Fat-Soluble Vitamin Deficiencies

Luminal (digestive) failure — no micelles, no absorption

• Pancreatic exocrine insufficiency: cystic fibrosis, chronic pancreatitis, Shwachman-Diamond — absent lipase leaves triglyceride undigested, so vitamins A/D/E/K never enter micelles. The Cystic Fibrosis Foundation recommends routine fat-soluble vitamin supplementation plus enzyme replacement in all patients with pancreatic insufficiency.
• Bile salt deficiency or diversion: biliary atresia, primary biliary cholangitis, extrahepatic obstruction, ileal resection or Crohn ileitis (loss of enterohepatic recycling), bacterial overgrowth with bile-salt deconjugation. AASLD guidance on cholestatic liver disease advises monitoring and replacing fat-soluble vitamins.

Mucosal and lymphatic disease

• Celiac disease, tropical sprue, Whipple disease, short bowel syndrome, radiation enteritis — reduced absorptive surface.
• Abetalipoproteinemia (MTP mutation) and intestinal lymphangiectasia — chylomicrons cannot be assembled or exported; produces the most profound vitamin E deficiency.

Impaired activation or storage

• Cirrhosis (loss of 25-hydroxylation and of clotting-factor synthesis) and CKD (loss of renal 1α-hydroxylase); KDIGO addresses the latter under CKD-MBD.

Modifiable risk factors

• Alcohol use disorder, anorexia/food insecurity, strict vegan or fat-free diets.
• Drugs: orlistat, bile-acid sequestrants, mineral oil, broad-spectrum antibiotics (kill menaquinone-producing flora → vitamin K), enzyme-inducing anticonvulsants (phenytoin, phenobarbital) and glucocorticoids accelerating 25-OH-D catabolism, warfarin as functional vitamin K antagonism.
• Malabsorptive bariatric surgery (Roux-en-Y, biliopancreatic diversion) — lifelong supplementation required.
• Minimal sun exposure, sunscreen, veiling, institutionalization; exclusive breastfeeding without supplementation, for which the AAP recommends 400 IU/day vitamin D from birth.

Non-modifiable

• Darker skin pigmentation (melanin absorbs UVB), advanced age (thin skin, less 7-dehydrocholesterol), prematurity, malabsorptive genetic disease, TTPA mutation causing ataxia with isolated vitamin E deficiency, and hereditary vitamin D-dependent rickets.

Vitamin A Deficiency

• Impaired absorption due to inadequate dietary fat, bile salts, or pancreatic lipase; stored in liver as retinyl esters
• Loss of retinal (light-sensitive chromophore) leads to night blindness and eventual photoreceptor degeneration
• Epithelial cell metaplasia (squamous replacement of columnar epithelium) in respiratory, GI, and urinary tracts increases infection risk
• Corneal xerosis and scarring result from loss of mucin-secreting goblet cells in conjunctival epithelium
• Immune dysfunction from impaired lymphocyte proliferation and antibody production

Vitamin D Deficiency

• Impaired absorption in proximal small intestine; requires hydroxylation in liver (25-OH) and kidney (1,25-diOH for active form)
• Decreased intestinal calcium absorption and increased urinary calcium wasting
• Secondary hyperparathyroidism develops as PTH attempts to restore serum calcium through increased bone resorption and renal reabsorption
• Chronic hypophosphatemia and impaired bone mineralization lead to rickets (children) or osteomalacia (adults)
• Skeletal deformities result from weakened bone matrix and growth plate abnormalities

Vitamin E Deficiency

• Fat malabsorption impairs intestinal uptake; vitamin E is major lipophilic antioxidant protecting cell membranes and lipoproteins
• Loss of free radical scavenging leads to lipid peroxidation and neuronal cell membrane damage
• Neurodegeneration particularly affects posterior columns, spinocerebellar tracts, and peripheral nerves (progressive demyelination)
• Myopathy develops from oxidative damage to muscle cell membranes
• Retinopathy results from photoreceptor lipid peroxidation

Vitamin K Deficiency

• Reduced absorption due to fat malabsorption; also disrupted by antibiotics eliminating gut flora that produce menaquinones (K2)
• Impaired synthesis of vitamin K-dependent clotting factors (II, VII, IX, X) and proteins C and S via carboxylation
• Elevated PT/INR occurs before elevated aPTT (Factor VII has shortest half-life)
• Reduced synthesis of osteocalcin and matrix Gla protein impairs bone mineralization

