Water-Soluble Vitamin Deficiencies

Inadequate intake (most common in the US)

• Chronic alcohol use: the single most tested cause — poor diet, impaired intestinal thiamine transport, reduced hepatic storage, and impaired conversion to thiamine pyrophosphate; typically produces combined B1, B6, folate, and niacin deficiency
• Restricted or monotonous diets: strict vegan/vegetarian diets (B12, since B12 is exclusively of animal/microbial origin), "tea and toast" elderly diets (folate, B12, vitamin C), polished-rice–predominant diets (thiamine), and maize-predominant diets without nixtamalization (niacin)
• Food insecurity, anorexia nervosa, institutionalization, and infants fed unsupplemented or goat's milk (folate)

Malabsorption

• Pernicious anemia: autoimmune destruction of parietal cells with anti–intrinsic factor and anti–parietal cell antibodies; the classic non-modifiable B12 cause
• Gastric and ileal surgery: gastrectomy and Roux-en-Y gastric bypass (loss of intrinsic factor and acid-dependent B12 release); ileal resection or Crohn disease (loss of cubilin-mediated B12 uptake). The AACE/TOS/ASMBS perioperative bariatric guidelines mandate lifelong multivitamin, B12, folate, and thiamine surveillance
• Celiac disease, tropical sprue, bacterial overgrowth, pancreatic insufficiency, and Diphyllobothrium latum infection

Increased requirement or loss

• Pregnancy and lactation, chronic hemolysis, hemodialysis (water-soluble vitamins are dialyzed off), refeeding after starvation, and hyperemesis gravidarum

Drug-induced (modifiable, heavily tested)

• Metformin: impairs calcium-dependent ileal B12 uptake — the ADA Standards of Care advise periodic B12 measurement in long-term metformin users
• Isoniazid, hydralazine, penicillamine: form inactive hydrazones with pyridoxine → B6 deficiency
• Methotrexate, trimethoprim, phenytoin, sulfasalazine: antifolate effects
• Chronic PPI/H2 blocker use and nitrous oxide (irreversibly oxidizes cobalamin)

Thiamine (Vitamin B1) Deficiency

• Acts as a coenzyme for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase; deficiency impairs carbohydrate metabolism and mitochondrial function, particularly affecting high-energy tissues (nervous system, cardiac muscle)
• Results in accumulation of lactate and pyruvate, causing metabolic acidosis and neurodegeneration
• Chronic deficiency leads to selective damage to mammillary bodies, medial thalamus, and periaqueductal gray matter (Wernicke encephalopathy pathology)
• Myelin degradation occurs secondary to impaired energy production in neurons

Riboflavin (Vitamin B2) Deficiency

• Required as a cofactor (FAD/FADH2) in electron transport chain; deficiency reduces ATP production and antioxidant defense
• Impairs mitochondrial oxidative metabolism and cellular energy generation
• Affects tissues with high metabolic demand (skin, mucous membranes, eyes)

Niacin (Vitamin B3) Deficiency

• NAD+/NADH involved in >400 enzymatic reactions; deficiency causes widespread metabolic dysfunction
• Particularly affects tryptophan metabolism and NAD+ synthesis
• Results in impaired DNA repair, protein synthesis, and energy metabolism

Pantothenic Acid (Vitamin B5) Deficiency

• Constituent of coenzyme A (CoA), critical for fatty acid and acetylcholine synthesis
• Deficiency reduces energy metabolism and neurotransmitter production

Pyridoxine (Vitamin B6) Deficiency

• Cofactor for aminotransferases, homocysteine metabolism, and neurotransmitter synthesis (serotonin, dopamine, GABA)
• Deficiency impairs immune function and causes peripheral neuropathy through disrupted myelin protein synthesis

Cobalamin (Vitamin B12) Deficiency

• Essential for methyl-malonyl CoA mutase (odd-chain fatty acid metabolism) and methionine synthase (DNA synthesis and myelin formation)
• Deficiency causes megaloblastic anemia (impaired DNA synthesis) and subacute combined degeneration (demyelination of dorsal columns, lateral corticospinal tracts, peripheral nerves)
• Elevated methylmalonic acid and homocysteine are pathognomonic

Folate Deficiency

• Required for one-carbon transfer reactions in nucleotide synthesis; deficiency impairs DNA replication
• Results in megaloblastic anemia and impaired cell division, particularly affecting rapidly dividing cells
• Does NOT cause neurologic damage (unlike B12)

Ascorbic Acid (Vitamin C) Deficiency

• Cofactor for prolyl and lysyl hydroxylase; deficiency impairs collagen cross-linking and stability
• Results in defective collagen IV in blood vessels and basement membranes
• Impairs iron absorption and leukocyte function

