NS 4410 Scurvy Lecture

Prevalence of Scurvy

Vitamin C is ____ soluble, an _____ nutrient for humans; and it refers to family of ____ molecules

water; essential; 5

Ascorbic acid appears at ___ ph, it is the _____ form; and is it more or less stable?

acidic; protonated; more stable

What is predominant form of Vitamin C at physiologic pH (7.4)?

Ascorbate monoanion

What form of Vitamin C is 80-90% of vit c in foods?

Ascorbate monoanion

Ascorbate monoanion is what two things for many physiological reactions?

electron donor and antioxidant (reducing agent)

What is the fully oxidized form of vit c?

dehydroascorbic acid (DHA)

Dehydroascorbic acid rapidly what at physiological pH?

degrades

DHA can be reduced to _____ via recycling pathways

ascorbate

What are 3 examples of Enzymatic functions of Vit C?

1. Neurotransmitter (NT) and catecholamine synthesis

2. Collagen synthesis

3. Carnitine synthesis

What are 3 examples of Non-enzymatic functions of vit c?

1. Anti-oxidant

2. Non-heme iron absorption

3. Enhances immune function

As an electron donor, vit c maximizes activity of several enzymes involved in what 3 things?

1. Synthesis of catecholamines → epinephrine & norepinephrine

2. Synthesis of vasopressin (ADH)

3. Posttranslational modification of peptide hormones and neurotransmitters → TRH, GnRH,

   oxytocin, CCK, gastrin, calcitonin, substance P,

   neuropeptide Y

Application: Vitamin C for septic shock” What is the rationale behind this?

Patients with severe sepsis often have hypovitaminosis C

• vitamin C is needed to synthesis of norepinephrine and ADH (both facilitate maintaining/increasing blood pressure)

• vitamin C is also a powerful anti-oxidant to reduce oxidative stress and prevent free-radical injury

Enzymatic functions of Vit C: Collagen Synthesis: Hydroxylation of proline and lysine in the procollagen polypeptide alpha chains required for proper?

crossing-linking which stabilizes the helical structure

Vit C is a cofactor for?

the proline and lysine hydroxylases

• with inadequate hydroxylation the collagen is degraded

Application: Vitamin C in wound healing: Vitamin C deficiency leads to what 3 things related to wound healing?

1. Impaired collagen formation

2. Reduced tensile strength of wounds (tear when stretched)

3. Increase risk of wound dehiscence (opening) and slowed healing

Vitamin C requirements may be increased with large open

wounds (pressure ulcers) to facilitate? For what reasons?

tissue regeneration

• collagen formation, antioxidant properties, and possibly increased proliferation of dermal fibroblast

Application: Vitamin C Deficiency can cause hemorrhaging: Inadequate Vit C leads to what 2 things involved with hemorrhaging (bleeding)?

1. Impaired collagen formation

2. Increased fragility of capillaries and small vessels

   ^Increased risk of hemorrhaging

Enzymatic Functions of Vitamin C: Carnitine Synthesis. Vitamin C participates in two ____reactions required for the synthesis of carnitine from its amino acid precursors?

hydroxylation; lysine and methionine

What does carnitine catalyze?

the transport of long chain fatty acids from cytosol of cells into the mitochondrial matrix for subsequent B oxidation and ATP synthesis

Reductions in carnitine biosynthesis theorized to contribute to symptoms of?

fatigue with vit C deficiency

Non-enzymatic functions of Vitamin C: It is a powerful biological antioxidant and free radical scavenger. Which form acts as a electron donor to free radicals, neutralizing them?

Ascorbate

Vit C protects against ______associated with inflammation

oxidative damage

Who has increased inflammation and therefore increase needs for vit c

Smokers → in conditions with high levels of inflammation observe lower levels of vit c and increases the need

How does Vit C increase non-heme iron absorption?

in the gut lumen, ascorbic acid reduces ferric form (Fe3+) to ferrous form (Fe2+) that can be absorbed

Fatigue is a common symptom in scurvy. Impairment of which of the following functions of vitamin C could result in fatigue when vitamin C is deficient?

i. Collagen synthesis

ii. Carnitine synthesis

iii. Catecholamine synthesis

iv. Biological antioxidant

v. Non-heme iron absorption

ii, v

Vit C is a water-soluble essential micronutrient because humans lack what needed for synthesis of vit c?

gluconolactone oxidase (GULO)

There is a limited ability to store vit c. What is the total body pool?

