Multisystem Processes & Disorders

Micronutrient deficiency workup in adults

Clinical Overview and When to Suspect Micronutrient Deficiency

— Older adults (≥65): B12, vitamin D, calcium; atrophic gastritis and PPI/metformin chronic use

— Post-bariatric surgery (especially Roux-en-Y, sleeve, BPD/DS): iron, B12, thiamine, vitamin D, calcium, copper, fat-soluble ADEK

— Chronic alcohol use disorder: thiamine, folate, magnesium, pyridoxine, zinc

— Malabsorption: celiac, Crohn disease, short bowel, chronic pancreatitis, cystic fibrosis → fat-soluble vitamin (A, D, E, K) deficiency

— Strict vegan diet: B12, iron, zinc, vitamin D, omega-3

— Pregnancy/lactation: folate, iron, iodine, vitamin D

— Refugees, food insecurity, eating disorders, prolonged TPN without supplementation

— Chronic kidney disease on dialysis: water-soluble vitamins lost in dialysate

— Unexplained macrocytic or microcytic anemia

— Peripheral neuropathy, ataxia, or cognitive decline without clear etiology

— Recurrent or atypical dermatologic findings (perifollicular hemorrhage, angular cheilitis, dermatitis triad)

— Failure to thrive, weight loss, or sarcopenia in a high-risk host

— Night blindness, bleeding diathesis, or unexplained INR elevation

Scope: Micronutrient deficiencies in US adults are common but underdiagnosed; the highest-yield panel for Step 3 includes vitamin B12, folate, vitamin D, iron, thiamine (B1), vitamin A, vitamin K, zinc, and copper.

Epidemiologic risk groups to flag on the stem:

When to suspect even without an obvious risk factor:

Step 3 management: Build the workup around the clinical syndrome plus the host risk profile — do not order a shotgun "vitamin panel." Pick targeted assays based on diet, GI surgical history, medications, and presenting deficiency phenotype.

Board pearl: Any patient with chronic PPI, metformin, or H2 blocker use who presents with paresthesias or unexplained dementia gets a B12 level before further neuro workup — it is reversible if caught early and devastating if missed.

Presentation Patterns and Key History

— Diet: vegan/vegetarian, food insecurity, "tea and toast," fad/restrictive diets, alcohol substituting calories

— GI/surgical: bariatric procedure type and year, bowel resections, chronic diarrhea, steatorrhea, celiac/IBD history, pancreatic insufficiency

— Medications: PPI, H2 blocker, metformin (B12); isoniazid, hydralazine, OCPs (B6); phenytoin, methotrexate, trimethoprim (folate); orlistat, cholestyramine (fat-soluble vitamins); chronic antibiotics (vitamin K)

— Social: alcohol use, tobacco, sun exposure, geographic origin, pregnancy/lactation

— Symptoms by syndrome cluster (see below)

— Glossitis + macrocytic anemia + neuropathy/dementia → B12

— Glossitis + macrocytic anemia, NO neuro signs → folate

— Confusion + ophthalmoplegia + ataxia → thiamine (Wernicke)

— High-output heart failure + neuropathy in alcoholic → wet beriberi

— Night blindness + Bitot spots + xerosis → vitamin A

— Bone pain + proximal weakness + falls → vitamin D (osteomalacia)

— Easy bruising + bleeding gums + perifollicular hemorrhage + corkscrew hairs → vitamin C (scurvy)

— Dermatitis + diarrhea + dementia → niacin (pellagra)

— Dermatitis (perioral, acral) + alopecia + diarrhea + poor wound healing + hypogeusia → zinc

— Anemia + neutropenia + myeloneuropathy mimicking B12 → copper

— Microcytic anemia + pica + restless legs → iron

— Bleeding + elevated PT/INR correcting with FFP → vitamin K

Take a structured deficiency history — five domains:

Syndrome-to-deficiency pattern recognition:

Board pearl: The classic Step 3 trap is folate replacement in a patient with combined B12/folate deficiency — this corrects the anemia but allows the neurologic deficit to progress. Always check B12 before giving folate.

Key distinction: B12 deficiency causes neuro signs; folate alone does not. Both cause megaloblastic anemia and hypersegmented neutrophils.

Physical Exam Findings

— Cachexia, temporal wasting, sarcopenia

— Orthostatic hypotension (volume depletion in severe deficiency or refeeding)

— High-output failure (wide pulse pressure, bounding pulses, S3) in wet beriberi

— Angular cheilitis, glossitis, magenta tongue → riboflavin (B2), niacin, B6, B12, folate, iron

— Atrophic smooth "beefy red" tongue → B12 or iron

— Bleeding/spongy gums, loose teeth → vitamin C

— Bitot spots (foamy gray conjunctival plaques), keratomalacia, night blindness → vitamin A

— Goiter → iodine

— Perifollicular hemorrhages, corkscrew hairs, ecchymoses → vitamin C

— Hyperpigmented photodistributed dermatitis ("Casal necklace") → niacin

— Perioral/acral dermatitis, alopecia → zinc; also biotin

— Koilonychia (spoon nails), pallor → iron

— Follicular hyperkeratosis → vitamin A or C

— Petechiae/ecchymoses with normal platelets → vitamin K or C

— Symmetric distal stocking-glove sensory loss, loss of vibration/proprioception, positive Romberg → B12 or copper (subacute combined degeneration of dorsal columns + lateral corticospinal tracts)

— Ophthalmoplegia (lateral rectus palsy, nystagmus), ataxia, confusion → thiamine (Wernicke triad)

— Confabulation, anterograde amnesia → Korsakoff (chronic)

— Peripheral neuropathy in isoniazid user → B6

— Tetany, Chvostek/Trousseau → calcium, magnesium, vitamin D

General/vitals:

HEENT:

Skin/hair/nails:

Neuro (highest-yield):

Musculoskeletal: proximal myopathy, bone tenderness, waddling gait → vitamin D/osteomalacia.

