Grand Rounds which summarizes the data pointing to fructose and sugar intake as the chief cause of hypertension and the use of allopurinal to treat pediatric hypertension.
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Uric Acid, Fructose and Hypertension
1. Gibbon Chimpanzees Humans Gorillas Old World Monkeys
2. nonsense mutation at codon 33 of urate oxidase
Gibbon Chimpanzees Humans Gorillas Old World Monkeys
20 million years ago
25 million years ago
3. nonsense mutation at codon 33 of urate oxidase
uric acid went from around 1 to 4 mg/dL
Gibbon Chimpanzees Humans Gorillas Old World Monkeys
20 million years ago
25 million years ago
4. So humans, chimps and
great apes separated
themselves from all other
mammals and joined
reptiles and birds in being
unable to convert uric acid
to allantoin...
14. lack of exercise?
modeling calorie intake versus weight gain allows one
to infer the effect of exercise
In children all of the weight gain (1971-2002) was
due to increase caloric consumption
In adults the weight observed weight gain, 8.6 kg,
was less than modeled from the increased caloric
consumption due to increased activity
Swinburn B. Increased energy intake alone virtually explains all the increase in body
weight in the United States from the 1970s to the 2000s. 2009 European Congress
on Obesity; May 6-9, 2009; Amsterdam, the Netherlands. Abstract T1:RS3.3.
15. lack of exercise?
modeling calorie intake versus weight gain allows one
to infer the effect of exercise
In children all of the weight gain (1971-2002) was
due to increase caloric consumption
In adults the weight observed weight gain, 8.6 kg,
was less than modeled from the increased caloric
consumption due to increased activity
Swinburn B. Increased energy intake alone virtually explains all the increase in body
weight in the United States from the 1970s to the 2000s. 2009 European Congress
on Obesity; May 6-9, 2009; Amsterdam, the Netherlands. Abstract T1:RS3.3.
20. 1898: William Osler reviewed
35,000 consecutive
admissions to Johns Hopkins
10 had
diabetes
21. 1898: William Osler reviewed
35,000 consecutive
admissions to Johns Hopkins
10 had
diabetes
22. 24 million americans have
diabetes
prevalence of diabetes has tripled
from 1980 to 2006
23. 24 million americans have
diabetes
prevalence of diabetes has tripled
from 1980 to 2006
24. hypertension
Johnson et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the
metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr (2007)
vol. 86 (4) pp. 899-906
25. 40%
hypertension
30%
20%
10%
6%
0%
1907 1939 1975 1990 2004
Johnson et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the
metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr (2007)
vol. 86 (4) pp. 899-906
26. 40%
hypertension
30%
20%
10%
140/90
6%
0%
1907 1939 1975 1990 2004
Johnson et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the
metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr (2007)
vol. 86 (4) pp. 899-906
27. 40%
hypertension
30% 31%
28%
25%
20%
10% 12%
140/90
6%
0%
1907 1939 1975 1990 2004
Johnson et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the
metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr (2007)
vol. 86 (4) pp. 899-906
30. 1940 Cardiology is established in the U.S.
1950 500 cardiologists in the United States
1960 World Health Organization pronounces a world
epidemic of cardiovascular disease
2006 over 25,000 cardiologists in the United States
2006 1,000,000 coronary angiograms yearly
2006 720,000 cardiovascular surgeries yearly
31. Diabetes Hypertension Glomerulonephritis
Polycystic disease Other
15%
47. 1319 England sugar costs
the equivalent of $100/kg
medicinal
1493 Columbus brings
sugar cane to the Caribbean
Slave labor was imported
from Africa to support the
harvesting of sugar
48. 1319 England sugar costs
the equivalent of $100/kg
medicinal
1493 Columbus brings
sugar cane to the Caribbean
Slave labor was imported
from Africa to support the
harvesting of sugar
49. 1747: a German chemist,
Andreas Marggraf discovered
how to extract sugar crystals
from sugarbeets
During the British naval
blockade during the Napoleonic
wars sugarbeets became a
major source of sugar
50. 1747: a German chemist,
Andreas Marggraf discovered
how to extract sugar crystals
from sugarbeets
During the British naval
blockade during the Napoleonic
wars sugarbeets became a
major source of sugar
world wide sugar production
51. 1866: Discovery of amylase
Allows food precessors to convert corn starch into a
syrup of pure glucose, corn syrup
Since there is no fructose in corn syrup, it is not as
sweet as sucrose
52. 1866: Discovery of amylase
Allows food precessors to convert corn starch into a
syrup of pure glucose, corn syrup
Since there is no fructose in corn syrup, it is not as
sweet as sucrose
53.
