Entry Level Clinical Nutrition Entry Level Clinical Nutrition

Entry Level Clinical Nutrition – Part 12
Dr. Jeff Moss
Entry Level Clinical Nutrition

Part XII
Micronutrient imbalances:
Water soluble vitamins
Jeffrey Moss, DDS, CNS, DACBN

jeffmoss@mossnutrition.com
413--530
413 530--0858 (cell)
Quality of life issues are the

major concerns more than
ever now.
Summer of work exposes medical students to system’s ills, The New

York Times, September 9, 2009
“…a tidal wave of chronic illness…”
© Dr. Jeff Moss

http://www.mossnutrition.com 1
http://www.FMTown.com
Dr. Jeff Moss
Baracos VE. Overview on
metabolic adaptation to
stress, pp. 1-13.
“An understanding of the

nature of stress is
fundamental to the rational
design of nutrient mixtures to
feed patients whose
homeostasis has been altered
by one or more stressors.”
“All stresses may be

presumed to be associated
with characteristic
modifications in the
metabolism of lipids,
carbohydrates, amino acids,
and micronutrients.”
Bengmark S. Acute and “chronic” phase

reaction – a mother of disease, Clin Nutr,
Vol. 23, pp. 1256-66, 2004
Su KP. Biological mechanism of antidepressant effect of omega-3

fatty acids: How does fish oil act as a ‘mind-body interface’?
Neurosignals,
g , Vol. 17,, pp.
pp 144-152,, 2009
© Dr. Jeff Moss

Dr. Jeff Moss
Key metabolic imbalances seen

with the acute phase response
• Metabolic acidosis
• Loss of lean body mass (sarcopenia)
• Insulin resistance
• I fl
Inflamm-aging
i (I(Increased
d iinnate
t iimmunity
it
and decreased adaptive immunity)
• Suboptimal caloric intake and
carbohydrate:protein ratio (Refeeding
syndrome)
• Gastrointestinal dysfunction/gut atrophy
• Deficiencies of key micronutrients such as
zinc, selenium, and vitamin D
8
Underlying hypotheses of
Entry Level Clinical Nutrition:
• Chief complaints in chronically ill

patients are not diseases but responses
that have gone on too long (Allostatic
load).
• The metabolic imbalances that combine
to form this response have been well
defined by critical care nutritionists.
© Dr. Jeff Moss

Dr. Jeff Moss
Entry Level Clinical Nutrition:
A new model of functional

medicine that incorporates
allostatic load and the “chronic”
acute phase response
10
Chronic inflammation,
inflammaging, metainflamm.
Key deficiencies or Low calorie intake
excesses, i.e., and excessive
Calories, carbohydrate/protein
macronutrients, B ratio – Refeeding
vitamins, zinc, syndrome
selenium, iodine,
sleep, psychological
and chemical stress,
movement against Hyperinsulinemia/Insulin
gravity, weight resistance
Sarcopenia/Loss of lean
Gut body mass
dysfunction/atrophy Low grade chronic
metabolic acidosis/fluid
electrolyte imbalance
THE CREATION OF THE EXCESSIVE CATABOLIC

PHYSIOLOGY “RESPONSE” 11
Foundational hypothesis
• Issues relating to micronutrient status in

chronically ill patients are more than just
issues of dietary adequacy and
bioavailability.
• How nutrients are metabolized after
absorption may be just as important to
resolving chief complaints in chronically
ill patients, if not more so.
12
© Dr. Jeff Moss

Dr. Jeff Moss
Foundational hypotheses
• What is the major driver of aberrant

micronutrient metabolism in chronically
ill patients?
INFLAMMATION!!
13
Shenkin A. The key role of micronutrients, Clin

Nutr, Vol. 25, pp. 1-13, 2006
“Micronutrients play a central role in metabolism and in the

maintenance of tissue function, but effects in preventing or
treating disease which is not due to micronutrient deficiency
cannot be expected from increasing the intake.”
“There is a a highly integrated system to control the flux of

micronutrients in illness…”
14
Shenkin A. Micronutrients in health and disease, Postgrad Med J, Vol.