Step 3 management: In a suspected Wernicke patient, give IV thiamine BEFORE any glucose-containing fluid to avoid precipitating or worsening encephalopathy. This is a CCS reflex order.

Board pearl: Copper deficiency neurologically mimics B12 — check copper and ceruloplasmin if B12 is normal but myelopathy persists, especially post-bariatric or with zinc overuse (denture cream, supplements).

Diagnostic Workup — Initial Labs

— CBC with differential and peripheral smear — micro vs macrocytic anemia, hypersegmented neutrophils, target cells

— Reticulocyte count — distinguishes hypoproliferative from responsive states

— CMP — albumin (nutritional status proxy), calcium, magnesium, phosphate, LFTs (synthetic function for vitamin K), creatinine

— Iron studies: ferritin, serum iron, TIBC, transferrin saturation

— Vitamin B12 and folate (RBC folate preferred if recent supplementation)

— 25-hydroxyvitamin D (the storage form; do NOT order 1,25-OH except in granulomatous disease or CKD-MBD workup)

— TSH (overlap with anemia/fatigue)

— CRP (ferritin is an acute phase reactant; interpret with CRP)

— Methylmalonic acid (MMA) + homocysteine — elevated MMA confirms B12 deficiency when level is borderline (200–400 pg/mL); homocysteine alone is elevated in both B12 and folate

— Whole-blood thiamine or erythrocyte transketolase activity — but treat empirically, don't wait for the result

— Serum zinc + copper + ceruloplasmin — interpret zinc with albumin; both are acute-phase modified

— Vitamin A (retinol), vitamin E (alpha-tocopherol/lipid ratio), PT/INR for vitamin K

— Vitamin C (ascorbate) — only if clinical scurvy

— Iodine: urinary iodine spot or 24-hr (rare)

— Anti-tTG IgA + total IgA if malabsorption suspected

Baseline panel for any suspected micronutrient deficiency:

Targeted second-tier labs based on syndrome:

Key distinction: Ferritin <30 ng/mL = iron deficiency (highly specific). With inflammation, the cutoff rises to <100 ng/mL or transferrin saturation <20%. In CKD, use TSAT <20% + ferritin <100 (non-dialysis) or <200 (HD).

Board pearl: MMA is the most sensitive early marker of B12 deficiency and will be elevated before the serum B12 falls below 200. Order MMA in any patient with neurologic findings and a "low-normal" B12.

Step 3 management: Don't repeat vitamin D levels more often than every 3 months during repletion — it's a frequent low-value test.

Diagnostic Workup — Advanced/Confirmatory Studies

— Borderline B12 (200–400 pg/mL) → MMA and homocysteine; both elevated confirms tissue deficiency

— Confirmed B12 deficiency in a non-vegan, non-bariatric adult → anti-intrinsic factor antibody (specific for pernicious anemia) and anti-parietal cell antibody (sensitive, less specific)

— Consider gastrin and chromogranin A if pernicious anemia confirmed (elevated due to achlorhydria; risk for gastric NETs)

— Schilling test is obsolete — do not pick it on the exam

— IDA in a man or postmenopausal woman → bidirectional endoscopy (EGD + colonoscopy) to exclude GI malignancy — this is a near-universal Step 3 trigger

— Premenopausal woman with menorrhagia → treat empirically; scope only if no menstrual source, age >50, family history, or failure to respond

— Celiac serology if microcytic anemia is refractory to oral iron

— Fecal elastase for pancreatic insufficiency

— 72-hr fecal fat (rarely used now), D-xylose, anti-tTG, small bowel imaging

— DEXA scan for vitamin D/calcium deficiency with osteomalacia features

— MRI brain may show mammillary body and periaqueductal gray T2/FLAIR hyperintensities in Wernicke — confirmatory but never required to treat

— Lactic acidosis with normal perfusion in a malnourished patient suggests thiamine deficiency

— Check both simultaneously — excess zinc supplementation induces metallothionein, blocking copper absorption

— Bone marrow biopsy in copper-deficient myelodysplasia shows vacuolated erythroid precursors and ring sideroblasts mimicking MDS

— Low 25-OH D + high PTH + low/normal calcium → secondary hyperparathyroidism from deficiency

— Order 1,25-OH vitamin D only when suspecting granulomatous hypercalcemia (sarcoid, TB, lymphoma) or CKD

B12 deficiency confirmation pathway:

Iron deficiency confirmation:

Fat-soluble vitamin deficiency in suspected malabsorption:

Thiamine:

Zinc/copper:

Vitamin D pathway:

CCS pearl: In a post-bariatric patient with new myelopathy, order copper and ceruloplasmin alongside B12 on the same draw — splitting the workup wastes a virtual visit and is a documented Step 3 efficiency hit.

Board pearl: Iron deficiency in an adult without an obvious menstrual or pregnancy source = colon cancer until proven otherwise.