Vitamin A Deficiency

• Night blindness (nyctalopia) — often first symptom; reversible if caught early
• Xerophthalmia: conjunctival xerosis → corneal xerosis → Bitot's spots (foamy triangular patches on conjunctiva) → corneal ulceration and scarring → permanent blindness
• Follicular hyperkeratosis and "toad skin" (keratotic bumps on extensor surfaces)
• Increased susceptibility to respiratory infections, diarrhea, measles
• Impaired taste and smell, alopecia
• Most common cause of preventable blindness worldwide (especially in developing countries with malnutrition)

Vitamin D Deficiency

• Early: nonspecific fatigue, myalgias, bone pain (especially lower back and pelvis)
• Rickets in children: delayed growth, bowing of legs, frontal bossing, dental delays, rachitic rosary (costochondral beading), Harrison's groove (horizontal indentation along lower chest)
• Osteomalacia in adults: muscle weakness, bone pain, waddling gait, increased fracture risk
• Secondary hyperparathyroidism may cause hypocalcemia, paresthesias, tetany, seizures
• Hypophosphatemia may cause rhabdomyolysis in severe cases
• Increased infection risk (impaired immune cell function)

Vitamin E Deficiency

• Progressive spinocerebellar ataxia: gait disturbance, dysmetria, dysarthria
• Posterior column signs: loss of vibration and proprioception, sensory ataxia, positive Romberg sign
• Peripheral neuropathy: distal weakness and numbness
• Myopathy: muscle weakness and cramps
• Ophthalmoplegia and retinitis pigmentosa (in severe cases)
• Often misdiagnosed as Friedreich ataxia or multiple sclerosis
• Classic association: abetalipoproteinemia (complete vitamin E malabsorption)

Vitamin K Deficiency

• Bleeding manifestations: easy bruising, hematuria, GI bleeding, intracranial hemorrhage
• Prolonged PT/INR (Factor VII deficiency — shortest half-life of vitamin K factors)
• Normal aPTT initially; prolonged only if severe (Factors II, IX, X depletion)
• Melena, epistaxis, menorrhagia
• Neonatal hemorrhagic disease (vitamin K prophylaxis now standard)
• Life-threatening intracranial hemorrhage in infants

Vitamin A Deficiency

• Serum retinol <20 μg/dL (<0.70 μmol/L) confirms deficiency; levels <10 μg/dL are severe
• Clinical diagnosis of night blindness in at-risk populations is often adequate
• Conjunctival xerosis, Bitot's spots on examination
• Associated hypoproteineamia (low albumin) suggests severe malnutrition
• Elevated prothrombin time may indicate concurrent vitamin K deficiency

Vitamin D Deficiency

• 25-hydroxyvitamin D is most reliable marker (reflects both dietary intake and skin synthesis)
• <20 ng/mL (<50 nmol/L) = deficiency
• 20-29 ng/mL = insufficiency
• ≥30 ng/mL = sufficient
• Secondary hyperparathyroidism: elevated PTH with low-normal or low calcium
• Elevated alkaline phosphatase and phosphate wasting
• X-rays show loss of bone density, metaphyseal lucencies, and characteristic bowing
• Rickets: costochondral beading, metaphyseal widening, subperiosteal resorption
• Rarely check 1,25-dihydroxyvitamin D (typically elevated due to secondary hyperparathyroidism)

Vitamin E Deficiency

• Serum alpha-tocopherol <5.0 mg/L (<11.6 μmol/L) suggests deficiency
• Serum tocopherol:lipid ratio more specific when hyperlipidemia present (ratio <0.8 μmol/mmol total lipids)
• Presence of ataxia with fat malabsorption history is highly suggestive
• Electromyography shows neurogenic pattern; nerve conduction shows sensorimotor polyneuropathy
• Genetic testing for abetalipoproteinemia or TTPA mutations if familial presentation

Vitamin K Deficiency

• Prolonged PT/INR with normal aPTT and normal platelet count and fibrinogen
• PIVKA-II (Proteins Induced by Vitamin K Absence) elevated (undercarboxylated prothrombin)
• Correction of PT after vitamin K administration confirms diagnosis
• Bleeding time normal (platelet function intact)
• Assess for underlying malabsorption: fecal fat, imaging of pancreas, assess for celiac disease