Thiamine Deficiency

• Wernicke encephalopathy (acute): Classic triad of ophthalmoplegia (CN VI palsy causing horizontal nystagmus), ataxia (gait disturbance), and confusion; develops over hours to days in severe deficiency
• Korsakoff syndrome (chronic): Irreversible anterograde and retrograde amnesia with confabulation; occurs if Wernicke not treated promptly
• Beriberi (peripheral neuropathy): Dry beriberi shows ascending symmetric polyneuropathy; wet beriberi presents with high-output cardiac failure, peripheral edema, and cardiomegaly
• Lactic acidosis, tachycardia, and hypotension in severe cases

Riboflavin Deficiency

• Cheilosis (cracked lips and mouth angles), glossitis, and angular stomatitis
• Photophobia, conjunctivitis, and corneal vascularization
• Seborrheic dermatitis (scaling rash on face, especially nasolabial folds and eyelids)
• Anemia (normocytic) from impaired heme synthesis

Niacin Deficiency (Pellagra)

• "4 Ds": Diarrhea (watery, bloody), Dermatitis (sun-exposed areas in symmetric distribution—classically on hands, neck, face), Dementia, Death (if untreated)
• Dermatitis is pathognomonic—appears as erythematous, scaly plaques with sharp demarcation at sun-exposure lines
• Psychiatric symptoms: anxiety, depression, paranoia, psychosis
• Gastrointestinal symptoms: loss of appetite, dysphagia, nausea

Pantothenic Acid Deficiency

• Rare, even in malnutrition; "burning feet syndrome" (dysesthesia and burning in soles)
• Fatigue, headache, paresthesias
• Gastrointestinal symptoms and immunosuppression

Pyridoxine Deficiency

• Peripheral neuropathy (symmetrical, affecting lower extremities first)
• Cheilosis, glossitis, seborrheic dermatitis (similar to riboflavin but less common)
• Seizures and ataxia
• Impaired immune function; recurrent infections
• Anemia (microcytic), depression, and confusion

Cobalamin Deficiency

• Megaloblastic anemia: Macrocytic, hypersegmented neutrophils, pancytopenia
• Subacute combined degeneration: Loss of vibration and proprioception (dorsal columns), weakness and hyperreflexia (lateral corticospinal tracts), peripheral neuropathy (paresthesias, especially in feet)
• Ataxia and positive Romberg sign
• Glossitis, angular cheilitis, and atrophic gastritis (in pernicious anemia)
• Paresthesias often precede anemia; neurologic damage is irreversible if untreated
• Cognitive changes, memory loss, dementia; psychiatric symptoms (irritability, personality change)

Folate Deficiency

• Megaloblastic anemia: Same blood smear findings as B12 deficiency
• Glossitis and angular cheilitis
• No neurologic manifestations (key distinction from B12)
• Fatigue, dyspnea, diarrhea

Ascorbic Acid Deficiency (Scurvy)

• Perifollicular hemorrhages (around hair follicles) and corkscrew hairs (pathognomonic)
• Bleeding gums, loose teeth, poor wound healing
• Petechiae, ecchymoses (severe defect in platelet function and vascular integrity)
• Follicular hyperkeratosis, anemia, joint pain
• Fatigue, irritability, depression
• Severe cases: hemorrhage (including intracranial), infection, and death

Important Clinical Pearls

• Water-soluble vitamin deficiencies often occur together (especially in alcoholism); always consider multiple deficiencies
• B12 deficiency can present with normal hemoglobin and normal MCV early; neurologic symptoms may occur before anemia develops
• Folate supplementation in B12 deficiency masks the hematologic abnormality while allowing neurologic damage to progress—dangerous combination
• Wernicke encephalopathy is a medical emergency requiring immediate treatment to prevent irreversible Korsakoff syndrome

Thiamine

• Serum thiamine level (<5.3 nmol/L indicates deficiency)
• Erythrocyte transket

Immediate stabilisation

• Parenteral thiamine before any glucose: giving dextrose to a thiamine-depleted patient consumes residual thiamine pyrophosphate in pyruvate dehydrogenase and can precipitate or worsen Wernicke encephalopathy. Empiric IV thiamine is standard in altered mental status of unclear cause; suspected Wernicke requires high-dose IV thiamine several times daily for days, then oral maintenance
• Magnesium repletion is required concurrently — magnesium is a cofactor for thiamine-dependent enzymes, and hypomagnesemia causes refractory deficiency
• ASPEN guidance recommends thiamine and electrolyte repletion before and during initiation of feeding in patients at refeeding risk