54. 1960s: glucose (D-Xylose)
isomerase is discovered. This
enzyme converts glucose to fructose
creating high fructose corn syrup
55. 1960s: glucose (D-Xylose)
isomerase is discovered. This
enzyme converts glucose to fructose
creating high fructose corn syrup
56. 1960s: glucose (D-Xylose)
isomerase is discovered. This
enzyme converts glucose to fructose
creating high fructose corn syrup
57. fructose compared to glucose
increases triglycerides metabolized in the liver
does not suppress appetite
does not stimulate insulin release
58. fructose compared to glucose
increases triglycerides metabolized in the liver
does not suppress appetite
does not stimulate insulin release
HFCS compared with sucrose
no difference in appetite cheaper
no difference in insulin made in the USA
no difference in triglycerides
71. Glucose
ATP hexokinase
ADP
Glucose-6-P
Fructose 6-P
ATP
phosphofructokinase
ADP
Fructose 1,6 bisphosphate
Dihydroxyacetone P Glyceraldehyde 3-P
1,3 Bisphosphoglycerate
ADP
ATP
3 Phosphoglycerate
2 Phosphoglycerate
Phosphoenolpyruvate
ADP
pyruvate kinase
ATP
Pyruvate Hultman E, Nilsson LH, Sahlin K. Scand J Clin Lab Invest. 1975
May;35(3):245-51.
Oberhaensli RD, Galloway GJ, Taylor DJ, Bore PJ, Radda GK. Br J
Radiol. 1986 Jul;59(703):695-9.
72. Glucose
ATP hexokinase
ADP
Glucose-6-P
Fructose 6-P
ATP
phosphofructokinase
ADP
Fructose 1,6 bisphosphate
Dihydroxyacetone P Glyceraldehyde 3-P
1,3 Bisphosphoglycerate
ADP
ATP
3 Phosphoglycerate
2 Phosphoglycerate
Phosphoenolpyruvate
ADP
pyruvate kinase
ATP
Pyruvate Hultman E, Nilsson LH, Sahlin K. Scand J Clin Lab Invest. 1975
May;35(3):245-51.
Oberhaensli RD, Galloway GJ, Taylor DJ, Bore PJ, Radda GK. Br J
Radiol. 1986 Jul;59(703):695-9.
73. Glucose Fructose
ATP hexokinase ATP
ADP ADP
Glucose-6-P Fructose-1-P
Fructose 6-P Glyceraldehyde
ATP +
phosphofructokinase
Dihydroxyacetone-P
ADP
Fructose 1,6 bisphosphate ATP
ADP
Dihydroxyacetone P Glyceraldehyde 3-P
1,3 Bisphosphoglycerate
ADP
ATP
3 Phosphoglycerate
2 Phosphoglycerate
Phosphoenolpyruvate
ADP
pyruvate kinase
ATP
Pyruvate Hultman E, Nilsson LH, Sahlin K. Scand J Clin Lab Invest. 1975
May;35(3):245-51.
Oberhaensli RD, Galloway GJ, Taylor DJ, Bore PJ, Radda GK. Br J
Radiol. 1986 Jul;59(703):695-9.
74. Glucose Fructose In vitro: Fructose infusion for 70
ATP hexokinase
ADP
ATP
ADP minutes resulted in 22.5%
Glucose-6-P Fructose-1-P decrease in ATP, glucose did
not change ATP
Fructose 6-P Glyceraldehyde
ATP +
phosphofructokinase
Dihydroxyacetone-P
ADP
Fructose 1,6 bisphosphate ATP
ADP
Dihydroxyacetone P Glyceraldehyde 3-P
1,3 Bisphosphoglycerate
ADP
ATP
3 Phosphoglycerate
2 Phosphoglycerate
Phosphoenolpyruvate
ADP
pyruvate kinase
ATP
Pyruvate Hultman E, Nilsson LH, Sahlin K. Scand J Clin Lab Invest. 1975
May;35(3):245-51.