82, pp. 559-567, 2006.
15
© Dr. Jeff Moss

Dr. Jeff Moss
• “The catabolism associated with acute

infection, surgery, or trauma leads to
increased energy expenditure and net
protein breakdown.”
• “Requirements for water soluble
vitamins, as coenzymes for these
metabolic pathways, will be increased,
as will the requirements for various
trace elements.”
16
• “Anabolism increases the requirement

for all nutrients; hence increased
micronutrients should be supplied when
patients are gaining weight.”
• “Trace
Trace element deficiencies are more
likely when patients become anabolic,
after a prolonged period of catabolism.”
17
Galloway P et al. Effect of the inflammatory

response on trace element and vitamin status
status,
Ann Clin Biochem, Vol. 37, pp. 289-297, 2000.
18
© Dr. Jeff Moss

Dr. Jeff Moss
19
A notable exception:
Refeeding syndrome and
vitamin B1 (Thiamine)
20
What is refeeding syndrome?
21
© Dr. Jeff Moss

Dr. Jeff Moss
Khan IUR et al. Refeeding syndrome: A literature review,

Gastroenterology Res Pract,
Pract Vol. 2011, Article ID: 410971,
Vol 2011 2010.
410971 2010
22
• “RFS describes a series of metabolic

and biochemical changes that occur
as a consequence of reintroduction
of feeding after a period of starvation
or fasting. This unfavorable
metabolic response
p causes
nonimmune-mediated harm to the
body and can be mild moderate, or
severe.”
23
• “The reintroduction of nutrition to a

starved or fasted individual results in a
rapid decline in both gluconeogenesis and
anaerobic metabolisms. This is mediated
by the rapid increase in serum insulin that
occurs on refeeding. Insulin stimulates
the movement of extracellular potassium,
phosphate and magnesium to the
phosphate,
intracellular compartment. Depleted
intracellular stores and a large
concentration gradient ensure a rapid fall
in the extracellular concentration of these
ions.”
24
© Dr. Jeff Moss

Dr. Jeff Moss
• “Osmotic neutrality must be

maintained resulting in the retention
of sodium and water. Reactivation of
carbohydrate-dependent metabolic
pathways increases demand for
thiamine, a cofactor required for
cellular enzymatic reactions. The
deficiencies of phosphate,
magnesium, potassium, and thiamine
occur to varying degrees and have
different effects in different patients.”
25
Boateng AA et al. Refeeding syndrome: Treatment considerations

based on collective analysis of literature case reports, Nutrition, Vol. 26,
pp. 156-167, 2010
26
• “The hallmark findings in refeeding

syndrome (RFS) are fluid and electrolyte
dysregulation including
hypophosphatemia, hypokalemia,
hypomagnesemia, abnormalities in
glucose metabolism, vitamin (importantly
thiamine),
), and trace element deficiencies.
RFS can be viewed as spectrum disorder
where symptoms range from mild to
severe depending on the degree of
starvation or malnourishment and the
form of management employed.”
27
© Dr. Jeff Moss

Dr. Jeff Moss
Thiamine
• “Vitamin deficiency results from the rapid

depletion of vitamins after onset of
refeeding due to their role in various
biochemical functions. For example,p ,
thiamine is necessary for glucose
metabolism but its stores are depleted
during starvation. Sudden introduction of
glucose drives already depleted thiamine
stores to a nadir, precipitating Wernicke’s
encephalopathy and lactic acidosis.”
28
Thiamine
• “Vitamin B1 (thiamine) is not stored

in sufficient amounts and, since it is
needed for glycolysis, it must be
provided before or along with
glucose administration.”
• “Deficiency in thiamine also causes a
buildup of pyruvic and lactic
acids…”
29
Stanga Z et al. Nutrition in clinical practice – the refeeding syndrome:

illustrative cases and guidelines for prevention and treatment, Eur J
Clin Nutr, Vol. 62, pp. 687-694, 2008.
“The refeeding syndrome was first reported among those released from
concentration camps following the Second World War. Oral feeding of
these grossly malnourished individuals often resulted in fatal diarrhoea,
heart failure and neurological complications, including coma and
convulsions.”
30
© Dr. Jeff Moss