Risk Stratification and Management Logic

— Mild/asymptomatic + intact GI tract → oral repletion, outpatient follow-up

— Symptomatic (neuro, hematologic, dermatologic) → higher-dose oral or parenteral, closer follow-up

— Severe/acute (Wernicke, scurvy with bleeding, vitamin K coagulopathy with active bleed, severe IDA with end-organ ischemia) → parenteral, often inpatient

— Oral preferred if: intact absorption, mild deficiency, adherent patient, no neuro symptoms

— Parenteral required if: malabsorption (post-bariatric, IBD, celiac refractory), pernicious anemia (lifelong IM B12 traditional, though high-dose oral 1000–2000 mcg works in many), Wernicke (always IV thiamine), severe IDA with intolerance/failure of PO iron, active bleeding from vitamin K deficiency

— Treat the underlying condition (celiac diet, alcohol cessation, switch PPI to H2 blocker if possible, manage IBD, pancreatic enzymes for CF/chronic pancreatitis)

— Address food insecurity with social work referral and SNAP enrollment — a legitimate Step 3 answer

— High risk: BMI <16, weight loss >15% in 3–6 months, little/no intake >10 days, low pre-feeding K/Mg/PO4

— Give thiamine 200–300 mg/day for 5–7 days BEFORE and during refeeding, start nutrition at 5–10 kcal/kg/day, advance slowly, replace K/Mg/PO4 daily

Tier severity before choosing route and dose:

Decision framework — choose oral vs parenteral:

Anchor the plan to the cause, not just the level:

Refeeding syndrome risk stratification (NICE criteria):

Step 3 management: In a hospitalized alcoholic patient, the standing orders should include IV thiamine 500 mg TID × 3 days then 250 mg daily, folate, multivitamin, and Mg repletion — the "banana bag" concept, though dosing matters more than the color.

Board pearl: Never give dextrose-containing IV fluids before thiamine in a malnourished or alcoholic patient — glucose metabolism consumes residual thiamine and can precipitate Wernicke encephalopathy.

Pharmacotherapy — First-Line Repletion Regimens

— Pernicious anemia/severe neuro: cyanocobalamin 1000 mcg IM daily × 1 week → weekly × 4 → monthly lifelong, OR high-dose oral 1000–2000 mcg daily (equivalent efficacy in most)

— Dietary deficiency: oral 1000 mcg daily

— Recheck CBC at 1 month (reticulocytosis in 1 week), B12 not routinely needed once on replacement

— Oral ferrous sulfate 325 mg (65 mg elemental) every other day — newer evidence shows alternate-day dosing improves absorption by avoiding hepcidin upregulation

— Take with vitamin C, avoid with PPI/calcium/tea

— Expect Hgb rise ~1 g/dL per 2–3 weeks; total course 3–6 months past normalization to refill stores

— IV iron (ferric carboxymaltose, iron sucrose, ferumoxytol) if: intolerance, malabsorption, CKD, IBD flare, ongoing blood loss, pre-op need

— Deficiency (<20 ng/mL): ergocalciferol 50,000 IU PO weekly × 6–8 weeks, then 1000–2000 IU daily maintenance

— Insufficiency (20–30): 1000–2000 IU daily

— In malabsorption: higher doses or calcitriol if 1-alpha-hydroxylation impaired (CKD, hypoparathyroidism)

— Suspected Wernicke: 500 mg IV TID × 2–3 days, then 250 mg IV/IM daily × 5 days, then 100 mg PO daily

— Prophylaxis in alcohol use disorder: 100 mg PO daily

— Asymptomatic elevated INR from deficiency: 1–2.5 mg PO

— Active bleeding: 10 mg IV slowly + 4-factor PCC if life-threatening; avoid IM (hematoma); SC absorption unreliable

Vitamin B12:

Folate: 1–5 mg PO daily × 1–4 months; always rule out B12 first

Iron deficiency:

Vitamin D:

Thiamine:

Vitamin K:

Zinc: elemental zinc 20–40 mg PO daily (gluconate or sulfate); monitor copper because zinc induces metallothionein

Vitamin A: 200,000 IU PO ×1, repeat day 2 and day 14 for xerophthalmia (WHO regimen); caution in pregnancy (teratogen >10,000 IU/day)

Vitamin C: 500–1000 mg PO daily for scurvy; symptoms resolve within days

Niacin (pellagra): nicotinamide 100 mg TID × several weeks (avoids flushing)

Board pearl: Alternate-day oral iron dosing is the new standard for uncomplicated IDA — better absorption, fewer GI side effects than daily dosing.

Step 3 management: After starting B12 or iron, schedule a 1-month CBC to confirm reticulocytosis and Hgb response — failure to respond mandates reassessment for ongoing loss, malabsorption, or wrong diagnosis.

Procedures, Parenteral Nutrition, and Specialized Therapy

— Ferric carboxymaltose 750 mg IV ×2 doses 7 days apart (max 1500 mg) — fastest repletion

— Iron sucrose 200 mg IV per session, multiple sessions — preferred in dialysis units

— Ferumoxytol — fastest infusion but interferes with MRI for 3 months

— Side effects: hypophosphatemia (especially ferric carboxymaltose, can be severe and prolonged), infusion reactions, rare anaphylaxis

— Monitor phosphate at 2 weeks after carboxymaltose

— IDA in adult male/postmenopausal female: EGD + colonoscopy same setting — efficient, single sedation

— Add small bowel video capsule if both negative and persistent IDA

— Lifelong supplementation post-RYGB/sleeve: bariatric MVI, B12 (oral 1000 mcg or IM monthly), iron 45–60 mg elemental daily (more for menstruating), calcium citrate 1200–1500 mg, vitamin D 3000 IU

— Annual screening labs: CBC, iron studies, B12, folate, 25-OH D, PTH, calcium, zinc, copper, thiamine if symptoms

— Standard adult TPN must include multivitamin infusion and trace elements daily

— Long-term TPN: monitor selenium, chromium, manganese, copper, zinc quarterly

— Pure thiamine deficiency outbreak historically linked to TPN without MVI — never run TPN without it

— Refeeding precautions apply

— Advance gradually with electrolyte monitoring BID for 3–5 days in high-risk patients

— Speech/swallow evaluation before PO in stroke/elderly to prevent aspiration

IV iron — practical Step 3 use:

Parenteral B12: cyanocobalamin or hydroxocobalamin IM; transition to oral once neuro symptoms stable if absorption adequate

Endoscopic workup as a procedural intervention:

Bariatric surgery considerations:

Total parenteral nutrition (TPN):

Enteral feeding transitions:

CCS pearl: When ordering TPN on the CCS case, the correct sequence is check baseline electrolytes including Mg/PO4 → give thiamine → start TPN at reduced kcal → monitor K/Mg/PO4 q12h × 72 h. Skipping thiamine triggers a poor performance score.

