Why must thiamine be given before glucose in alcoholic patients?

Pyruvate dehydrogenase requires thiamine pyrophosphate (TPP) as a cofactor. Giving glucose without thiamine floods the cell with pyruvate while depleting the last remaining B1 stores, precipitating or worsening Wernicke encephalopathy.

How does carcinoid syndrome cause pellagra?

Carcinoid tumors overproduce serotonin using tryptophan as substrate. Since niacin (B3) is synthesized from tryptophan, depleting tryptophan causes niacin deficiency and pellagra (the 3 D's: dermatitis, diarrhea, dementia).

What distinguishes B12 deficiency from folate deficiency?

Both cause megaloblastic anemia with elevated homocysteine. Only B12 deficiency elevates methylmalonic acid (MMA), because B12 is required by methyl malonyl-CoA mutase. B12 deficiency also causes subacute combined degeneration while folate deficiency does not.

B Vitamins: Thiamine, Niacin, and Cofactor Deficiencies

An alcoholic is brought in confused, ataxic, with bilateral gaze palsy. Before giving glucose · wait, actually: what do you give FIRST?

The Mechanism

B1 → TPP → Four Enzymes

Thiamine must be activated to TPP before it does anything. TPP then locks onto four enzymes that run aerobic metabolism and neuronal function.

Clinical Findings

What You See in the Exam Room

Tap any image to expand

Pellagra skin rash showing photosensitive dermatitis on sun-exposed areas

Pellagra: photosensitive dermatitis on sun-exposed skin (B3 deficiency)

Early stage of dry beriberi with peripheral neuropathy

Dry beriberi: peripheral neuropathy and limb weakness (B1 deficiency)

Scorbutic gums showing perifollicular hemorrhages and bleeding in Vitamin C deficiency

Scorbutic gums: perifollicular hemorrhage (Vitamin C / Scurvy)

Alcoholic pellagra showing niacin deficiency skin changes

Alcoholic pellagra: niacin deficiency from poor diet and tryptophan depletion

The Pattern

The 3 Dehydrogenases

Five B vitamins feed the same three enzymes. Understand this once and you understand half the chapter.

💡

Three critical dehydrogenases need B1 + B2 + B3 + B5 + Lipoic acid as cofactors:
1. Pyruvate dehydrogenase (pyruvate → acetyl-CoA)
2. Alpha-ketoglutarate dehydrogenase (TCA cycle step 4)
3. Branched-chain amino acid dehydrogenase

B1 also feeds a 4th enzyme: transketolase (pentose phosphate pathway · critical for neuronal NADPH)

Vitamin	Active Form	Pyr DH	a-KG DH	BCAA DH	Other Role
B1 Thiamine	TPP	✔	✔	✔	Transketolase (PPP)
B2 Riboflavin	FAD, FMN	✔	✔	✔	ETC complexes I & II
B3 Niacin	NAD+, NADP+	✔	✔	✔	VLDL synthesis (pharmacologic)
B5 Pantothenic	CoA	✔	✔	✔	Coenzyme A (central metabolism)
Lipoic Acid	Lipoamide	✔	✔	✔	No clinical deficiency

⚠️

Board trap: The heart depends on all three dehydrogenases for aerobic ATP. The brain specifically depends on transketolase (B1 → PPP → NADPH). Same B1 deficiency → different organs fail → that's why beriberi (heart) and Wernicke's (brain) are separate diseases from the same root cause.

The B Vitamins

Tap Each to Expand

One concept per card. Click to reveal clinical details and board pearls.

Thiamine

TPP · The Brain & Heart Vitamin

Wernicke’s

Active form: Thiamine pyrophosphate (TPP)

Enzymes: Pyruvate DH, alpha-KG DH, BCAA DH + Transketolase

Wernicke’s Encephalopathy (acute, reversible):
Classic triad: confusion + ophthalmoplegia + ataxia
Lesion: mammillary bodiesThiamine-sensitive regions include the mammillary bodies and dorsomedial thalamus. The mammillary bodies mediate memory; their destruction causes Korsakoff's anterograde amnesia. Not Wernicke's speech area, which is a language center in the temporal lobe. + dorsomedial thalamus (NOT Wernicke's area, which is language)

