Introduction

Vitamins play a vital role in many biochemical functions in the human body and are essential components for maintaining optimal health. There are two main groups of vitamins – fat-soluble (easily stored in fat upon absorption) and water-soluble (washed out and not easily stored). Although adequate intake of all vitamins is important, regular intake is required to avoid deficiency due to the transient nature of water-soluble vitamins. The water-soluble vitamins include Vitamin C and Vitamin B complex (thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folate, and cobalamin).

Vitamin B complex and vitamin C are found in many foods, especially vegetables and fruits, as well as dairy, meat, legumes, peas, liver, eggs, and fortified grains and cereals. In addition to serving as cofactors in biochemical reactions, the vitamin B complex is vital for normal body growth and development, healthy skin, the proper function of nerves and the heart, and red blood cell formation. The overall lack of water-soluble vitamins is rare in North America, though it can present in alcohol use disorder, malabsorption syndromes, strict veganism, and malnourished states.

Issues of Concern

As stated above, the deficiency of water-soluble vitamins is rare in North America. However, deficiency may be a presenting feature in alcohol use disorder, malnourishment, and malabsorption syndromes such as short-bowel syndrome. In short-bowel syndrome, there is the removal of a large portion of the small intestine for various reasons such as Crohn disease, necrotizing enterocolitis, traumatic injury, obstruction, or cancer. The small bowel is the site of absorption for all vitamins, and if a significant portion is surgically removed (typically enough so that less than or equal to 200 cm of bowel remains), the body will be unable to absorb vitamins adequately. Treatment includes vitamin supplementation.[1]

Testing

Although it is tempting to simply obtain urine or serum levels of water-soluble vitamins, these reflect only presently circulating vitamin levels and cannot approximate storage levels. Alternate forms of testing include immunoassays, chromatographic methods, chemical methods, high-pressure liquid chromatography, and capillary electrophoresis, depending on the vitamin being tested.[2] For vitamin B12 (cyanocobalamin) and folate deficiency, as discussed below, it is essential to obtain a complete blood cell count  (checking MCV, hematocrit, and hemoglobin) in addition to methylmalonic acid and homocysteine levels.

Clinical Significance

Vitamins are classified into two categories based on how they are absorbed and if they are stored. Water-soluble vitamins dissolve in water upon entering the body. Because of this, humans cannot store excess amounts of water-soluble vitamins for later use. There are nine water-soluble vitamins: the B vitamins -- folate, thiamine, riboflavin, niacin, pantothenic acid, biotin, vitamin B6, and vitamin B12 -- and vitamin C. Deficiency of any of these water-soluble vitamins results in a clinical syndrome that may result in severe morbidity and mortality.

• Thiamine (B1) is a cofactor (TPP) for multiple enzymes, including pyruvate dehydrogenase, alpha-ketoglutarate, transketolase, and branched-chain ketoacid dehydrogenase, all of which are involved in glucose breakdown. Deficiency can result in adenosine triphosphate (ATP) depletion and often affects highly aerobic tissues such as the brain, nerves, and heart first. With heart involvement, it is called wet beriberi and is characterized by high-output heart failure, edema, and dyspnea on exertion. When the nervous system is involved, it is called dry beriberi, characterized by polyneuritis and symmetrical muscle wasting. Damage to the medial dorsal nucleus of the thalamus and the mammillary bodies in the brain can result in a condition called Wernicke encephalopathy, recognized by the classic triad of confusion, ophthalmoplegia, and ataxia, or Wernicke-Korsakoff syndrome when accompanying confabulation, personality change, and memory loss is present.[3] Thiamine deficiency often is part of the presentation in patients with alcohol use disorder secondary to malnutrition and malabsorption, in addition to patients suffering from malnutrition. 
• Riboflavin (B2) is a cofactor in redox reactions (FAD and FMN). Deficiency leads to cheilosis (inflammation of lips and fissures of the mouth) and corneal vascularization. Of note, ultraviolet (UV) light can destroy riboflavin; hence it is always packaged in opaque containers.[4]
• Niacin (B3) is also utilized in redox reactions (as NAD+ and NADP+) and derives from tryptophan. Deficiency can present as pellagra, otherwise known as the 3-D’s: diarrhea, dermatitis, and dementia. Deficiency is rare in the USA but can occur in alcoholics and those with malnutrition. Niacin can be used to treat dyslipidemia, and a side effect is facial flushing, which can be avoided by treatment with aspirin.[5]
• Pantothenic acid (B5) is a component of coenzyme A and fatty acid synthase, both of which are necessary for energy production and the formation of hormones. Deficiency is characterized by dermatitis, enteritis, alopecia, and adrenal insufficiency.[6]
• Pyridoxine (B6) is converted to pyridoxal phosphate (PLP) and is part of reactions including transamination, decarboxylation, and glycogen phosphorylase. It is critical for the formation of red blood cells, and deficiency can result in sideroblastic anemia, hyperirritability, convulsions, peripheral neuropathy, and mental confusion. Peripheral neuropathy is a potential side effect of isoniazid, a key drug utilized in treating tuberculosis, and it is customary to supplement treatment with B6.[7]
• Biotin (B7) is necessary for the metabolism of protein, fats, and carbohydrates. Deficiency can lead to muscle pain, heart problems, anemia, and depression. Additionally, since biotin is a contributor to keratin, biotin has become popularized as a supplement to improve the quality of hair, skin, and nails. Large, unregulated doses of biotin can skew a variety of clinical tests, including thyroid tests T3 and T4, which can be either falsely elevated or falsely lowered depending on the particular assay; this is because nearly all immunoassays rely on the biotin-streptavidin attraction. This binding is also responsible for the biotin deficiency seen as a result of chronic consumption of large amounts of raw egg whites, as raw egg whites contain a high volume of intact avidin, which strongly binds biotin. When egg whites are cooked, the avidin denatures and does not bind biotin as avidly.[8] Of note, TSH levels are unaffected by biotin supplementation.  
• Folate (B9) is converted to tetrahydrofolate and is vital for DNA and RNA synthesis. Deficiency can result in neural tube defects, prompting folate supplementation during pregnancy, and macrocytic (MCV>100) megaloblastic anemia. Folate deficiency may also be a feature of alcohol use disorder.[9]
• Cobalamin (B12) is essential for erythropoiesis and the growth of the nervous system. Deficiency may lead to pernicious anemia and subacute combined degeneration of the spinal cord. The macrocytic megaloblastic anemia from B12 deficiency presents similarly to folate deficiency, and to differentiate them, it is imperative to obtain serum homocysteine and methylmalonic acid levels. In folate deficiency, homocysteine will elevate, but methylmalonic acid levels will be normal. In vitamin B12 deficiency, both homocysteine and methylmalonic acid levels will present as elevated. Additionally, B12 deficiency will present with neurologic symptoms, whereas folate deficiency will not.[10]
• Vitamin C (ascorbic acid, ascorbate) is needed for collagen growth, wound healing, bone formation, enhancing the immune system, absorption of iron, strengthening blood vessels, and acting as an antioxidant. When deficiency occurs, it can result in scurvy which can present with swollen and bleeding gums, loss of teeth, poor wound healing, and poor tissue growth.[11]