Board pearl: Hypophosphatemia after IV ferric carboxymaltose is a real and tested adverse event — check phosphate post-infusion and supplement if symptomatic.

Special Populations — Elderly, Renal, and Hepatic

— Atrophic gastritis prevalence 20–50% → impaired B12 release from food protein → food-bound B12 malabsorption; crystalline (supplement) B12 still absorbed orally

— Reduced cutaneous vitamin D synthesis, less sun exposure → screen 25-OH D in fall/fracture workup

— Polypharmacy: PPI, metformin, levothyroxine interactions with calcium/iron

— Anorexia of aging: protein-energy malnutrition; address dentition, depression, dysphagia, social isolation, medications (the "9 D's")

— Higher risk of refeeding when hospitalized for failure to thrive

— Iron: target ferritin 100–500 ng/mL, TSAT >20%; use IV iron freely in HD; ESA therapy requires iron sufficiency

— Vitamin D: nutritional 25-OH D repletion with cholecalciferol; activated analogs (calcitriol, paricalcitol) for secondary hyperPTH in CKD 4–5 or dialysis

— Water-soluble vitamins (B-complex, C, folate) are dialyzed off — give renal MVI; avoid vitamin A (accumulates, causes hepatotoxicity and hypercalcemia)

— Carnitine deficiency in long-term HD — case-by-case repletion

— Avoid magnesium-based supplements in advanced CKD

— Cirrhosis impairs vitamin D activation and storage of fat-soluble vitamins (cholestasis worsens this); supplement A (cautiously — hepatotoxic at high dose), D, E, K

— Alcohol-related liver disease: thiamine, folate, B6, zinc, magnesium routinely

— Vitamin K coagulopathy in cholestasis corrects with parenteral K; in hepatocellular failure it doesn't (synthetic dysfunction)

— Wernicke encephalopathy can occur in cirrhotics without overt alcohol use — low threshold to treat

Elderly (≥65):

Chronic kidney disease (CKD):

Hepatic impairment:

Key distinction: Cholestatic vs hepatocellular INR elevation — give vitamin K 10 mg IV/SC; if INR corrects in 24–48 h, the deficit was vitamin K (cholestasis/malabsorption); if not, it's true synthetic failure.

Step 3 management: In CKD stage 4 with secondary hyperparathyroidism and 25-OH D <30, replete with cholecalciferol first, then add calcitriol or paricalcitol if PTH remains above target after 8–12 weeks.

Special Populations — Pregnancy, Lactation, and Other Subgroups

— Folic acid 400–800 mcg daily preconception and first trimester to prevent NTDs; 4 mg daily if prior NTD-affected pregnancy, on antiepileptics, or with diabetes

— Iron: 27 mg elemental daily routine; treat IDA aggressively (oral first; IV iron after 1st trimester if severe or intolerant)

— Vitamin D: 600 IU daily minimum; higher if deficient

— Calcium: 1000 mg daily

— Iodine: 150 mcg daily (220 in pregnancy, 290 lactation) — prenatal vitamins should contain iodine

— Vitamin A: avoid >10,000 IU/day (teratogen — retinoic acid embryopathy); use beta-carotene

— B12: vegan mothers require supplementation to prevent infant deficiency (irreversible neuro injury in nursing infants)

— Pica (ice, clay) is a clue to maternal iron deficiency

— Female athlete triad: low energy availability, menstrual dysfunction, low BMD — assess vitamin D, calcium, iron

— Eating disorders: thiamine, magnesium, phosphate, zinc; refeeding precautions

— B12 supplementation mandatory for vegans (no reliable plant sources)

— Iron (non-heme — absorbed less; pair with vitamin C)

— Zinc, calcium, vitamin D, omega-3 (algal DHA)

— Iodine if no iodized salt

Pregnancy:

Lactation: continue prenatal vitamin; vitamin D 400 IU daily for the breastfed infant (breast milk is vitamin D-low); B12 critical in vegan mothers

Adolescents and athletes:

Vegans/vegetarians:

Postpartum: screen for IDA at 4–6 weeks if antepartum anemia; lactational amenorrhea reduces iron loss but ongoing demand persists

Refugees, asylum seekers: screen for vitamin D, iron, B12, vitamin A, parasitic infections contributing to deficiency

Board pearl: Infants of vegan mothers breastfed without supplementation present at 4–12 months with failure to thrive, hypotonia, developmental regression, and megaloblastic anemia from maternal B12 deficiency — devastating and tested.

Step 3 management: Folate 4 mg (not 400 mcg) for women with prior NTD pregnancy starting at least 1 month before conception and continuing through first trimester.