Progression → Korsakoff Syndrome (irreversible):
Mammillary body destruction → confabulation (fabricating memories without knowing it) + inability to form new long-term memories (anterograde amnesia)

Beriberi (heart failure from B1 deficiency):
• Dry beriberi: peripheral neuropathy, symmetric muscle wasting, no cardiac failure yet
• Wet beriberi: massive ventricular dilation, pulmonary edema, high-output heart failure (vasodilation drops resistance → heart overcompensates → eventually fails)

CRITICAL: Glucose Rule. Always give thiamine BEFORE glucose in any alcoholic or malnourished patient. Glucose metabolism requires B1 (pyruvate dehydrogenase). In B1-depleted state, giving glucose burns through the last reserves and precipitates or worsens Wernicke’s irreversibly.

Riboflavin

FAD · FMN

Cheilosis

Active forms: FAD and FMN (electron carriers in ETC) • FAD also powers Glutathione Reductase (regenerates reduced glutathione → antioxidant defense). Without B2, oxidative protection stalls.

Best source: Milk • Destroyed by: sunlightRiboflavin is photolabile. This is why milk historically came in opaque containers. Light exposure degrades riboflavin within hours.

Deficiency - the 2 C's: Angular cheilosis (cracking at corners of mouth) + corneal vascularization + cheilitis + glossitis

Niacin

NAD+ · NADP+ · Nicotinic Acid

Pellagra

Made from: TryptophanTryptophan can be shunted to make serotonin OR niacin. In carcinoid syndrome, serotonin overproduction consumes the tryptophan pool, leaving none for niacin synthesis. Result: pellagra despite normal niacin intake. (requires B2 and B6 in the pathway)

Pellagra - the 4 D’s: 🔑Diarrhea → Dermatitis → Dementia → Death. Skin finds sun-exposed areas (C3/C4 dermatome, Casal necklace).
Diarrhea · Dermatitis (photosensitive, sun-exposed) · Dementia · Death

Causes of pellagra besides diet:
• Hartnup disease · defective renal tryptophan transporter → tryptophan leaks in urine, can’t make niacin
• Carcinoid syndrome · tumor diverts tryptophan to serotonin synthesis
• Isoniazid (INH) · depletes B6, which is needed to convert tryptophan to niacin

Pharmacologic niacin (dyslipidemia):
• Blocks VLDL production → lowers TG · best drug for raising HDL (up to 45%)
• 3 side effects the clinical medicine always test:
  ➞ Flushing · prostaglandin D2 (PGD2) from skin → vasodilation. Block with aspirin before the dose.
  ➞ Hyperuricemia · niacin competes with uric acid for renal tubular secretion → can precipitate gout
  ➞ Hyperglycemia · niacin causes insulin resistance → caution in diabetics

Pyridoxine

PLP (Pyridoxal Phosphate)

Neuropathy

Roles: Makes heme (required by ALA synthase, rate-limiting step) • All transaminasesAST and ALT both require pyridoxal phosphate (PLP) as cofactor. Severe B6 deficiency affects aminotransferase activity. INH-induced B6 depletion can artificially lower AST/ALT. (AST, ALT) • Neurotransmitter synthesis (GABA, dopamine, serotonin)

Depleted by: INH (isoniazid) · TB drug structurally similar to B6, acts as competitive inhibitor. Always co-prescribe B6 with INH.

Deficiency: Peripheral neuropathy • Sideroblastic anemia (iron accumulates in mitochondrial ring around erythroblast nucleus because heme synthesis failed) • Seizures in infants

Folate

THF (Tetrahydrofolate)

Megaloblastic Anemia

Body stores: Lasts 3-4 months · first B vitamin to run out with poor intake or high demand

Role: Makes THF → provides carbon units for thymidine → DNA synthesis → cell division

Deficiency:
• Megaloblastic anemia + hypersegmented neutrophilsDNA can't replicate properly. The nucleus tries and tries but can't divide. Cytoplasm divides normally (it doesn't need DNA synthesis). Result: giant cells with over-lobulated nuclei. More than 5 lobes = hypersegmented. Shared with B12 deficiency.
• Neural tube defects (spina bifida, anencephaly) in fetuses
• NO neurological symptoms (that's B12, not folate)

Common causes: Overcooked vegetables (heat destroys folate) · Alcoholism · Phenytoin (inhibits absorption) · Pregnancy (high demand)