~1500 mg (need nearly daily intake to maintain tissue stores)

The RDA for vit c is higher than amount needed for prevention of?

deficiency, set at levels adequate to support antioxidant and physiologic functions

What populations have an increased need of vit c? What is the upper limit and why?

1. Infants, pregnancy, lactation, smokers

2. 2000 mg/day for adults, due to GI side effects of nausea, cramping, diarrhea

Are Current Vit C Recommendations Adequate?Collagen related pathologies and Vitamin C requirements: Recent re-analysis of data from depeletion/repletion studies suggest HIGHER intake (95 mg/day) vit c needed to prevent and treat?

collagen related pathologies (Weak scar strength) for 97.5% of the population

Bleeding tendency and Vit C requirements: Gingival bleeding and retinal hemorrhages occur at low or high plasma ascorbic acid levels which are above the plasma level for?

low'; diagnosis of scurvy

Food Sources of Vitamin C: Vit c is very unstable; lost in cooking due to? and in storage due to? It is best preserved in?

1. Lost in cooking due to heat sensitivity and water soluble

2. Storage → oxygen and light exposure

3. Best preserved in acidic pH (most stable form)

10 mg of vit c may be adequate to?

prevent overt symptoms and signs of frank scurvy but fails to maximize health

Absorption and Bioavailability of Vitamin C: Ascorbate and dehydroascorbic acid are absorbed in?

jejunum; absorption near complete with typical dietary intake

>90 % of typical dose (up to ___ mg) of vit c is absorbed in healthy persons

200 mg

At higher doses, we see less bioavailability; What are the absorption rates with 500 mg and 1250 mg?

500 mg → 70%

1250 mg → 50%

Vitamin C absorption is dose-dependent: There is what type of relationship between oral intake of vit C and plasma levels?

sigmoidal

• steep rise in plasma levels with increases intake 30-100 mg/day

• SLOWER rise in plasma levels with higher doses

• Reach steady state plasma ascorbic acid levels (70-85 mol/L) with higher doses

There is decreased absorption with higher doses. Why?

Sodium dependent vit c transporters (SVCT1) gets saturated

Plasma Vit C levels tightly controlled. Single doses (over 200 mg) produce what in plasma level?

transient peak in plasma level

• vitamins C plasma concentrations tightly controlled

What are the 2 ways the could body maintain a steady state Vit C plasma level with increasing oral doses above 200mg?

1. Decrease absorption of vit C from the GI tract

2. Increase excretion of vit C (via the kidney, in the urine)

Excretion of Vit C as a Function of Dose Higher doses (>100mg) lead to More Excretion: Excretion of vit C minimal until 100 mg dose; Excretion increases for BOTH IV and and oral over 100 mg dose. Why is urinary excretion of vitamin C lower after a 500–1250 mg oral dose compared to the same IV dose?

Because high oral doses exceed the gut’s absorption capacity (saturation of SVCT1 transporters), so less vitamin C is absorbed into the bloodstream than with IV administration.

Lower bioavailability of oral Vit C with higher doses helps maintain?

steady state plasma level

Tissue Levels of Vitamin C Higher Doses (>100mg) do not lead to more Storage: Dose dependent increase in tissue vit C levels up to _____ mg/day of Vit C and then?

200; tissue levels plateau

Intracellular concentration of Vit C is?

tightly controlled

This data suggests that above an oral intake of 100 mg, there may be?

increases in the amount of plasma vit C, but not tissue levels of vit C (not helping maintain steady state plasma levels)

Vitamin C transported into cells via?

Sodium dependent Vit C Transporters

• SVCT1 and SVCT2

What does SVCT1 mediate?

systemic homeostasis

• absorption in the GI tract (jejunum)

• reabsorption in the kidney

What does SVCT2 control?

local demands

• widely expressed in all organs

• mediates movement INTO tissues

Vitamin C Tissue Distribution and Homeostasis: Total body content of Vit C is ?

300-2000 mg

• 300 is near scurvy levels

Ascorbate tissue concentrations depends on?

tissue and organs

There are higher ascorbate tissue concentrations where?

