Phrynoderma – follicular papules with central keratotic plug; favors extensor surfaces of extremities ( Fig. 51.7 ) & buttocks

Generalized xerosis

Sparse, fragile hair

Night blindness

Xerophthalmia (dryness of the cornea & conjunctivae)

Bitot spots (gray–white patches on the conjunctivae)

Keratomalacia (softness of the cornea, sometimes with ulceration)

Stunted growth

Increase in measles-related mortality (see Ch. 81 )

Increased susceptibility to and mortality from respiratory and diarrheal illnesses

Serum: LC–MS/MS for vitamin A levels

Reference values (fasting):

• 
  

  0–6 yrs: 11–65 mcg/dl

  
  
• 
  

  7–12 yrs: 13–80 mcg/dl

  
  
• 
  

  13–17 yrs: 14–98 mcg/dl

  
  
• 
  

  ≥18 yrs: 32–78 mcg/dl

Supplementation recommended when <20 mcg/dl

Severe deficiency when <10 mcg/dl

Based on severity of ophthalmologic impairment

Infants (<6 mos): 50 000 IU PO × 3 on days 1, 2, and at least 14

Infants (6–12 mos): 100 000 IU PO × 3 doses (see above)

Children >1 yr, men, post-menopausal women: 200 000 IU PO × 3 doses (see above) *

Higher doses given if keratomalacia

None

Muscle weakness

Rickets in children

Osteomalacia in adults

Possible decrease in innate immunity (see Table 51.3 )

Possible increase in internal malignancies (e.g. colon, prostate)

Total serum or plasma 25(OH) vitamin D is measured (D ₂ plus D ₃ )

Deficiency: <20 ng/ml (IU: <50 nmol/l)

Insufficiency: 20–29 ng/ml (IU: 51–75 nmol/l)

For deficiency, 20 000 IU of vitamin D ₃ (preferred) or 50 000 IU of vitamin D ₂ PO once weekly × 8 weeks

Maintenance dose is age-dependent (see text)

Plus 1 g/day of oral calcium if deficient

None

Ophthalmoplegia, ptosis

Muscle weakness, ataxia, areflexia

Pigmentary retinopathy

Serum: LC–MS/MS for vitamin E levels

Reference values (fasting):

• 
  

  0–17 yrs: 3.8–18.4 mg/l

  
  
• 
  

  ≥18 yrs: 5.5–17.0 mg/l

Significant deficiency: <3.0 mg/l

Children 200–300 mg/day PO

Adults 800–1000 mg/day PO

If severe hypoprothrombinemia, extensive hemorrhage at any body site

Hemorrhagic disease of the newborn – infants not given vitamin K at birth plus inadequate diet or mother on medications which inhibit vitamin K function ^{, †}

Elevated prothrombin time & INR

Serum or plasma vitamin K ₁ level is measured

≥18 yrs: 0.10–2.20 ng/ml versus 0.2–3.2 ng/ml

Newborns: 0.5–1 mg sc or IM

Children: 2 mg

Adults: 5–10 mg

PO if asymptomatic

Intravenously in emergencies (risk of anaphylaxis)

Fresh frozen plasma

Doses for K ₁ and K ₂ similar

Spongy gingivae with bleeding & erosions

Petechiae, ecchymoses

Follicular hyperkeratosis, especially forearms, abdomen & legs

Corkscrew hairs (flattened & curled) with perifollicular erythema or hemorrhage ( Fig. 51.8 )

Subperiosteal hemorrhage with “pseudoparalysis”, especially in children

Arthralgias, joint swelling, edema

Loose teeth

Impaired wound healing

Weakness, malaise, depression

Vasomotor instability

In infants, hemorrhage into GI and GU tracts

Anemia

Impeded growth

Cerebral & femoral sheath hemorrhages

Many of the signs of scurvy are related to impaired collagen synthesis

Fractures of cartilaginous matrix

Positive Rumpel–Leede capillary fragility test (>20 petechiae/inch ) ^‡

Plasma: HPLC for ascorbic acid levels

Conventional (fasting): 0.6–2.0 mg/dl

<0.3 mg/dl = significant deficiency

Absence of vitamin C in urine

Adults: 200–800 mg/day PO (in divided doses)

Children: 100–300 mg/day PO (in divided doses)

Higher dosage (1–2 g/day) may decrease symptom duration

Skin breakdown may be seen in “wet” beriberi due to edema

Glossitis and glossodynia

Early – fatigue, apathy, irritability, depression, drowsiness, anorexia, nausea, abdominal pain

Late – peripheral neuropathy, weakness, cardiac failure, mental alterations, growth retardation

Prolonged deprivation – meningismus, coma

Beriberi is divided into “wet” and “dry” forms ^§

Korsakoff syndrome – amnesia, confabulation & peripheral neuropathy

Wernicke encephalopathy – ophthalmoplegia, horizontal nystagmus, ataxia, confusion

Whole blood or erythrocytes: HPLC for thiamin diphosphate (active form of vitamin B ₁ ) levels ^¶

Reference values (fasting): 70–180 nmol/l

Thiamin diphosphate level <70 nmol/l suggests deficiency

100 mg TID IV × several days, followed by 100 mg/day PO until complete recovery

Infantile beriberi: 5–20 mg IV

Angular cheilitis

Glossitis – pebbly appearance, then atrophic with irregular denudation of papillae

In periorificial sites (head & neck, anogenital region) – painless scaly papules, ulcers, indolent fissures & seborrheic dermatitis-like lesions

Conjunctivitis

Superficial keratitis

Photophobia

Changes in iris (pigment clumping)

Anemia due to bone marrow hypoplasia

Mental retardation in newborns

In adults, oro-oculo-genital syndrome can occur, especially if there are additional B vitamin deficiencies

