleared or approved it. The thiamine loading test, which measures erythrocyte transketolase in red blood cells, is still the best indicator for thiamine deficiency. However, the test is expensive and time-consuming.

³Diagnosis of pyridoxine deficiency is usually made clinically. There is no single acceptable laboratory testing to confirm diagnosis. However, serum pyridoxal phosphate is usually the most common.

⁴A complete blood count, in conjunction with B12 and folate levels, should be obtained to detect megaloblastic anemia. Folate levels should also be measured to differentiate B12 from folate deficiency as a cause of anemia, as folate supplementation may alleviate megaloblastic anemia but worsen neurologic deficits.

⁵Vitamin C deficiency is a clinical diagnosis based on risk factors and gingival or skin findings. Laboratory diagnosis requires the measurement of blood ascorbic values. < 0.2 mg/dL (< 11 mcmol/L) indicate vitamin C deficiency.

PT: Prothrombin time; INR: International normalized ratio; EDTA: Ethylenediaminetetraacetic acid.

Treatment of fat-soluble vitamin deficiencies

Treatment of fat-soluble vitamin deficiencies depends on multiple factors, including the severity, deficiency type, and the patient's individual needs (i.e., pregnancy, growth, and underlying disease)[169]. The most common method for the treatment of fat-soluble vitamin deficiency is supplementation with specific preparations of vitamins A, D, E, or K[33,47,68,166,168,170]. These vitamins can be taken in the form of capsules, tablets, or drinkable preparations, but they can also be administered intravenously (IV) or intramuscularly (IM), depending on the severity of the deficiency[26-36,41-47,168]. There are a wide variety of therapeutic regimens that have been proposed by several academic societies (i.e., internal medicine, endocrine, rheumatology, and others)[30,165-170]. It is important to emphasize that the suggested therapeutic regimens are mostly based on studies that do not meet evidence-based medicine criteria and are rather a combination of suggestions from multiple medical societies from mostly the United States and Europe (Table 2).

Table 2 Summary of medical therapy for several micronutrient deficiencies in adult patients.

Vitamin	Clinical manifestations of deficiency	Recommended treatment
A	Nyctalopia, xerosis cutis, xeropthalmia, immunosuppression, keratomalacia, and conjunctival squamous metaplasia Bitot spots	Vitamin A palmitate 60000 IU (18000 mcg RAE) orally once per day for 2 days, followed by 4500 IU once a day
D	Bone pain, muscle weakness, depression, hair loss, and hypocalcemic tetany	Ergocalciferol (vitamin D2) 50000 IU orally every 7 days for 8 weeks
E	Hemolytic anemia, muscle weakness, ataxia, and decreased proprioception and vibration	α-tocopherol is 15 to 25 mg/kg orally once daily or 200 IU of mixed tocopherols daily. Injections should be used to treat neuropathy and patients with malabsorption syndromes
K	Increased risk for bleeding	Phytonadione 1 to 10 mg orally for nonemergent correction of prolonged INR in patients taking anticoagulants. When partial correction of INR is desirable (i.e., prosthetic heart valve), 1 to 2.5 mg doses should be used
Thiamine	Wernicke encephalopathy: Confusion, ophthalmoplegia, nystagmus, and ataxia. Korsakoff syndrome: Confabulations, personality changes, and permanent memory loss. Wernicke-Korsakoff syndrome: Presentation is a combination of Wernicke and Korsakoff syndrome. Dry beriberi: Polyneuropathy and symmetric muscle wasting. Wet beriberi: High-output heart failure	IV thiamine 250-500 mg/day should be given for 3-5 days, followed by oral thiamine 250-300 mg/day for chronic alcoholics and other patients at risk for deficiency. Patients with suspected Wernicke receive 500 mg of thiamine diluted in 50-100 mL of normal saline infused over 30 minutes three times daily for three days, followed by 250 mg IV daily for 3 to 5 days or until clinical improvement. 100 mg IV once per day for several days in patients with edema and congestion due to cardiovascular beriberi
Riboflavin	Cheilosis and corneal vascularization	5 to 30 mg orally once per day until recovery. Other water-soluble vitamins should also be given
Niacin	Diarrhea, dermatitis, and dementia (also hallucinations)	Nicotinamide 250 to 500 mg orally once per day
Pantothenic acid	Enteritis, dermatitis, alopecia, and adrenal insufficiency may lead to “burning feet syndrome”	Pantothenic acid 5-10 mg orally once per day
Pyridoxine	Hyperirritability, peripheral neuropathy, convulsions, and sideroblastic anemia	Pyridoxine 50-100 mg orally once per day. Patients taking isoniazid should be given 30-50 mg orally once a day
Biotin	Isolated deficiency is relatively rare. Enteritis, dermatitis, and alopecia	Biotin 5-20 mg orally once per day
Folate	Megaloblastic anemia, glossitis, fatigue, and pale skin	Folic acid 400-1000 mcg orally once per day. Women who plan on becoming pregnant should be supplemented with 400 to 800 mcg once per day
Cobalamin	Megaloblastic anemia, paresthesias, depression/anxiety, pale skin, cognitive dysfunction, and SCD	Vitamin B12 1000-2000 mcg orally once per day in patients who are significantly deficient or possess neurologic symptoms. For severe deficiency, 1 mg IM 1-4 times per week for several weeks until anemia and symptoms resolve
Ascorbic acid	Scurvy-swollen gums, petechiae, anemia, poor wound healing, hemarthrosis, “corkscrew” hair, and perifollicular and subperiosteal hemorrhages	For scurvy, use 500-1000 mg orally once per day for 1-2 weeks until symptoms and signs resolve

IU: International units; RAE: Retinol activity equivalents; INR: International normalized ratio; IV: Intravenous; SCD: Subacute combined degeneration; IM: Intramuscular.

