Vitamins — Water-Soluble

• Coenzyme and cofactor roles: Water-soluble vitamins function primarily as coenzymes (B vitamins) or reducing agents (vitamin C) in critical metabolic pathways including energy metabolism, one-carbon transfer reactions, amino acid metabolism, and oxidative stress defense; deficiency impairs these pathways leading to cellular dysfunction
• Limited body stores and urinary excretion: Unlike fat-soluble vitamins, water-soluble vitamins are minimally stored in tissues (except B12, which accumulates in liver); excess amounts are renally excreted, resulting in rapid depletion when dietary intake is inadequate (typically depleted within weeks to months)
• Absorption site-specificity: These vitamins are absorbed in the terminal ileum and proximal jejunum via specific transporters (B12 requires intrinsic factor in stomach for absorption); conditions affecting small bowel mucosa or gastric function directly impair absorption and cause deficiency
• Metabolic interdependencies: B vitamins work as an integrated system; deficiency of one (particularly folate or B12) often impairs metabolism of others, and combined deficiencies are common in alcoholics and chronically malnourished patients, producing overlapping clinical syndromes

Thiamine (Vitamin B1) Deficiency — Beriberi

• Wet beriberi: High-output congestive heart failure with dilated cardiomyopathy, peripheral edema, and pulmonary congestion in acute presentations; seen in alcoholics and populations on refined rice diets
• Dry beriberi: Peripheral neuropathy (distal, symmetrical, predominantly sensory then motor), muscle atrophy, and depression; classic in chronic malnutrition
• Wernicke-Korsakoff syndrome: Ophthalmoplegia, ataxia, confusion (Wernicke); followed by irreversible amnesia and confabulation (Korsakoff); medical emergency requiring immediate treatment

Riboflavin (Vitamin B2) Deficiency — Ariboflavinosis

• Angular cheilitis (cracks at corners of mouth), glossitis (magenta/beefy tongue), seborrheic dermatitis (scaling around nose and eyes), and photophobia
• Often coexists with other B vitamin deficiencies in alcoholics and those on certain medications (phenothiazines)

Niacin (Vitamin B3) Deficiency — Pellagra

• Classic 4 Ds: Dermatitis (photosensitive, symmetric on sun-exposed areas), Diarrhea (enteritis with malabsorption), Dementia (psychosis, depression, memory loss), and Death if untreated
• Dermatitis characteristically appears as Casal's collar (symmetric erythema on neck and upper chest)
• Common in populations dependent on corn without niacin fortification (especially if corn treated with lye) and in alcoholics with poor nutrition

Pantothenic Acid (Vitamin B5) Deficiency

• "Burning feet syndrome": Dysesthesias and paresthesias of lower extremities (rare; seen primarily in severe malnutrition)
• Fatigue, numbness, muscle cramps; very rare in humans due to widespread food distribution

Pyridoxine (Vitamin B6) Deficiency

• Peripheral neuropathy (paresthesias, sensory ataxia), seizures (especially in infants), dermatitis, glossitis, and angular cheilitis
• Increased homocysteine (functional deficiency affects homocysteine metabolism)
• Associated with isoniazid use, oral contraceptives, and alcoholism

Biotin (Vitamin B7) Deficiency

• Alopecia (hair loss), periodontal disease, dermatitis (seborrheic, around eyes and mouth), and nail dystrophy
• Rare; primarily seen in patients on long-term parenteral nutrition without biotin supplementation or those consuming raw eggs (avidin binds biotin)

Folate Deficiency

• Megaloblastic anemia with macrocytic RBCs, hypersegmented neutrophils, and glossitis; elevated LDH and indirect bilirubin
• Neural tube defects in pregnancy (spina bifida, anencephaly) if deficient in first trimester
• Neuropsychiatric symptoms: depression, cognitive changes, personality changes; does NOT cause the subacute combined degeneration seen with B12 deficiency

Cobalamin (Vitamin B12) Deficiency

• Megaloblastic anemia similar to folate deficiency
• Subacute combined degeneration: Progressive neurologic syndrome with paresthesias, loss of vibration and proprioception (dorsal columns), weakness, spasticity, ataxia, and positive Romberg sign; IRREVERSIBLE if not treated promptly
• Cognitive changes, depression, psychosis ("megaloblastic madness")
• Pernicious anemia: autoimmune destruction of gastric parietal cells causing intrinsic factor deficiency