First-line replacement by vitamin

• Cobalamin: parenteral cyanocobalamin/hydroxocobalamin (1000 mcg IM, loading doses then monthly) for pernicious anemia, ileal disease, or any neurologic involvement; high-dose oral B12 is an acceptable alternative in dietary deficiency and many malabsorptive states
• Folate: oral folic acid; USPSTF recommends 400–800 mcg daily for all persons planning or capable of pregnancy to prevent neural tube defects, and ACOG endorses periconceptional supplementation
• Niacin: oral nicotinamide preferred over nicotinic acid because it does not cause prostaglandin-mediated flushing
• Pyridoxine: oral B6; give prophylactically with isoniazid, and as the antidote for INH overdose seizures (gram-for-gram with ingested INH)
• Vitamin C: gram-level daily oral ascorbic acid reverses scurvy — perifollicular hemorrhage and gum bleeding resolve within days
• Riboflavin, pantothenate: oral repletion, usually as part of a B-complex

Escalation and definitive care

• Treat the cause: gluten-free diet in celiac disease, antibiotics for overgrowth, praziquantel for D. latum, drug substitution, alcohol use disorder treatment. Pernicious anemia and post-bypass anatomy require lifelong supplementation

Contraindicated/avoid

• Folate alone when B12 deficiency is possible — corrects the anemia while demyelination progresses
• Glucose before thiamine; chronic high-dose pyridoxine (causes a dose-dependent sensory ataxic neuropathy); nitrous oxide in B12-deficient patients

Neurologic (often irreversible — treat empirically rather than await levels)

• Korsakoff syndrome: untreated Wernicke progresses to permanent anterograde amnesia with confabulation from mammillary body and dorsomedial thalamic necrosis; signalled by persistent memory deficit after ophthalmoplegia resolves. Emergency at the Wernicke stage
• Subacute combined degeneration: B12-dependent methionine synthase failure impairs myelin methylation; dorsal column and lateral corticospinal tract demyelination gives loss of vibration/proprioception, spastic weakness, and a positive Romberg. Deficits present beyond months of duration typically do not fully recover
• Dry beriberi: length-dependent axonal polyneuropathy with distal sensory loss and foot drop

Cardiovascular

• Wet beriberi: impaired oxidative metabolism causes systemic vasodilation and high-output failure — warm extremities, wide pulse pressure, edema, cardiomegaly
• Shoshin beriberi: fulminant lactic acidosis with cardiogenic shock; an emergency reversed dramatically by IV thiamine

Hematologic and vascular

• Megaloblastic anemia with ineffective erythropoiesis → indirect hyperbilirubinemia and elevated LDH, mimicking hemolysis
• Hyperhomocysteinemia (B12, folate, B6 deficiency): endothelial injury and prothrombotic risk
• Scurvy: defective collagen cross-linking → perifollicular and subperiosteal hemorrhage, hemarthrosis, and rarely intracranial hemorrhage — an emergency
• Folate deficiency in pregnancy: neural tube defects, the outcome USPSTF supplementation targets

Treatment-related

• Hypokalemia and hypophosphatemia during B12/folate repletion: brisk erythropoiesis consumes potassium and phosphate — watch for arrhythmia in the first days
• Refeeding syndrome: carbohydrate load drives insulin-mediated intracellular phosphate shift; ASPEN advises thiamine and electrolyte monitoring
• Pyridoxine toxicity: sensory ataxic neuropathy; nicotinic acid: flushing, hepatotoxicity, hyperglycemia, hyperuricemia

• Thiamine before glucose, always: a malnourished or alcohol-using patient given IV dextrose who then develops confusion, ophthalmoplegia, and ataxia is the classic iatrogenic Wernicke vignette. Single best next step in suspected Wernicke = IV thiamine now, not imaging, not levels
• B12 vs folate: both give macrocytic anemia with hypersegmented neutrophils; only B12 deficiency raises methylmalonic acid and only B12 deficiency causes neurologic disease. If the stem has neuro findings, it is B12 — and homocysteine is elevated in both, so MMA is the discriminator
• Never give folate alone empirically: it corrects the smear and hemoglobin while subacute combined degeneration silently advances. This is the commonest distractor answer in a macrocytic anemia stem
• Metformin and nitrous oxide are the two drug associations examiners plant for B12; isoniazid is the one for B6 (give prophylactic pyridoxine, and pyridoxine is the antidote for INH-overdose seizures)
• Corkscrew hairs with perifollicular hemorrhage = scurvy. Bleeding gums plus normal platelet count and normal PT/PTT points to a collagen defect, not a coagulopathy
• Pellagra's 4 Ds (diarrhea, dermatitis, dementia, death) with a photodistributed Casal necklace; think Hartnup disease and carcinoid syndrome (tryptophan shunted to serotonin) when diet is normal
• Wet beriberi is high-output failure with warm extremities and a wide pulse pressure — do not confuse it with the low-output alcoholic cardiomyopathy in the same patient population
• After starting B12 or folate, watch potassium: rapid erythropoiesis can precipitate symptomatic hypokalemia
• Per the USPSTF, all persons capable of pregnancy should take daily folic acid before conception — the classic prevention question