Oberhaensli RD, Galloway GJ, Taylor DJ, Bore PJ, Radda GK. Br J
Radiol. 1986 Jul;59(703):695-9.
75. Glucose Fructose In vitro: Fructose infusion for 70
ATP hexokinase
ADP
ATP
ADP minutes resulted in 22.5%
Glucose-6-P Fructose-1-P decrease in ATP, glucose did
not change ATP
Fructose 6-P Glyceraldehyde
ATP +
phosphofructokinase
ADP
Dihydroxyacetone-P
In vivo: following a fructose load
Fructose 1,6 bisphosphate ATP
ADP hepatic fructose-1-P rose 800%
and ATP fell 75%
Dihydroxyacetone P Glyceraldehyde 3-P
1,3 Bisphosphoglycerate
ADP
ATP
3 Phosphoglycerate
2 Phosphoglycerate
Phosphoenolpyruvate
ADP
pyruvate kinase
ATP
Pyruvate Hultman E, Nilsson LH, Sahlin K. Scand J Clin Lab Invest. 1975
May;35(3):245-51.
Oberhaensli RD, Galloway GJ, Taylor DJ, Bore PJ, Radda GK. Br J
Radiol. 1986 Jul;59(703):695-9.
76. Every fructose molecule available is consumed in an
unregulated metabolic fire burning all available ATP in
the process
Consumption can consume all of the ATP leading to
Lactic acidosis
Ischemia
Lots and lots of adenosine, a purine
77. Glucose Fructose In vitro: Fructose infusion for 70
ATP hexokinase
ADP
ATP
ADP minutes resulted in 22.5%
Glucose-6-P Fructose-1-P decrease in ATP, glucose did
not change ATP
Fructose 6-P Glyceraldehyde
ATP +
phosphofructokinase
ADP
Dihydroxyacetone-P
In vivo: following a fructose load
Fructose 1,6 bisphosphate ATP
ADP hepatic fructose-1-P rose 800%
and ATP 75%
Dihydroxyacetone P Glyceraldehyde 3-P
21 men placed on a diet
1,3 Bisphosphoglycerate containing 25-30% of calories
ADP
ATP from sucrose developed
3 Phosphoglycerate
increase in SGPT, SGOT within
18 days. Transaminases
2 Phosphoglycerate
normalized with 10% of calories
Phosphoenolpyruvate
from sucrose
ADP
pyruvate kinase
ATP
Hultman E, Nilsson LH, Sahlin K. Scand J Clin Lab Invest. 1975
Pyruvate May;35(3):245-51.
Oberhaensli RD, Galloway GJ, Taylor DJ, Bore PJ, Radda GK. Br J
Radiol. 1986 Jul;59(703):695-9.
Porikos KP, Van Itallie TB. Am J Med. 1983 Oct;75(4):624-30.
78. Fructose and non-alcoholic fatty liver
disease
16-23% of Americans have non-
alcoholic fatty liver disease
Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM,
Johnson RJ, Abdelmalek MF. J Hepatol. 2008 June; 48(6): 993–999.
79. Fructose and non-alcoholic fatty liver
disease
16-23% of Americans have non-
alcoholic fatty liver disease
Daily fructose intake (cal/day)
Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM,
Johnson RJ, Abdelmalek MF. J Hepatol. 2008 June; 48(6): 993–999.
80. Fructose and non-alcoholic fatty liver
disease
16-23% of Americans have non-
alcoholic fatty liver disease
Daily fructose intake (cal/day)
NHANES 1999-2000
Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM,
Johnson RJ, Abdelmalek MF. J Hepatol. 2008 June; 48(6): 993–999.