Dr. Jeff Moss
Key metabolic features
• “salt and water retention leading to oedema and heart

failure, which may be exacerbated by cardiac
atrophy,
• hypokalemia due to rapid cellular uptake of
potassium as glucose and amino acids are taken up
during cellular synthesis of glycogen and protein,
• hypophosphataemia due to increased phosphorylatin
of glucose,
• rapid depletion of thiamine, a cofactor in glycolysis,
leading to Wernicke’s encephalopathy and/or
cardiomyopathy, and
• Hypomagnesaemia due to cellular uptake of this
mineral.”
31
Clinical presentation
“in the trenches”
• “It is difficult to give a precise definition for the

refeeding syndrome, since many otherwise
well nourished patients, refed after only a few
days starvation, will show a modest change in
biochemical values, for example a fall in
serum potassium and phosphate
concentrations, without displaying any
symptoms.”
32
Clinical presentation
“in the trenches”
• “There is a spectrum or gradation in the features of
this condition from such asymptomatic cases to those
with severe malnutrition who are at risk of overt and
even life-threatening symptoms.”
• “We
We have taken the view that the full
full-blown
blown syndrome
should be defined by the presence of symptoms, but
that biochemical changes of sufficient degree to pose
a potential risk should be acted upon without delay in
order to prevent the clinical features developing.”
• “Perhaps, we should adopt the terms ‘symptomatic
refeeding syndrome’ and ‘potential or biochemical
refeeding syndrome.’”
33
© Dr. Jeff Moss

Dr. Jeff Moss
34
35
B vitamins and the pyruvate

dehydrogenase complex
36
© Dr. Jeff Moss

Dr. Jeff Moss
Lord RS &
Bralley JA. Eds.,
Laboratory
Evaluations for
Integrative and
Functional
Medicine, 2nd
Edition,
Edition
Metametrix
Institute, Duluth
GA, 2008
37
38
Harris RA et al. Regulation of the activity of the pyruvate

dehydrogenase complex
complex, Advan Enzyme RegulRegul, Vol.
Vol 42
42, pp
pp. 249
249-259,
259
2002
“Prolonged fasting or meals rich in fat bring about inhibition and

inactivation of the pyruvate dehydrogenase complex in order to minimize
loss of pyruvate carbon.”
39
© Dr. Jeff Moss

Dr. Jeff Moss
40
Interconversion of Metabolic Fuels
Interconversion of metabolic fuels, Coffee CJ. Metabolism, Fence Creek Publ., Madision, CT,
1998, p. 102 41
Samuel VT. Fructose induced lipogenesis: from sugar to fat to insulin

resistance, Trends Endocrinol Metab, Vol. 22, No. 2, pp. 60-65, February,
2011.
“Fructose promotes lipogenesis by…increasing PDH activity…”
42
© Dr. Jeff Moss

Dr. Jeff Moss
43
Wells JCK & Siervo M. Obesity and energy balance: is the tail wagging
the dog? Eur J Clin Nutr, Vol. 65, No. 11, pp. 1173-1189, November
2011.
“This model cannot explain why weight accumulates persistently rather

than reaching a plateau, and underplays the effect of variability in dietary
constituents on energy and intermediary metabolism.”
44
• “An alternative model emphasises the

capacity of fructose and fructose-derived
sweeteners (sucrose, high-fructose corn
syrup) to perturb cellular metabolism…which
favour[s] adipose tissue accretion and
increased appetite while depressing physical
activity.”
• “This model implicates chronic
hyperinsulinaemia in the presence of a
paradoxical state of ‘cellular starvation’ as a
key driver of the metabolic modifications
inducing chronic weight gain.”
45
© Dr. Jeff Moss