Complications and Adverse Outcomes

— Severe IDA → high-output failure, angina in CAD, pre-op transfusion need

— B12/folate megaloblastosis → pancytopenia mimicking MDS or leukemia; ineffective erythropoiesis → indirect hyperbilirubinemia, elevated LDH

— Copper deficiency → cytopenias with ringed sideroblasts (MDS mimic — avoid unnecessary bone marrow transplant referral)

— B12: subacute combined degeneration (dorsal columns, lateral corticospinal tracts) → permanent gait/sensory loss if untreated >6 months

— Thiamine: Korsakoff syndrome (irreversible anterograde amnesia, confabulation) follows untreated Wernicke

— Vitamin E: spinocerebellar degeneration, peripheral neuropathy

— B6 deficiency: peripheral neuropathy; B6 toxicity also causes neuropathy (>200 mg/day chronic)

— Niacin: pellagra dementia, encephalopathy

— Wet beriberi (thiamine) → high-output HF

— Selenium deficiency → Keshan cardiomyopathy (rare, endemic regions)

— Severe anemia → demand ischemia

— Vitamin D/calcium deficiency → osteomalacia, fragility fractures, falls, secondary hyperparathyroidism

— Vitamin C deficiency → impaired collagen, poor wound healing, dehiscence

— Vitamin A excess → idiopathic intracranial hypertension, hepatotoxicity, teratogenicity

— Vitamin A deficiency increases measles mortality (WHO supplements during outbreaks)

— Zinc deficiency → recurrent infections, impaired wound healing

— Vitamin D and infection risk: associated, but not definitive

— Vitamin K deficiency → GI/intracranial hemorrhage, especially in malabsorption or warfarin/antibiotics

— Vitamin C → bleeding gums, hemarthroses, scurvy

— Hypercalcemia from vitamin D + calcium oversupplementation

— Iron overload from chronic unnecessary supplementation (especially in HH carriers)

— Selenium toxicity (alopecia, garlic breath)

Hematologic:

Neurologic — often irreversible if late:

Cardiovascular:

Skeletal:

Immune/infectious:

Bleeding:

Iatrogenic from over-replacement:

Key distinction: Neurologic deficits from B12 deficiency are time-dependent — full reversal possible if treated <3 months from onset; partial after 6 months; minimal after 12 months. Early recognition is the entire game.

Board pearl: Treating folate without B12 in combined deficiency = hematologic correction with neurologic progression — a classic malpractice scenario.

When to Escalate — ICU, Consults, and Inpatient Triage

— Suspected Wernicke encephalopathy → admit for IV thiamine and observation; neurology if persistent symptoms

— Severe symptomatic anemia (Hgb <7 or symptomatic <8 in cardiac disease, angina, dyspnea, syncope) → admit for transfusion + workup

— Active bleeding with vitamin K coagulopathy → ICU/step-down, IV vitamin K + PCC

— Refeeding syndrome with K, Mg, or PO4 derangement causing arrhythmia, weakness, or respiratory failure → ICU telemetry, aggressive electrolyte repletion

— Severe malnutrition with hemodynamic instability or organ dysfunction → inpatient with nutrition consult

— Nutrition/dietitian — every malnutrition or post-bariatric or chronic deficiency case

— Gastroenterology — IDA workup with endoscopy, suspected celiac/IBD, chronic pancreatitis, post-bariatric malabsorption

— Hematology — refractory anemia, pancytopenia, suspected MDS overlap (copper deficiency)

— Endocrinology — refractory vitamin D deficiency, hypoparathyroidism, secondary hyperPTH in CKD

— Neurology — persistent deficits despite repletion, atypical presentations, Wernicke

— Psychiatry/addiction medicine — alcohol use disorder, eating disorders

— Social work — food insecurity, SNAP/WIC enrollment, transportation barriers

— Bariatric surgery clinic — for postoperative micronutrient management

— Ophthalmology — vitamin A deficiency with corneal involvement (xerophthalmia/keratomalacia)

— Stable, ambulatory, mild deficiency → outpatient repletion, close follow-up

— New neuro symptoms, hemodynamic compromise, inability to take PO → inpatient

Admit/escalate immediately:

Consults to use on the CCS case:

Outpatient vs inpatient triage:

CCS pearl: On a Wernicke case, the sequence is IV access → IV thiamine 500 mg → check glucose → IV fluids (with thiamine already given) → admit to monitored bed → neurology consult. Do not order glucose-containing dextrose before thiamine.

Step 3 management: A patient with severe symptomatic IDA in the ED gets transfusion for symptom relief + IV iron + outpatient endoscopy referral within 2 weeks, not "discharge on PO iron and follow up in 3 months."

Key Differentials — Within the Nutritional Category

— B12 deficiency → MMA + homocysteine elevated; neuro signs

— Folate deficiency → homocysteine elevated, MMA normal; no neuro signs

— Alcohol use (direct marrow toxicity, often without true deficiency)

— Hypothyroidism

— Drug-induced (methotrexate, hydroxyurea, zidovudine, phenytoin, trimethoprim)

— MDS — especially in older adults; smear with dysplasia, persistent macrocytosis

— Reticulocytosis (large young RBCs from hemolysis or recovery)

— Liver disease (round macrocytes, target cells)

— Iron deficiency — low ferritin, high TIBC, low TSAT

— Thalassemia — normal ferritin, elevated RBC count, Mentzer index <13, Hb electrophoresis confirms

— Anemia of chronic disease — normal/high ferritin, low TIBC, low TSAT

— Sideroblastic anemia (B6 responsive, lead, alcohol) — ring sideroblasts on marrow

— Lead poisoning — basophilic stippling

— B12, copper, B6 (deficiency OR toxicity), thiamine, vitamin E, niacin

— Distinguish by associated features: B12 has dorsal column signs; copper mimics B12 ± cytopenias; thiamine with confusion/ophthalmoplegia; E with cerebellar signs

— Vitamin K (PT prolonged, PTT prolonged late) vs vitamin C (scurvy: capillary fragility, normal coags) vs factor deficiency

— Pellagra (niacin) vs acrodermatitis enteropathica (zinc) vs biotin deficiency vs essential fatty acid deficiency (TPN without lipids)

Macrocytic anemia differential (mean corpuscular volume >100):

Microcytic anemia differential (MCV <80):

Peripheral neuropathy with nutritional differential:

Bleeding diathesis with normal platelets:

Dermatitis triad differentials:

Key distinction: MMA + homocysteine is the cleanest way to separate B12 from folate when both serum levels are borderline. MMA elevated → B12. MMA normal, homocysteine elevated → folate.