Vitamin A Deficiency

• Oral retinol 200,000 IU (60,000 μg) daily × 2 days, then repeat at 2 weeks for moderate deficiency
• Severe deficiency with corneal involvement: 200,000 IU immediately, then daily × 3-5 days
• Intramuscular dosing for vomiting/severe malabsorption
• Add supplementation for 2 months after

Vitamin A

• Keratomalacia and corneal perforation: corneal stromal melting after goblet-cell loss; signaled by a hazy, softening cornea in a child with Bitot's spots. This is an ocular emergency — WHO advises immediate high-dose retinol, since blindness becomes irreversible within days.
• Infection-related mortality: squamous metaplasia of respiratory/GI epithelium plus impaired lymphocyte function; WHO recommends vitamin A for children hospitalized with measles because it reduces mortality.

Vitamin D

• Hypocalcemic tetany, laryngospasm, and seizures in infants — an emergency requiring IV calcium; look for carpopedal spasm, stridor, prolonged QT. Infantile hypocalcemic dilated cardiomyopathy can present as heart failure.
• Fragility fractures and pseudofractures (Looser zones) from unmineralized osteoid; ALP is elevated while calcium may be near-normal.
• Tertiary hyperparathyroidism: chronic PTH drive produces autonomous glands and hypercalcemia after repletion.

Vitamin E

• Irreversible spinocerebellar and posterior column degeneration if repletion is delayed; hemolytic anemia in premature neonates from RBC membrane peroxidation.

Vitamin K

• Vitamin K deficiency bleeding of the newborn, especially late VKDB at 2–12 weeks in exclusively breastfed infants who missed prophylaxis — intracranial hemorrhage is the emergency, and the AAP recommends a single IM dose of phytonadione 0.5–1 mg at birth to prevent it.

Treatment-related

• Vitamin A toxicity: pseudotumor cerebri (headache, papilledema, diplopia), hepatotoxicity, hypercalcemia; retinoids are potent teratogens, so high-dose regimens are avoided in pregnancy.
• Vitamin D over-repletion: hypercalcemia, nephrolithiasis, nephrocalcinosis — check calcium during therapy.
• High-dose vitamin E antagonizes vitamin K–dependent carboxylation and potentiates warfarin; excess has been linked to hemorrhagic stroke.
• IV phytonadione: anaphylactoid reaction — give by slow infusion; menadione (K3) causes neonatal hemolysis and kernicterus.

• Night blindness is the earliest and most reversible vitamin A sign: retinal is the chromophore for rhodopsin in rods, so scotopic vision fails before Bitot's spots or keratomalacia. Buzzword pairing: foamy conjunctival patches + follicular hyperkeratosis + a malnourished child.
• Vitamin K deficiency versus liver disease is the classic distractor. Both prolong PT/INR. Factor V is not vitamin K–dependent — it is low in hepatocellular failure and normal in isolated vitamin K deficiency. Correction of the INR after parenteral phytonadione also points to deficiency.
• Order 25-hydroxyvitamin D, not 1,25-dihydroxyvitamin D, when deficiency is suspected; the active metabolite is often normal or high because secondary hyperparathyroidism drives 1α-hydroxylase. The biochemical triad is low/normal calcium, low phosphate, high PTH, high alkaline phosphatase.
• Vitamin E mimics B12 deficiency — posterior column loss, ataxia, positive Romberg — but there is no megaloblastic anemia and no elevated methylmalonic acid. Vitamin E deficiency may instead cause hemolysis.
• Abetalipoproteinemia is the association examiners love: failure to thrive, steatorrhea, acanthocytes on smear, near-absent apoB-containing lipoproteins, and ataxia/retinitis pigmentosa from vitamin E deficiency. Treatment is very high-dose vitamin E plus dietary fat restriction.
• The bleeding neonate at 2–12 weeks who was exclusively breastfed and born at home: the single best next step is parenteral vitamin K, and the AAP-recommended prevention is IM phytonadione 0.5–1 mg at birth.
• In cholestasis and cystic fibrosis, use water-miscible preparations — fat-soluble formulations will not be absorbed without bile salts or lipase.
• Don't over-supplement: vitamin A excess causes pseudotumor cerebri and is teratogenic, and vitamin D excess causes hypercalcemia and nephrocalcinosis. The USPSTF has found the evidence insufficient to recommend routine screening for vitamin D deficiency in asymptomatic adults.