Dr. Jeff Moss
46
Pyridoxine
(Vitamin B6)
47
Midttun O et al. Low plasma vitamin B6 status affects metabolism

through the kynurenine pathway in cardiovascular patients with systemic
inflammation, J Nutr, Vol. 141, pp. 611-617, 2011
48
© Dr. Jeff Moss

Dr. Jeff Moss
• “Low plasma concentrations of the

vitamin B-6 form of pyridoxal 5’-
phosphate (PLP) have been reported
in patients with high levels of
inflammatory markers and with
conditions associated with
inflammation, including rheumatoid
arthritis, cardiovascular disease, and
diabetes.”
49
• “…in patients with an inflammatory

condition like rheumatoid arthritis,
erythrocyte PLP seems to be a
measure of vitamin stores restricted
to the erythrocyte compartment, and
plasma PLP may be a better indictor
of overall vitamin B-6 status.”
50
• “We…demonstrated in this study

population of patients with coronary
artery disease that inflammation is
the main predictor of impaired
vitamin B-6 status, and 94% of the
participants with PLP below the 5th
percentile had increased
concentrations of 1 or several
markers of inflammation.”
51
© Dr. Jeff Moss

Dr. Jeff Moss
• “Our data confirm published reports

on an association between elevated
CRP and low PLP in healthy
individuals and patients with
inflammatory conditions, including
CVD.”
• “Vitamin B-6 depletion during
inflammation and immune activation
may be related to the involvement of
PLP in cytokine production and
lymphocyte proliferation.”
52
• “…pyridoxine supplementation did

not affect the plasma concentration
off any off th
the inflammatory
i fl t
mediators.”
53
Gray A et al. The relationship between plasma and red cell

concentrations
t ti off vitamins
it i thiamine
thi i di diphosphate,
h h t flflavin
i adenine
d i
dinucleotide and pyridoxal 5-phosphate following elective knee
arthroplasty, Clin Nutr, Vol. 23, pp. 1080-1083, 2004.
“The results of the present study indicate that plasma concentrations of

FAD and PLP are transiently reduced following an inflammatory insult
and therefore unlikely to be a reliable measure of status in the presence
of a systemic inflammatory response. It may be that during such a
response red cell concentrations provide a more reliable measure.”
54
© Dr. Jeff Moss

Dr. Jeff Moss
Vitamin B12
55
Sviri S et al. Increased vitamin B12 levels are associated with mortality
in critically ill medical patients, Clin Nutr, Published online ahead of print,
2011.
“More recently, the negative associations of high serum levels of

Vitamin B12 are being recognized.”
56
• “High serum levels of this vitamin are

seen in the following conditions: renal
failure, cancer, hematological
malignancy (e.g. acute and chronic
leukemias), polycythemia rubra vera,
hypereosinophilic syndrome and hepatic
disease (e.g. cirrhosis, hepatitis,
hepatocellular carcinoma and
metastatic liver tumors.”
57
© Dr. Jeff Moss

Dr. Jeff Moss
• “Although traditionally not considered an

acute phase reactant, a weak
association has been shown between
serum Vitamin B12 levels and markers
of sepsis (C-reactive protein levels)…”
• “Vitamin B12 levels were also positively
correlated with severity of illness…”
• “Decreased intracellular cobalamin
levels may parallel increased plasma
levels.”
58
“The concurrent elevation of

cobalamin together with
homocysteine and/or methylmalonic
acid (implying functional deficiency)
was described in various clinical
situations.”
59
Celik T et al. Urinary methylmalonic acid in patients with acute myocardial

infarction, Med Princ Pract, Vol. 18, pp. 217-222, 2009
“The conversion of methymalonyl CoA to succinyl-CoA requires vitamin B12, so

impaired cobalamin function causes an increased concentration of extracellular
methylmalonic acid (MMA), which thereby becomes a sensitive marker of
cobalamin status.”
60
© Dr. Jeff Moss

Dr. Jeff Moss
“In the present study, a strong positive

correlation was found between
uMMA and hs-CRP in patients with
acute myocardial infarction.”
61
Vitamin C
62
Evans-Olders R et al. Metabolic origin of hypovitaminosis C in acutely

hospitalized patients, Nutrition, Vol. 26, pp. 1070-1074, 2010.
63
© Dr. Jeff Moss