Board pearl: In refractory "MDS" with neuropathy in a post-bariatric or denture-cream user, always check copper before recommending allogeneic transplant — copper repletion can fully reverse the picture.

Key Differentials — Other-Category Mimics

— Multiple sclerosis — relapsing-remitting CNS demyelination; MRI lesions, oligoclonal bands

— HIV myelopathy / vacuolar myelopathy — check HIV serology in any unexplained myelopathy

— Tabes dorsalis (tertiary syphilis) — RPR + FTA-ABS; Argyll Robertson pupil

— Cervical spondylotic myelopathy — older adults, MRI cervical spine

— Hereditary spastic paraparesis, Friedreich ataxia

— Paraneoplastic — anti-Hu, anti-Yo, often with subacute sensory neuronopathy

— Drug toxicity — nitrous oxide (inactivates B12), chemotherapy

— Hemolytic anemia — elevated LDH and bilirubin overlap with megaloblastic ineffective erythropoiesis; check haptoglobin, reticulocyte count, Coombs

— GI malignancy — IDA from chronic blood loss, the highest-yield mimic in adults

— Renal anemia (low EPO) — normocytic, hypoproliferative

— Anemia of chronic inflammation

— Hypothyroidism, neurosyphilis, HIV, depression (pseudodementia), normal pressure hydrocephalus, Alzheimer, vascular dementia, medication effects, sleep apnea

— Polymyalgia rheumatica (ESR), inflammatory myopathy (CK, anti-Jo), hypothyroid myopathy, statin myopathy, hypophosphatemia, Cushing, primary hyperparathyroidism

— Lichen planus, candidiasis, contact dermatitis, autoimmune (lupus), HIV-associated

— Adrenal insufficiency, SIADH, hyperaldosteronism, diuretic effect

— Platelet dysfunction (uremia, aspirin), von Willebrand disease, vasculitis

Neurologic mimics of B12 deficiency:

Anemia mimics:

Cognitive decline differentials beyond B12/thiamine:

Bone pain/proximal weakness mimics:

Dermatitis/glossitis differentials:

Refeeding/electrolyte mimics:

Bleeding without coagulopathy:

Step 3 management: In a patient with progressive myelopathy and normal B12, the next step is MRI cervical/thoracic spine to exclude compressive cause before chasing rare deficiencies; then copper, HIV, RPR, MS workup.

Key distinction: Nitrous oxide abuse (recreational "whippets" or dental exposure) causes a clinical and lab picture identical to B12 deficiency with a normal serum B12 — ask about it in young patients with myelopathy.

Secondary Prevention, Discharge, and Long-Term Plan

— Specific repletion drug with dose, route, frequency, duration

— Daily multivitamin if multifactorial

— Underlying disease therapy: pancreatic enzymes, gluten-free diet, alcohol cessation, IBD maintenance

— Avoid drugs that worsen deficiency where possible (deprescribe chronic PPI if feasible; switch to lowest effective dose or H2 blocker)

— Counsel on food sources: leafy greens (folate, K), animal products (B12), fortified cereals, citrus (C), nuts/seeds (Mg, Zn, E), oily fish (D), iron-rich foods + vitamin C pairing

— Pernicious anemia: lifelong B12 (monthly IM or daily oral high-dose)

— Post-RYGB/sleeve: lifelong bariatric multivitamin + B12 + iron + calcium citrate + vitamin D

— Celiac disease on gluten-free diet: check iron, B12, folate, D, zinc, copper at diagnosis and annually

— Cystic fibrosis/chronic pancreatitis: lifelong ADEK with pancreatic enzymes

— Vegan diet: lifelong B12, vitamin D, omega-3, iodine

— Chronic alcohol use: thiamine + folate + MVI; address use disorder

— Older adults: vitamin D 800 IU + adequate dietary calcium, B12 screening; fall prevention

— Pneumococcal, influenza, COVID-19 in chronic disease patients with deficiency-related immunosuppression risk

— DEXA scan for vitamin D/osteomalacia patients; consider bisphosphonate if osteoporosis confirmed after repletion

Discharge medication checklist (build into the After Visit Summary):

Long-term supplementation strategies:

Vaccinations and overlap prevention:

Lifestyle: sunlight 10–15 min midday for vitamin D where appropriate; resistance training for sarcopenia; weight-bearing exercise for bone health

Health-system supports: SNAP/WIC enrollment, Meals on Wheels for homebound elderly, food pantry connections, registered dietitian visits

Board pearl: Patients with pernicious anemia have a 2–3× increased risk of gastric adenocarcinoma and type 1 gastric carcinoids — surveillance EGD every 3–5 years is reasonable in those with confirmed atrophic gastritis.

Step 3 management: Deprescribe unnecessary PPIs at every visit in B12-deficient or osteoporotic older adults; document indication review in the chart.