A multitude of studies have concluded that vitamin A supplementation reduces childhood morbidity and mortality, especially in patients with serum retinol concentrations less than 20 mcg/dL[171-173]. In regions with a high prevalence of vitamin A deficiency, the WHO recommends a one-time dose of 100000 IU in children 6 to 11 months, followed by 200,000 IU every 4 to 6 months up to age five[174,175]. For pregnant women who are at risk, the WHO recommends 10000 IU daily or 25,000 IU weekly for 12 weeks[176]. There are currently no international guidelines for the treatment of asymptomatic vitamin A deficiency for adults in resource-rich regions.

The most cost-effective method of replenishing 25(OH)D levels in patients with vitamin D deficiency is oral ergocalciferol at 50000 IU per week for eight weeks[177]. The optimal time for rechecking vitamin D stores after therapy is not defined, but the goal is to achieve at least a minimum of 30 ng/mL[177,178]. Serum 25(OH)D levels should be obtained again after completion of therapy, and if values have not reached or surpassed the minimum, a second eight-week course should be prescribed. If the target goal is still not achieved, the most likely cause is nonadherence or malabsorption. Patients with suspected malabsorption should be referred to a gastroenterologist for further evaluation. Once levels are replete, vitamin D should be instituted at 800 to 2000 IU daily from supplemental and dietary sources[177-179].

Vitamin E deficiency is extremely rare in humans and is mainly caused by irregularities in dietary fat absorption or metabolism[180]. A supplementation of 15 to 25 mg/kg/day or 200 IU of tocopherols can be used in patients who are deficient[180-182]. IM or subcutaneous injection can be used in patients who have oral ingestion and/or intestinal issues. The treatment of vitamin K deficiency is limited to neonates and anticoagulation overdoses (i.e., warfarin)[183-185].

Treatment of water-soluble vitamin deficiencies

The treatment of thiamine deficiency is based on the severity and the clinical presentation of the patient. In patients at high risk for thiamine deficiency, such as chronic alcoholics, IV thiamine 250-500 mg/day should be given for 3-5 days, followed by oral thiamine 250-300 mg/day[186,187]. Patients with suspected Wernicke encephalopathy should receive 500 mg of thiamine diluted in 50-100 mL of normal saline infused over 30 minutes three times daily for 3 days, followed by 250 mg IV daily for 3 to 5 days or until clinical improvement[188,189].

Vitamin B₁₂ deficiency can be treated with oral therapy or IM injections of cyanocobalamin[190,191]. More than 8% of the standard injectable dose of 1 mg is absorbed, which allows for swift replacement in patients with severe neurologic symptoms or deficiency[190-192]. Guidelines from the British Society for Hematology recommend IM injections three times per week for two weeks in patients without neurologic deficits and every other day for up to three weeks or until improvement in patients with deficits[191]. In general, patients with irreversible causes of B₁₂ deficiency should remain on lifelong therapy, whereas those with reversible causes should be treated until the deficiency is corrected or until symptoms resolve[193,194]. Oral high-dose B₁₂ (1-2 mg daily) is equally effective to IM for correcting neurologic symptoms and anemia in patients with no contraindications to oral therapy[193-195].

Folate levels below two ng/mL are generally considered deficient[196,197]. All patients with folate deficiency should receive supplemental folic acid for treatment[198,199]. Oral folic acid (1-5 mg/day) typically suffice for management[198-200]. Other forms of therapy, including IV, IM, or subcutaneous, can be used in patients who are intolerant to oral medications. The duration of treatment is based on whether the cause of the initial deficiency persists. Patients with short gut or malabsorption syndromes typically require long-term management[196,198,199,201]. It is essential to obtain B₁₂ levels in patients who are folate deficient as folic acid supplementation may correct the anemia but worsen the neurological signs and symptoms of B₁₂ deficiency if present[202,203].

CONCLUSION

In summary, micronutrients are essential to sustain life, and nutrition is a modifiable risk factor that can be targeted to optimize health and well-being. Nutritional deficiencies can often lead to loss of bodily functions, developmental failure, and other medical conditions, including vision loss and lack of immunity. The major causes of nutritional deficiencies are insufficient food intake, malabsorption, and consumption of diets lacking essential nutrients. MNDs are the most prevalent type of nutritional deficiency and are a leading cause of worldwide morbidity and mortality. Deficiency in either fat or water-soluble vitamins can lead to serious conditions such as vision loss, pellagra, beriberi, recurrent infections, and decreased cognitive function, among others. Developing countries are most susceptible to these deficiencies, and diagnosis starts with a good clinical history and physical examination. Prompt recognition and treatment can drastically reduce morbidity and mortality, especially in developing countries.