81. Fructose and non-alcoholic fatty liver
disease
16-23% of Americans have non-
alcoholic fatty liver disease
Daily fructose intake (cal/day)
NHANES 1999-2000
Uric Acid was 41% higher in patients with NAFLD
(p<0.03) Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM,
Johnson RJ, Abdelmalek MF. J Hepatol. 2008 June; 48(6): 993–999.
82. Fructose and non-alcoholic fatty liver
disease
16-23% of Americans have non-
alcoholic fatty liver disease
Daily fructose intake (cal/day)
NHANES 1999-2000
Uric Acid was 41% higher in patients with NAFLD
(p<0.03) Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM,
Johnson RJ, Abdelmalek MF. J Hepatol. 2008 June; 48(6): 993–999.
84. glycolysis
Intermediates AMP GMP
Consumption of ATP PRPP Adenosine Guanosine
creates adenosine, a
purine IMP Inosine Guanine
All purines are Hypoxanthine
Xanthine oxidase
metabolized to uric
acid by xanthine Xanthine
oxidase Xanthine oxidase
Uric Acid
85. glycolysis
Intermediates AMP GMP
Consumption of ATP PRPP Adenosine Guanosine
creates adenosine, a
purine IMP Inosine Guanine
All purines are Hypoxanthine
Xanthine oxidase
metabolized to uric
acid by xanthine Xanthine
oxidase Xanthine oxidase
Uric Acid
86. Stirpe et al. Fructose-induced hyperuricaemia. Lancet (1970) vol. 2 (7686) pp. 1310-1
87. 6
5.9
5.7
5.6
Uric Acid (mg/dL)
5
fructose (g/kg) equal to a
liter of pepsi for a 70 kg
4.4 woman
4
0 30 60 120
Time (minutes)
Stirpe et al. Fructose-induced hyperuricaemia. Lancet (1970) vol. 2 (7686) pp. 1310-1
88. Perheentupa and Raivio. Fructose-induced hyperuricaemia. Lancet (1967) vol. 2 (7515) pp. 528-31
89. fructose (0.5 g/kg) IV
infusion
peak uric acid was seen
within 15 minutes and
persisted over 5 hours
Perheentupa and Raivio. Fructose-induced hyperuricaemia. Lancet (1967) vol. 2 (7515) pp. 528-31
90. If fructose increases
uric acid, and fructose
consumption has sky
rocketed in the last
few decades, are we
seeing more gout?
91. 10.0
7.5
gout/1000 patients
gout in England
5.0
2.5
0
1970/71 1981/82 1991
Harris et al. The prevalence and prophylaxis of gout in England. J Clin Epidemiol (1995) vol. 48 (9) pp. 1153-8
92. Arromdee et al. Epidemiology of gout: is the incidence rising?.
J Rheumatol (2002) vol. 29 (11) pp. 2403-6
93. Arromdee et al. Epidemiology of gout: is the incidence rising?.
J Rheumatol (2002) vol. 29 (11) pp. 2403-6
94. 1977
VERSUS
1995
Arromdee et al. Epidemiology of gout: is the incidence rising?.
J Rheumatol (2002) vol. 29 (11) pp. 2403-6
95. Annual Incidence
70.0
1977-78 1995-96 p
62
52.5 age 43.5 53.5 0.07
New cases/100,000
45 weight 84.5 85.5 0.50
42
35.0
BMI 28.8 29.8 0.36
17.5 uric acid 8.3 8.4 0.28
16
0
all cases no HCTZ
1977-78 1995-96
96.
97.