Dr. Jeff Moss
• “Hypovitaminosis C usually implies

vitamin C deficiency, but it could
also occur as part of the acute phase
response.”
• “In the European studies of non-
critically ill patients cited earlier,
circulating vitamin C and C-reactive
protein (CRP) concentrations were
inversely related, suggesting that the
acute-phase response could indeed
account for the hypovitaminosis C
observed n this setting.”
64
• “In agreement with previous reports,

baseline CRP concentrations were
inversely related to plasma vitamin C
concentrations. In light of the
present findings and previous
observations, it is reasonable to
suggest that systemic inflammation
increases vitamin C catabolism, but
induces deficiency only when
vitamin C intake is inadequate .”
65
• “Congruent with this possibility,

there is evidence that cigarette
smoking increases vitamin C
turnover, reduces plasma vitamin C
concentrations, and increases the
dietary vitamin C requirement. The
same mechanism could act even
more strongly in acutely hospitalized
patients.”
66
© Dr. Jeff Moss

Dr. Jeff Moss
Vitamin C and sickness behavior
• “There is a well-known but little-studied

relation between vitamin C deficiency and
affective state. It is not surprising that
such a relation exists,, because vitamin C
is involved in neuronal transmission and
neurotransmitter metabolism, and its
cerebrospinal fluid concentration is
approximately three-fold higher than, and
tightly linked to, its plasma
concentration.”
67
• “Vitamin C therapy increased plasma

(P < 0.0001 and mononuclear
leukocyte (P = 0.014) vitamin C
concentrations and was associated
with a 34% reduction in mood
disturbance (P = 0.013).”
68
• “Hypovitaminosis C usually implies

vitamin C deficiency, but the
response to systemic inflammation
could redistribute the vitamin into
leukocytes or other tissues, without
necessarily indicating nutritional
deficiency It is also possible,
deficiency. possible
however, that systemic inflammation
increases vitamin C catabolism and
induces true biochemical deficiency
when vitamin C provision is
inadequate.”
69
© Dr. Jeff Moss

Dr. Jeff Moss
• “Indeed, whether hypovitaminosis C

is caused by redistribution of the
vitamin into tissues, increased
catabolism,, or both,, a predictable
p
consequence is reduced vitamin C
availability to the brain.”
70
Micronutrients and chronic

illness:
The big picture
71
Hou CT et al. Higher plasma pyridoxal 5’-phosphate is associated with

better blood glucose responses in critically ill surgical patients with
inadequate vitamin B-6 status, Clin Nutr, Vol. 30, No. 4, pp. 478-483, August
2011.
“Stress, inflammation, and clinical conditions may increase the utilization

and metabolic turnover of vitamin B-6 and lower the body pool of vitamin B-
6.”
72
© Dr. Jeff Moss

Dr. Jeff Moss
• “Pyridoxal 5’-phosphate (PLP), the

physiological active coenzyme form of vitamin
B-6,is involved in gluconeogenesis and
glycogenolysis through its role in
transaminase reactions and in the action of
glycogen phosphorylation.”
• “Decreased
Decreased vitamin B B-6
6 concentrations were
observed in diabetic animals and patients,
and there was a significant association
between glucose intolerance and vitamin B-6
deficiency in rats.”
73
Huang YC et al. Vitamin B6 intakes and status of mechanically ventilated

critically ill patients in Taiwan, Eur J Clin Nutr, Vol. 56, pp. 387-392, 2002.
“Patients had an adequate mean vitamin B6 intake (16.26 ± 19.39 mg)

during the 14 day study. Mean vitamin B6 intake was significantly higher
on day 14 than on day 1”
“…we noted that plasma pyridoxal 5’-phosphate (PLP) and pyridoxal (PL)
concentrations significantly decreased while vitamin B6 intake significantly
increased on day 14. Critical clinical conditions and complex metabolism in
the critically ill may account for the reduction of plasma PLP and PL.”
74
Chang HJ and Liang MH. The quiet epidemic, JAMA, Vol. 306,
No. 17, pp. 1843-1844, November 2, 2011
“To sin by silence when they should protest makes cowards of men.”
Abraham Lincoln
75
© Dr. Jeff Moss