1. Higher in CNS (brain), eyes, WBCs and neuroendocrine tissues (adrenal, pituitary)

2. High concentrations in bone, connective tissue, and skin

Describe the tissue hierarchy

levels in tissues do NOT change at the same rate during depletion/repletion

• in deficiency brain loses vit C more slowly

• in repletion brain is one of the first to replete

• the most sensitive tissues are protected

Don’t store vit C: What happens to excess ascorbate is?

excreted by the kidney

Summary

Scurvy Etiology: Inadequate Vitamin C

Etiology of Scurvy: What are the 4 causes of scurvy?

1. Increased needs

2. Decreased absorption

3. Increased excretion

4. Inadequate intake

Clinical Presentation of Scurvy: Variable & Depends on length of time deficient in Vit C

Clinical Presentation: Symptoms/signs appear progressively because of?

tissue hierarchy

What are 3 early symptoms/signs?

1. Fatigue

2. Malaise

3. Lethargy (enzymatic functions)

What are 4 late symptoms and signs?

1. Cognitive changes

2. Confusion

3. Depression

4. Cognitive impairment

Time to development of deficiency depends on?

baseline vit c intake

What are 7 clinical manifestations of scurvy?

1. Ecchymosis (large bruised areas)

2. Purpura and Petechiae (red dots)

3. Perifollicular hemorrhages and corkscrew hairs

4. Malaise/fatigue & myalgias

5. Follicular hyperkeratosis

6. Splinter hemorrhages

7. Bleeding swollen gums (loose teeth)

About 90% of matrix of mature bone is ____ & hence a lack of it will have severe effect on bone

collagen

How does lack of collagen affect children?

altered endochondral bone formation- leads to poor bone growth, bone lesions and fractures, pseudo paralysis

How does lack of collagen affect adults?

joint pain, related to hemarthrosis, subperiosteal hemorrhages

Depression and Asthenia (lack of energy) is associated with low?

serum/plasma levels of ascorbic acid

• Observed in experimental depletion studies and cross

  sectional studies

• Reversible with repletion of Vitamin

Association of cognitive impairments with lower?

plasma ascorbic acid levels (<11-28 umol/L) as compared to those with higher levels

• cross sectional studies

Pathophysiology of Scurvy

Pathophysiology: Disrupted ____ bond formation and disrupted ___ formation leads to?

disulfide; keratin

1. Impaired hair growth

2. Coiled corkscrew hairs (pathognomonic)

3. broken hairs

Scurvy reduces iron absorption in the GI tract which can cause?

Iron deficiency anemia

Which of the following clinical manifestations observed in the case study is correctly paired with its pathophysiology?

A. Petechiae: carnitine deficiency

B. Bleeding gums: decreased iron absorption

C. Corkscrew hairs: catecholamine synthesis

D. Ecchymosis: decreased collagen synthesis

D. Ecchymosis: decreased collagen synthesis

We can diagnose scurvy with history and physical findings alone

What are the 6 reasons for inadequate vit c intake?

1. Alcohol use disorder or substance use

2. Autism spectrum disorder

3. Institutionalization or those without housing

4. Limited food access, nutrition insecurity (children, older, adults)

5. Poor dentition (impacts foods consumed)

6. Food preferences

Clinical presentation in order for scurvy

Laboratory tests: Plasma Ascorbate Levels

Plasma ascorbate (vitamin C) concentration plasma levels reflect what?

recent dietary intake; concentration in plasma can be a POOR indicator of tissue levels

With Vit C intake more than 100 mg/day the levels plateaus at ~70-80 umol/l due to?

decreased absorption rates and increased renal excretion

Laboratory Tests: WBC ascorbate (vit c) con; is a more ____ measure of tissue stores; correlates with? BUT is not routinely measured in the clinic

accurate; longer term dietary intake

Lab Test: Urinary excretion of ascorbic acid after IV

ascorbic acid administration is reliable indicator of?

tissue stores; not used clinically

Treatment: Supplemental Vit C: dose and timing individualized: Describe the difference between infants and children

Infants and children: 100-300 mg/day to start

Adults: 500-1000mg/day (divided doses!) to start

Duration: supplementation until full recovery (1-3 months)

Which type of supplementation is preferred?

oral supplementation over injection or intravenous

• Use injection or intravenous when oral intake not possible, GI malabsorption, and/or unable to take adequate oral intake

Treatment: Increase dietary intake of Vit C rich foods

Education: Foods, storage, preparation

Address barriers to access