98. 1.Fructose increases uric acid
2.Uric acid and gout are increasing increasing
3.Uric acid causes hypertension
circumstantial
animal
interventional
105. prospective trial
total and CV mortality based on baseline uric acid
6,763 participants in the Framingham Heart Study
no association in men
positive association in women
when adjusted for: age, BMI, SBP, use of
antihypertensive agents, use of diuretics, diabetes,
cholesterol level, smoking status, alcohol intake,
LVH, and menopausal status
the data in women was no longer significant
Culleton et al. Serum uric acid and risk for cardiovascular disease and death: the
Framingham Heart Study. Ann Intern Med (1999) vol. 131 (1) pp. 7-13
106. NHANES I
n=5,926
after excluding prior CVD, gout, or currently pregnant
16.4 years follow-up
1,293 deaths
731 CVD
429 Cancer
Fang and Alderman. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up
study, 1971-1992. National Health and Nutrition Examination Survey. JAMA (2000) vol. 283 (18) pp. 2404-10
107. NHANES I
n=5,926
after excluding prior CVD, gout, or currently pregnant
16.4 years follow-up
1,293 deaths
731 CVD
429 Cancer
Fang and Alderman. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up
study, 1971-1992. National Health and Nutrition Examination Survey. JAMA (2000) vol. 283 (18) pp. 2404-10
108. Fang and Alderman. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up
study, 1971-1992. National Health and Nutrition Examination Survey. JAMA (2000) vol. 283 (18) pp. 2404-10
109. Fang and Alderman. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up
study, 1971-1992. National Health and Nutrition Examination Survey. JAMA (2000) vol. 283 (18) pp. 2404-10
110. For each increase in the uric acid of one
Fang and Alderman. JAMA (2000) vol. 283 (18) pp. 2404-10
111. MEN
Death from CVD rose 9%
Fatal MI increased 17%
For each increase in the uric acid of one
WOMEN
Death from CVD rose 26%
Fatal MI increased 30%
Fang and Alderman. JAMA (2000) vol. 283 (18) pp. 2404-10
113. increased uric acid
Uric acid causes
hypertension
kidney disease
Uric acid is
associated but doesn’t
cause hypertension
hypertension
114. increased uric acid hypertension
Uric acid causes
hypertension
kidney disease kidney disease
Uric acid is
associated but doesn’t
cause hypertension
hypertension increased uric acid
115. Framingham population
3,329 subjects had blood pressure and uric acid
assessed
4 years later the blood pressure was reassessed
analysis looked at the patients who developed new
hypertension or had their hypertension become more
severe
Sundström et al. Relations of serum uric acid to longitudinal blood pressure tracking
and hypertension incidence. Hypertension (2005) vol. 45 (1) pp. 28-33
116. An increase in the uric acid of
1.2 mg/dL increased risk of
worsening hypertension by 27%
Developed Hypertension Worsening Hypertension
20 40
15 35
10 30
5 25
0 20
1st 2nd 3rd 4th 1st 2nd 3rd 4th
Sundström et al. Relations of serum uric acid to longitudinal blood pressure tracking
and hypertension incidence. Hypertension (2005) vol. 45 (1) pp. 28-33
117. 1.Fructose increases uric acid
2.Uric acid and gout are increasing increasing
3.Uric acid causes hypertension
circumstantial
animal
interventional
118. The problem with animal models: uricase or urate oxidase
Uric acid + O2 + H2O → 5-hydroxyisourate + H2O2→ allantoin + CO2
Normal rat uric acid is 1 mg/dL
119. The problem with animal models: uricase or urate oxidase
Uric acid + O2 + H2O → 5-hydroxyisourate + H2O2→ allantoin + CO2
Normal rat uric acid is 1 mg/dL
You need to feed them oxanic acid,
which inhibits uricase.