Dr. Jeff Moss
Mursu J et al. Dietary supplements and mortality rate in older

women, Arch Int Med, Vol. 171, No. 18, pp. 1625-1633, October
10, 2011
76
77
78
© Dr. Jeff Moss

Dr. Jeff Moss
79
With the above in mind, how

should we proceed with
micronutrient supplementation
with chronically ill patients?
80
Supplement using amounts

based on patient need rather
than RDA/RDI dogma
81
© Dr. Jeff Moss

Dr. Jeff Moss
PLUS
82
Key metabolic imbalances seen

with the acute phase response
• Metabolic acidosis
• Loss of lean body mass (sarcopenia)
• Insulin resistance
• I fl
Inflamm-aging
i (I(Increased
d iinnate
t iimmunity
it
and decreased adaptive immunity)
• Suboptimal caloric intake and
carbohydrate:protein ratio (Refeeding
syndrome)
• Gastrointestinal dysfunction/gut atrophy
• Deficiencies of key micronutrients such as
zinc, selenium, and vitamin D
83
84
© Dr. Jeff Moss

Dr. Jeff Moss
Thank you!!
85
© Dr. Jeff Moss


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Entry Level Clinical Nutrition – Part 12

Dr. Jeff Moss

Entry Level Clinical Nutrition

Jeffrey Moss, DDS, CNS, DACBN

Quality of life issues are the

Summer of work exposes medical students to system’s ills, The New

“…a tidal wave of chronic illness…”

© Dr. Jeff Moss

“An understanding of the

“All stresses may be

Bengmark S. Acute and “chronic” phase

Su KP. Biological mechanism of antidepressant effect of omega-3

© Dr. Jeff Moss

Key metabolic imbalances seen

• Chief complaints in chronically ill

© Dr. Jeff Moss

Entry Level Clinical Nutrition:

A new model of functional

THE CREATION OF THE EXCESSIVE CATABOLIC

• Issues relating to micronutrient status in

© Dr. Jeff Moss

• What is the major driver of aberrant

Shenkin A. The key role of micronutrients, Clin

“Micronutrients play a central role in metabolism and in the

“There is a a highly integrated system to control the flux of

Shenkin A. Micronutrients in health and disease, Postgrad Med J, Vol.

© Dr. Jeff Moss

• “The catabolism associated with acute

• “Anabolism increases the requirement

Galloway P et al. Effect of the inflammatory

© Dr. Jeff Moss

What is refeeding syndrome?

© Dr. Jeff Moss

Khan IUR et al. Refeeding syndrome: A literature review,

• “RFS describes a series of metabolic

• “The reintroduction of nutrition to a

© Dr. Jeff Moss

• “Osmotic neutrality must be

Boateng AA et al. Refeeding syndrome: Treatment considerations

• “The hallmark findings in refeeding

© Dr. Jeff Moss

• “Vitamin deficiency results from the rapid

• “Vitamin B1 (thiamine) is not stored

Stanga Z et al. Nutrition in clinical practice – the refeeding syndrome:

© Dr. Jeff Moss

Key metabolic features

• “salt and water retention leading to oedema and heart

• “It is difficult to give a precise definition for the

© Dr. Jeff Moss

B vitamins and the pyruvate

© Dr. Jeff Moss

Harris RA et al. Regulation of the activity of the pyruvate

“Prolonged fasting or meals rich in fat bring about inhibition and

© Dr. Jeff Moss

Interconversion of Metabolic Fuels

Samuel VT. Fructose induced lipogenesis: from sugar to fat to insulin

“Fructose promotes lipogenesis by…increasing PDH activity…”

© Dr. Jeff Moss

“This model cannot explain why weight accumulates persistently rather