Plasma: LC–MS/MS for riboflavin levels

Reference values (fasting): 1–19 mcg/l

Riboflavin level <1 mcg/l = deficiency; marginally low levels should also be corrected

Riboflavin 3–10 mg/day PO

In refractory cases, 2 mg IM TID

Photodistributed erythema that becomes scarlet or hyperpigmented, with scale-crust; surface has shellac-like appearance ( Fig. 51.9 )

“Casal necklace” – well-demarcated band around the neck

Painful fissures of the palms & soles

Peri-anal & oral inflammation & erosions

Cheilitis & glossitis (atrophic, red)

Vaginitis with ulceration

Peripheral neuropathy with dysesthesias, including burning

Esophagitis

Anorexia

Lassitude

Dizziness

Irritability, disorientation

Abdominal pain

Late – irritability, anxiety, apathy, diarrhea, nausea, dementia

The classic triad of pellagra is dermatitis, diarrhea & dementia, with the fourth “d” possibly death

Because of large tissue stores, symptoms develop after months of niacin or tryptophan deficiency

Other causes of pellagra include carcinoid syndrome, Hartnup disease, and medications, e.g. isoniazid ^¶¶

Plasma; HPLC for niacin levels

Reference values (fasting; mcg/ml):

• 
  

  Children <10 yrs

  
  
  
  
  • 
    

    0.50–8.91 (normal)

    
    
  • 
    

    <0.50 (low)

  
  
  
  
• 
  

  Adults & children >10 yrs:

  
  
  
  
  • 
    

    0.50–8.45 (normal)

    
    
  • 
    

    <0.50 (low)

  
  

Nicotinamide 300 mg PO in divided doses × 3–4 weeks

None

Fatigue, headache & vomiting

Hypoglycemia

Paresthesias

Rare

Serum: microbiological assay

Reference values (mcg/l):

• 
  

  ≤1 yr: 3.45–845

  
  
• 
  

  1–10 yrs: 3.45–229.2

  
  
• 
  

  >10 yrs: 37–147

Periorificial seborrheic dermatitis-like lesions

Angular cheilitis, stomatitis

Glossitis – atrophic with ulceration

Conjunctivitis

Intertrigo

Anorexia, nausea, vomiting

Neurologic symptoms including peripheral neuropathy, somnolence, confusion & seizures

Sideroblastic anemia, eosinophilia, lymphopenia

LC–MS/MS for pyridoxal 5-phosphate levels

Reference value (fasting): 5–50 mcg/l

Pyridoxine 50–100 mg/day PO to prevent neuropathy

100 mg/day IV in those with seizures

Alopecia

Seborrheic dermatitis of the scalp, face, flexures & perianal region

Nummular eczema

Blepharitis, conjunctivitis

Erythroderma in neonatal form

Juvenile form may resemble acrodermatitis enteropathica

Depression, lassitude

Anorexia, nausea & vomiting

Paresthesias & hyperesthesias

Hypotonia, muscle pain

Developmental delay, hearing loss

Seizures, ataxia

Both forms fatal if not treated

Neonatal form – holocarboxylase synthetase deficiency (see Fig. 51.13 )

Juvenile form – biotinidase deficiency

Two forms have overlap; both autosomal recessive

Metabolic acidosis, lactic acidosis, hyperammonemia

Serum: microbiological assay

Reference values (pg/ml):

• 
  

  <12 yrs: 57.0–2460.2

  
  
• 
  

  ≥12 yrs: 221–3004

Increased urinary excretion of organic acids (e.g. 3-hydroxy-isovaleric acid)

Additional diagnostic tests include enzyme activity and genetic analysis (see Fig. 51.13 )

Infants & children: 5–20 mg/day PO or IM

Adults: 10–40 mg/day PO or IM

Cheilitis, glossitis, mucosal erosions

Diffuse hyperpigmentation, with accentuation in sun-exposed sites

Megaloblastic anemia (macrocytosis plus hypersegmented neutrophils is pathognomonic)

Weakness secondary to anemia

Neuropsychiatric symptoms due to impaired synthesis of myelin

While folate can reverse the megaloblastic anemia of B ₁₂ deficiency, it cannot reverse the neurologic degeneration

Serum folate levels: <4 mcg/l suggests folate deficiency

RBC folate levels: 140–628 ng/ml in packed RBCs

IU: 317–1422 nmol/l in packed RBCs

Replace folate and exclude B ₁₂ deficiency

Folate 1 mg TID PO, followed by 1 mg/day

Folate 1–5 mg/day IV if acutely ill

Cutaneous findings are uncommon

Diffuse or patchy hyperpigmentation, including flexural areas, palms, soles, nails, oral cavity

Glossitis with fissures of the oral mucosa (early sign prior to anemia)

Painful, red, swollen tongue

Megaloblastic anemia due to altered folic acid metabolism

Peripheral neuropathy, ataxia

Pernicious anemia – decrease in gastric intrinsic factor

Juvenile form – normal gastric acid secretion (in contrast to adult form)

Use of Schilling test has been supplanted by serologic testing for anti-parietal cell and anti-intrinsic factor antibodies

As an autoimmune endocrinopathy, associated with vitiligo, alopecia areata

Megaloblastic anemia with decreased serum B ₁₂ levels

Conventional: 200–835 pg/ml

IU: 148–616 pmol/l

More sensitive assay is serum levels of methylmalonic acid and homocysteine **

CNCbl 1 mg IM twice weekly × 2 weeks then weekly × 2 months then monthly

Sublingual route is felt to be appropriate, even in pernicious anemia or in states of abnormal absorption – 500 mcg/day of CNCbl