๏ Give too much, the rat dies of urate nephropathy
๏ Give too little and the uric acid remains too low
๏ Titrate dose and you can safely double the uric acid
120. normal salt diet
Mice randomized to
Control Oxanic acid
control diet or oxanic 151
acid
Oxanic acid doubles p=0.05
Systolic BP
p=0.05
the serum uric acid 130
Within a month, a
significant increase in
blood pressure 109 Baseline
4 weeks
7 weeks
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
121. All mice are fed a low
Control Oxanic acid
salt diet Oxanic Acid + Allopurinol
Then randomized to diet
alone, oxanic acid or
oxanic acid plus
allopuriniol
If the culprit is uric acid,
allopurinol should
neutralize it
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
122. All mice are fed a low
Control Oxanic acid
salt diet Oxanic Acid + Allopurinol
151
Then randomized to diet
alone, oxanic acid or
Systolic BP
oxanic acid plus
130
allopuriniol
If the culprit is uric acid,
allopurinol should 109
neutralize it Baseline
week 2
week 4
week 5
week 7
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
123. All mice are fed a low
Control Oxanic acid
salt diet Oxanic Acid + Allopurinol
151
Then randomized to diet
alone, oxanic acid or
Systolic BP
oxanic acid plus
130
allopuriniol
If the culprit is uric acid,
allopurinol should 109
neutralize it Baseline
week 2
week 4
week 5
week 7
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
124. All mice are fed a low
Control Oxanic acid
salt diet Oxanic Acid + Allopurinol
151
Then randomized to diet
alone, oxanic acid or
Systolic BP
oxanic acid plus
130
allopuriniol
If the culprit is uric acid,
allopurinol should 109
neutralize it Baseline
week 2
week 4
week 5
week 7
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
125. Control Oxanic acid
Oxanic Acid + Allopurinol
151
Systolic BP
130
109
Baseline
week 2
week 4
week 5
week 7
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
126. Control Oxanic acid
Mice randomized to Oxanic Acid + Benziodarone
control, oxanic acid or
oxanic acid +
benziodarone
benziodarone is a
uricosuric agent so it
can decrease uric acid
without affecting
xanthine oxidase
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
127. Control Oxanic acid
Mice randomized to Oxanic Acid + Benziodarone
control, oxanic acid or 170
oxanic acid +
benziodarone
Systolic BP
135
benziodarone is a
uricosuric agent so it
can decrease uric acid
without affecting 100
Baseline
week 2
week 3
week 4
week 5
week 6
week7
xanthine oxidase
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
128. Control Oxanic acid
Mice randomized to Oxanic Acid + Benziodarone
control, oxanic acid or 170
oxanic acid +
benziodarone
Systolic BP
135
benziodarone is a
uricosuric agent so it
can decrease uric acid
without affecting 100
Baseline
week 2
week 3
week 4
week 5
week 6
week7
xanthine oxidase
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
129. Control Oxanic acid
Oxanic Acid + Benziodarone
170
Systolic BP
135
10 mg/kg 15 mg/kg
100
Baseline
week 2
week 3
week 4
week 5
week 6
week7
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
130. Correction of hyperuricemia after 7 weeks
Oxanic Acid
Oxanic Acid -> Withdrawl
Oxanic Acid ->Allopurinol
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
131. Correction of hyperuricemia after 7 weeks
Oxanic Acid
Oxanic Acid -> Withdrawl
Oxanic Acid ->Allopurinol
170
Systolic BP
135
100
Baseline
week 2
week 4
week 6
week 7
week 8
week 9
week 10
week 11
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
132. Correction of hyperuricemia after 7 weeks
Oxanic Acid
Oxanic Acid -> Withdrawl
Oxanic Acid ->Allopurinol
170
Systolic BP
135
100
Baseline
week 2
week 4
week 6
week 7
week 8
week 9
week 10
week 11
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
133. Correction of hyperuricemia after 7 weeks
Oxanic Acid
Oxanic Acid -> Withdrawl
Oxanic Acid ->Allopurinol
170
Systolic BP
135
100
Baseline
week 2
week 4
week 6
week 7
week 8
week 9
week 10
week 11
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
134. uric acid can account 56% of
the variability in blood pressure
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
135. At 7 weeks, the renal function and routine
light microscopy was unremarkable...
However, immunohistochemical stains
revealed early interstitial fibrosis and
tubular injury. The administration of
allopurinol... prevented...