B12

Cobalamin

Cyanocobalamin

Megaloblastic + Neuro

Body stores: Lasts 3-5 years in the liver (massive stores; explains why deficiency takes years to develop)

Enzymes:
• Homocysteine methyltransferase (also needs folate → converts homocysteine → methionine)
• Methyl malonyl-CoA mutase (converts methylmalonyl-CoA → succinyl-CoA; deficiency accumulates methylmalonic acid [MMA], which is toxic to myelin)

Absorption: Needs intrinsic factorMade by parietal cells in the stomach. Binds B12 in the duodenum. The B12-IF complex is absorbed in the terminal ileum. Pernicious anemia = autoimmune destruction of parietal cells = no IF = no B12 absorption despite adequate intake. → absorbed in terminal ileum

Deficiency:
• Megaloblastic anemia + hypersegmented neutrophils (same as folate)
• PLUS subacute combined degeneration: posterior columns (proprioception, vibration loss) + lateral corticospinal tracts (hyperreflexia, Babinski) → ataxia + spastic paresis
• Elevated MMA (methylmalonic acid) distinguishes B12 from folate deficiency

Causes: Pernicious anemia · Vegan diet · Crohn’s / terminal ileum resection · Diphyllobothrium latumFish tapeworm. Competes with the host for B12 absorption. Classic: immigrant who eats raw freshwater fish develops megaloblastic anemia over months to years. (fish tapeworm) · Metformin

Vitamin C

Ascorbic Acid

Scurvy

Role: Cofactor for prolyl and lysyl hydroxylaseThese enzymes add hydroxyl groups to proline and lysine residues in procollagen. Without hydroxylation, collagen cannot form stable triple helices. The result: structurally weak connective tissue throughout the body. → collagen triple helix formation • Reduces Fe3+ → Fe2+ for iron absorption • Antioxidant

Deficiency · Scurvy:
• Bleeding gums, loose teeth, poor wound healing
• Perifollicular hemorrhages + corkscrew hairs
• Easy bruising, petechiae • Subperiosteal hemorrhage in children

Excess: Kidney stones (oxalate excess) · Diarrhea · False-negative guaiac test

High-Yield Comparison

Folate (B9) vs B12

Both cause megaloblastic anemia. The clinical medicine will make you tell them apart. Here's how.

Feature	B9 Folate	B12 Cobalamin
Duration in body	3-4 months	3-5 years
Megaloblastic anemia	✔	✔
Hypersegmented neutrophils	✔	✔
Neurological symptoms	✘ None	✔ Subacute combined degeneration
Methylmalonic acid (MMA)	Normal	Elevated
Homocysteine	Elevated	Elevated
Neural tube defects	✔ Yes	✘ No
Common causes	Overcooked vegetables, alcoholism, phenytoin	Pernicious anemia, vegan diet, ileal disease

⚠️

The distinguisher: Megaloblastic anemia + neurological symptoms (numbness, ataxia, proprioception loss) = B12. Confirm with elevated MMA. Folate does NOT cause neuro symptoms. Treating with folate alone masks B12 deficiency while subacute combined degeneration silently progresses.

From the Attending

"The Wernicke trap gets attendings too. You see the glucose, you see the confusion, you give the glucose. The mechanism is why that's a mistake: pyruvate dehydrogenase requires TPP. No TPP, no pyruvate processing. More glucose, more pyruvate, zero enzyme to handle it. The window between reversible Wernicke's and permanent Korsakoff closes in hours. Give thiamine, then glucose. That's the whole rule.

Same principle teaches the carcinoid-pellagra connection. Why does a serotonin-producing tumor cause a niacin deficiency disease? Because tryptophan can only go one way at a time: serotonin or niacin. When the tumor hogs tryptophan for serotonin, the niacin pathway runs dry. Know the mechanism and the board answer is automatic."

Board Walkthrough

One at a Time

Six original 3rd-order clinical vignettes · one at a time · shuffle any time

Question 1 of 6

Medically reviewed by Fatima Ali, DO and Kaitlyn Cocuzzo, MD · Last reviewed June 2026

Bone Wizardry is an independent educational resource for visual learning in the medical sciences. It is not affiliated with, endorsed by, or sponsored by any licensing or examination board, contains no real or recalled examination questions, and does not guarantee any educational or examination outcome.