Follow-Up, Monitoring Parameters, and Counseling

— Iron deficiency: CBC + reticulocyte at 2–4 weeks (expect retic rise in 7–10 days, Hgb +1 g/dL/2–3 weeks); ferritin/TSAT at 3 months; continue therapy 3 months past Hgb normalization; recheck at 6 and 12 months

— B12 deficiency: CBC at 1 month (expect reticulocytosis at 1 week, Hgb normalization in 6–8 weeks); MMA normalization confirms biochemical correction; neurologic recovery may take 6–12 months

— Folate: CBC at 1 month; once-yearly maintenance check if underlying cause persists

— Vitamin D: recheck 25-OH D at 3 months after starting repletion (NOT sooner); annual after maintenance achieved

— Post-bariatric: annual full micronutrient panel lifelong

— Celiac: annual labs + nutritional review; repeat tTG to confirm dietary adherence

— Iron tablets: take with vitamin C or orange juice, avoid coffee/tea/calcium within 2 hours, expect dark stools (not GI bleeding), alternate-day dosing improves tolerability

— B12 oral high-dose: take on empty stomach

— Vitamin D: take with fat-containing meal for absorption

— Calcium citrate (not carbonate) preferred in PPI users (no acid required for absorption)

— Alcohol cessation conversations using motivational interviewing

— Pregnancy planning: start folate 1–3 months pre-conception

— Vitamin D + calcium → check calcium and 25-OH D; watch for hypercalcemia, nephrolithiasis

— Iron → ferritin not to exceed upper limits; consider iron studies before continuing past 6 months in absence of ongoing loss

— Vitamin A → liver enzymes, headache (pseudotumor cerebri)

— Zinc → monitor copper annually if long-term use

— Pyridoxine → neuropathy if chronic >100 mg/day

Standard follow-up intervals:

Counseling pearls (use teach-back):

Monitoring for over-replacement and toxicity:

CCS pearl: Schedule week-2 reticulocyte count after starting iron or B12 — a documented retic response is the cheapest, fastest confirmation that you treated the right deficiency.

Board pearl: Failure of IDA to respond to 4–6 weeks of oral iron means one of three things: wrong diagnosis, ongoing bleeding, or malabsorption (celiac, H. pylori, autoimmune gastritis) — investigate, don't just push more iron.

Ethical, Legal, and Patient Safety Considerations

— Thiamine before glucose in alcohol use/malnutrition is a hard-wired safety reflex; many hospitals have it as an order-set requirement

— B12 check before folate replacement to prevent neurologic progression — a documented quality measure

— Avoid IM vitamin K in coagulopathic patients (hematoma risk); use IV with slow infusion or SC if mild

— Hypophosphatemia monitoring after IV ferric carboxymaltose

— IV iron infusion: anaphylaxis risk small but real → document discussion of alternatives (oral, transfusion) and reaction signs

— Transfusion refusal (Jehovah's Witness): preoperative iron + EPO repletion plan; document discussion and alternatives

— Bariatric patients: informed consent must include lifelong supplementation and the consequences of nonadherence (Wernicke, B12 myelopathy, osteoporosis)

— Enteral/parenteral nutrition in end-of-life or dementia care: shared decision-making; data show no mortality or aspiration benefit from PEG in advanced dementia

— Severe malnutrition in a dependent adult or child without medical explanation → Adult Protective Services or Child Protective Services report

— Eating disorders in adolescents: parental notification with adolescent confidentiality balancing

— Document food insecurity screening and intervention referrals as a quality metric

— Discharge after Wernicke admission without continued thiamine → relapse

— Post-bariatric patients lost to follow-up → cumulative deficiencies present years later

— Medication reconciliation: ensure new PPI scripts include B12/calcium counseling

— Hospital-to-SNF transfer: micronutrient supplements often dropped from reconciled lists — explicitly continue

— Food insecurity screening (Hunger Vital Sign 2-item) at every primary care visit

— Vitamin D deficiency disproportionately affects darker-skinned and veiled populations — culturally informed counseling

— SNAP/WIC eligibility check is a legitimate clinical intervention

Patient safety priorities in nutritional care:

Informed consent edge cases:

Mandatory reporting and protective concerns:

Transitions of care risks:

Health equity:

Step 3 management: A patient with anorexia nervosa who refuses refeeding has decision-making capacity assessed for each specific decision; involuntary feeding is reserved for life-threatening situations under court/ethics review and varies by state.

Board pearl: Failure to give thiamine before glucose in a Wernicke-risk patient is a never event in many institutional safety protocols — it shows up as the "wrong answer" on Step 3 stems.

High-Yield Associations and Rapid-Fire Clinical Facts

— Metformin, PPI, H2 blocker → B12

— Isoniazid, hydralazine, OCPs, penicillamine → B6

— Phenytoin, methotrexate, trimethoprim, sulfasalazine → folate

— Cholestyramine, orlistat, mineral oil → fat-soluble (ADEK)

— Broad-spectrum antibiotics, warfarin → vitamin K

— Loop diuretics, PPIs → magnesium

— Nitrous oxide → functional B12 deficiency

— Bitot spots → vitamin A

— Casal necklace → niacin (pellagra)

— Corkscrew hairs + perifollicular hemorrhage → vitamin C

— Magenta tongue + angular cheilitis → riboflavin

— Hypersegmented neutrophils → B12 or folate

— Pencil cells + Howell-Jolly absent → iron deficiency (Howell-Jolly suggests post-splenectomy or hyposplenia)

— Ringed sideroblasts in post-bariatric or denture-cream patient → copper

— Wernicke: confusion + ophthalmoplegia + ataxia

— Pellagra: dermatitis + diarrhea + dementia (+ death if untreated — "the 4 D's")