significant
these low-grade but
inflammatory and fibrotic
changes. Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
138. 1.Fructose increases uric acid
2.Uric acid and gout are increasing increasing
3.Uric acid causes hypertension
circumstantial
animal
interventional
139. Human interventional data
Ideal test subjects
Homogenous population
No comorbidities to complicate interpretation
New onset disease without end-organ damage
146. 125 consecutive referrals to the pediatric renal division
for hypertension were enrolled in trial
After a hypertension work-up the diagnosis were:
Primary hypertension: 63
Secondary hypertension: 40
White coat hypertension: 22
Primary
Secondary
White Coat Hypertension
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
147. uric acid levels by diagnosis
6.7
4.3 3.5 3.6
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
148. uric acid levels by diagnosis
6.7
3.5 3.6
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
149. uric acid levels by diagnosis
essential normal (control or
hypertension white coat)
100% 56
uric acid > 5.5 56 0 ppv 56+0
89% 62
uric acid ≤ 5.5 7 62 npv 62+7
88% sensitive 100% specific
56 62
56+7 62+0
6.7
3.5 3.6
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
150. uric acid levels by diagnosis
6.7
4.3 3.5 3.6
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
151. uric acid levels by diagnosis
pathology normal (control or
(1° or 2°) white coat)
100% 68
uric acid > 5.5 68 0 ppv 68+0
63% 62
uric acid ≤ 5.5 36 62 npv 62+36
65% sensitive 100% specific
68 62
68+36 62+0
6.7
4.3 3.5 3.6
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
152. uric acid levels by diagnosis
6.7
4.3
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
155. allopurinol to treat hypertension
if uric acid causes hypertension then reducing uric
acid should treat hypertension
that’s impossible allopurinol can’t treat hypertension
156.
157. Randomized, double- blind, placebo-controlled,
crossover trial of allopurinol in children with newly
diagnosed essential hypertension
Aged 11 - 17
BP in the 95th percentile for sex, age, and height
excluded stage II hypertension (SBP > 99% + 5)
Serum uric acid level of 6 mg/dL or higher
No evidence for target organ damage or secondary
hypertension
No current or prior treatment with an hypertensive medication
for any indication
159. 73% over weight or obese
30% met criteria for metabolic syndrome
160. 73% over weight or obese
30% met criteria for metabolic syndrome
161. 0
3
6
9
enrollment
begin placebo
end placebo
uric acid
begin allopurinol
end allopurinol
162. 115
125
135
145
enrollment
begin placebo
in-clinic
end placebo
systolics
begin allopurinol
24-hr
end allopurinol
60
70
80
90
enrollment
begin placebo
in clinic
end placebo
diastolics
begin allopurinol
24-hr
end allopurinol
163. 20 of the 30 participants achieved normal
BP during the allopurinol phase, whereas
only 1 of 30 achieved normal BP during the
placebo phase.
Of the 10 participants who remained
hypertensive while taking allopurinol, 7 had
a uric acid level of 5.0 mg/dL or higher at
the end of the allopurinol phase.
173. Because the disruption of a functional gene
by independent events in two different
evolutionary lineages is unlikely to occur on
a chance basis, our data favor the
hypothesis that the loss of urate oxidase
may have evolutionary advantages.
Wu XW, Muzny DM, Lee CC, Caskey CT.
Mol Evol. 1992 Jan;34(1):78-84.
174. twice evolution selected for a loss of uricase
perhaps our Paleolithic diet was so low in sodium and
potassium rich that having a higher blood pressure
thanks to uric acid was advantageous
perhaps we are currently living in the new normal
where uric acid, after long being selected for, is now
harmful
176. allopurinol for hyperuricemia
retrospective analysis of allopurinol
use in patients with uric acid >7
mg/dL
9,924 veterans
2,483 subjects received
allopurinol
7,441 in the control group
Luk et al. Allopurinol and mortality in hyperuricaemic patients. Rheumatology (2009) vol. 48 (7) pp. 804-806
glucose can be metabolized by every tissue
fructose a 5 carbon carbohydrate. metabolized primarily by the liver
sucrose (table sugar) is a disaccharide of fructose and glucose
HFCS is a mixture of 45-52% fructose with the balance being glucose
fresh biopsies bathed in various concentrations of fructose
MR spectroscopy
fresh biopsies bathed in various concentrations of fructose
MR spectroscopy
fresh biopsies bathed in various concentrations of fructose
MR spectroscopy
fresh biopsies bathed in various concentrations of fructose
MR spectroscopy
fresh biopsies bathed in various concentrations of fructose
MR spectroscopy
fresh biopsies bathed in various concentrations of fructose
MR spectroscopy
fresh biopsies bathed in various concentrations of fructose
MR spectroscopy
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