Vitamin C (Ascorbic Acid) Deficiency — Scurvy

• Bleeding manifestations: Petechiae, ecchymoses, gum bleeding, loose teeth, and poor wound healing; bleeding gums with edematous, hyperplastic gums
• Follicular hyperkeratosis (especially around hair follicles of legs and buttocks), perifollicular hemorrhages (corkscrew hairs)
• Anemia (iron absorption deficiency), weakness, fatigue, and mood disturbances
• Bone disease: Subperiosteal hemorrhages and scorbutic rosary (ground-glass osteoporosis) in children

• Direct serum/plasma measurement: Thiamine (erythrocyte transketolase activity preferred), riboflavin (urinary excretion or erythrocyte glutathione reductase activity), niacin (NAD/NADH ratios or urinary metabolites), B6 (plasma pyridoxal phosphate), biotin (plasma biotin or urinary biotin), folate (serum folate and RBC folate; RBC folate more sensitive for tissue stores), B12 (serum cobalamin; elevated methylmalonic acid and homocysteine are sensitive indicators of deficiency even with low-normal B12)
• Functional tests and indirect markers: Elevated homocysteine and methylmalonic acid (both elevated in B12 deficiency; only homocysteine elevated in folate deficiency—key distinction), erythrocyte transketolase activity coefficient (thiamine), activated partial thromboplastin time prolongation and bleeding time (vitamin C deficiency affects collagen synthesis and platelet function)
• Peripheral blood smear: Macrocytic, hypochromic RBCs; hypersegmented neutrophils (>5 segments in B12/folate deficiency); schistocytes and target cells may appear in severe hemolysis; nucleated RBCs in severe cases
• Bone marrow examination: Reveals megaloblastic erythropoiesis with megaloblastic precursors, giant metamyelocytes, and nuclear-cytoplasmic asynchrony (primarily for B12/folate deficiency confirmation when diagnosis unclear)
• Schilling test (if available): Intrinsic factor-independent B12 absorption—abnormal in pernicious anemia; helps distinguish gastric vs. ileal causes of B12 deficiency
• Clinical context and history: Dietary assessment, alcoholism history, medication review (metformin, PPIs, H2 blockers reduce B12; isoniazid reduces B6), malabsorption symptoms, and neurologic exam findings guide diagnosis

Thiamine (Vitamin B1)

• First-line for Wernicke-Korsakoff: 100 mg IV/IM daily × 3-5 days, then

The reflexive "next best step" traps

• Thiamine before glucose: in any malnourished or alcohol-using patient with altered mental status, give thiamine before or with IV dextrose — a glucose load drives pyruvate into a thiamine-dependent pyruvate dehydrogenase bottleneck and can precipitate or worsen Wernicke encephalopathy. The stem's giveaway is ophthalmoplegia + ataxia + confusion.
• Never treat with folate alone when B12 deficiency is possible: folate corrects the megaloblastic anemia but does not stop subacute combined degeneration, so the neurologic disease progresses silently. Always establish B12 status first.
• Pyridoxine (B6) is the answer twice: prophylaxis with isoniazid (recommended alongside INH in the ATS/CDC/IDSA tuberculosis guidelines for pregnancy, alcohol use, HIV, malnutrition, and other at-risk groups) and as the antidote for isoniazid-overdose seizures refractory to benzodiazepines.

The one association examiners keep testing

• MMA is the discriminator: homocysteine is elevated in both B12 and folate deficiency; methylmalonic acid rises only in B12 deficiency, because methylmalonyl-CoA mutase requires adenosylcobalamin.
• Pellagra is not only dietary: consider carcinoid syndrome (tryptophan shunted to serotonin), Hartnup disease (neutral amino acid transport defect), and isoniazid (B6 needed to make niacin from tryptophan).
• Pernicious anemia is an atrophic gastritis: anti-intrinsic factor/anti-parietal cell antibodies, achlorhydria, other autoimmune disease, and an increased long-term risk of gastric adenocarcinoma and carcinoid.

Distractors to avoid

• B6 is the water-soluble vitamin with a classic toxicity: chronic high-dose pyridoxine causes a dose-dependent sensory peripheral neuropathy/ganglionopathy — do not assume "water-soluble means harmless."
• Niacin flushing is prostaglandin-mediated and blunted by aspirin; pharmacologic niacin is no longer favored for lipid lowering in the ACC/AHA cholesterol guideline, so it is a wrong answer for ASCVD risk reduction.
• Biotin supplements interfere with streptavidin–biotin immunoassays (FDA has warned about falsely low troponin and distorted thyroid panels) — think artifact, not thyroid disease.
• Folic acid is preconception, not first-trimester rescue: USPSTF recommends daily supplementation (0.4–0.8 mg) for all persons planning or capable of pregnancy, since the neural tube closes before most pregnancies are recognized.