— Subacute combined degeneration: dorsal column + corticospinal + peripheral nerve

— Ferritin <30 = IDA; <100 with inflammation

— 25-OH D: deficient <20, insufficient 20–30, sufficient >30 ng/mL

— B12 deficient <200 pg/mL; borderline 200–400 (check MMA)

— Folate <2 ng/mL deficient

— INR correction with vitamin K in 24–48 h indicates true K deficiency

— Folate 4 mg/day for prior NTD; 400–800 mcg routine

— Vitamin D toxicity: 25-OH D >150 ng/mL with hypercalcemia

— Tea/toast diet → multiple deficiencies in elderly

— Hartnup disease → niacin (tryptophan malabsorption)

— Carcinoid syndrome → niacin (tryptophan diverted to serotonin)

Drug-induced deficiencies (memorize):

Pathognomonic findings:

Triads:

Numbers to know:

Diet-disease links:

Board pearl: The exam loves the post-bariatric patient years later with myelopathy → check copper AND B12; both can be deficient and copper is often forgotten.

Key distinction: Anemia of chronic disease vs IDA: ferritin and TIBC move in opposite directions — ACD has high ferritin/low TIBC; IDA has low ferritin/high TIBC.

Board Question Stem Patterns

Stem 1 — "Elderly on chronic PPI/metformin with paresthesias": Macrocytic anemia, vibration loss, positive Romberg. Best next step: serum B12 + MMA + homocysteine. Treat with parenteral or high-dose oral B12; check intrinsic factor antibodies if no other cause.

Stem 2 — "Alcoholic in ED with confusion": Disoriented, lateral gaze palsy, ataxic gait. Best next step: IV thiamine BEFORE dextrose. Wrong answers: glucose first, MRI first, CT first, neurology consult before treatment.

Stem 3 — "Iron deficiency in 65-year-old man": Microcytic anemia, ferritin 12, fatigue. Best next step: bidirectional endoscopy (EGD + colonoscopy) to rule out GI malignancy — not just oral iron.

Stem 4 — "Post-RYGB patient 4 years out": Progressive gait instability, cytopenias, normal B12. Best next step: serum copper and ceruloplasmin. Treat with oral copper; counsel against excess zinc.

Stem 5 — "Patient on warfarin and antibiotics with bleeding": Elevated INR, GI bleed. Best next step: IV vitamin K + 4-factor PCC. Avoid FFP unless PCC unavailable; avoid IM K.

Stem 6 — "Vegan mother breastfeeding infant": Infant with developmental regression, hypotonia, macrocytic anemia. Diagnosis: maternal B12 deficiency causing infant deficiency. Treat both.

Stem 7 — "Cirrhotic with elevated INR": Give vitamin K 10 mg IV; if INR corrects in 24–48 h, deficit is vitamin K (cholestasis/malabsorption); if not, hepatic synthetic failure.

Stem 8 — "Refractory IDA despite oral iron": Next steps: check celiac serology (tTG IgA + total IgA), H. pylori testing, consider IV iron.

Stem 9 — "Hospitalized severely malnourished patient on day 3": New weakness, hypophosphatemia, hypokalemia. Diagnosis: refeeding syndrome. Slow nutrition advance, replete electrolytes, continue thiamine.

Stem 10 — "Prior NTD pregnancy planning": Folate 4 mg daily preconception (not 400 mcg).

Stem 11 — "Bleeding gums, corkscrew hairs, perifollicular petechiae in homeless adult": Scurvy → vitamin C repletion, rapid resolution.

Stem 12 — "Young patient with myelopathy and normal B12, recreational drug use": Nitrous oxide abuse → functional B12 deficiency. Treat with B12 + counseling.

Step 3 management: When two interventions seem reasonable, choose the one that prevents the worst irreversible harm (e.g., thiamine before glucose; B12 before folate).

Board pearl: Watch for distractor answers like "Schilling test" (obsolete) and "bone marrow biopsy" before basic micronutrient labs.

One-Line Recap

The micronutrient deficiency workup is anchored on matching the clinical syndrome to the host's risk profile, ordering targeted assays rather than shotgun panels, treating empirically when delay risks irreversible neurologic harm, and addressing the underlying cause through long-term supplementation, lifestyle change, and system-level support.

— Thiamine before glucose in any malnourished or alcoholic patient with confusion — Wernicke is reversible only with early treatment

— B12 before folate in every macrocytic anemia — folate alone corrects blood counts while neurologic damage progresses

— Endoscopy in adult IDA without a clear menstrual or pregnancy source — assume GI malignancy until ruled out

— Copper and B12 together in post-bariatric or chronic zinc-exposed patients with myelopathy or unexplained cytopenias

— MMA + homocysteine to disambiguate B12 vs folate

— Ferritin <30 (or <100 with inflammation) defines iron deficiency

— 25-OH vitamin D for storage status; 1,25-OH only for granulomatous or CKD workup

— PT/INR + response to vitamin K differentiates K deficiency from hepatic synthetic failure

— Lifelong B12 in pernicious anemia and post-RYGB

— Bariatric MVI + iron + calcium citrate + vitamin D forever after bariatric surgery

— Folate 4 mg preconception for prior NTD; 400–800 mcg routinely

— Deprescribe unnecessary PPIs; screen B12 annually in chronic users

Top reflexes to never miss:

Top tests to know cold:

Top long-term plays:

Board pearl: Every Step 3 nutrition vignette rewards the candidate who gives empiric thiamine, sequences B12 before folate, refers IDA for endoscopy, and addresses the social-and-system root cause — that quartet covers >80% of the testable territory.