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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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Gibbon Chimpanzees Humans Gorillas Old World Monkeys
Gibbon Chimpanzees Humans Gorillas Old World MonkeysGibbon Chimpanzees Humans Gorillas Old World Monkeys
25 million years ago
20 million years ago
nonsense mutation at codon 33 of urate oxidase
Gibbon Chimpanzees Humans Gorillas Old World MonkeysGibbon Chimpanzees Humans Gorillas Old World Monkeys
25 million years ago
20 million years ago
nonsense mutation at codon 33 of urate oxidase
uric acid went from around 1 to 4 mg/dL
So humans, chimps and great apes separated themselves from all other mamma ls and j o i ned reptiles and birds in being unable to convert uric acid to allantoin...
...and twenty-five million years later this has resulted in the
epidemic of hypertension
fructose, uric acid and hypertensionJoel M. Topf, MD
The new normal
The new normal
32% of americans are obese
32% of americans are obese
110 years ago 3% were obese
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.
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.
The new normal: diabetes
1898: William Osler reviewed 35,000 consecutive admissions to Johns Hopkins
1898: William Osler reviewed 35,000 consecutive admissions to Johns Hopkins
10 had diabetes
1898: William Osler reviewed 35,000 consecutive admissions to Johns Hopkins
10 had diabetes
24 million americans have diabetesprevalence of diabetes has tripled from 1980 to 2006
24 million americans have diabetesprevalence of diabetes has tripled from 1980 to 2006
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
hypertension
1907 1939 1975 1990 20040%
10%
20%
30%
40%
6%
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
hypertension
1907 1939 1975 1990 20040%
10%
20%
30%
40%
6%
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
140/90
hypertension
1907 1939 1975 1990 20040%
10%
20%
30%
40%
6%
12%
25%
28%
31%
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
140/90
diabetes+
hypertension+
obesity
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
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
15%
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
0%
100%
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
15%
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
0%
100%
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
15%
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
0%
100%
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
15%
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
0%
100%
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
15%
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
0%
100%
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
15%
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
0%
100%
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
15%
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
0
10,000
20,000
30,000
40,000
50,000
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
0
10,000
20,000
30,000
40,000
50,000
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
0
10,000
20,000
30,000
40,000
50,000
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
0
10,000
20,000
30,000
40,000
50,000
Diabetes Hypertension GlomerulonephritisPolycystic disease Other
sugar and fructose
glucose
fructose
sucrose
high fructose corn syrup (HFCS)
lactose
galactose
glucose
honey
sucrose
HFCS 42
fructose
0 50 100 150 200
173
100
100
97
50
32
16
relative sweetness
on this scale saccharine would be 30,000 and aspartame 18,000
Sucrose
10,0
00 y
ears
ago
Indians boil the cane juice and produce crystal sugar500 B.C.
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
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
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
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
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
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
1960s: glucose (D-Xylose) isomerase is discovered. This
enzyme converts glucose to fructose
creating high fructose corn syrup
1960s: glucose (D-Xylose) isomerase is discovered. This
enzyme converts glucose to fructose
creating high fructose corn syrup
1960s: glucose (D-Xylose) isomerase is discovered. This
enzyme converts glucose to fructose
creating high fructose corn syrup
fructose compared to glucose
increases triglycerides
does not suppress appetite
does not stimulate insulin release
metabolized in the liver
fructose compared to glucose
increases triglycerides
does not suppress appetite
does not stimulate insulin release
metabolized in the liver
HFCS compared with sucrose
no difference in appetite
no difference in insulin
no difference in triglycerides
cheaper
made in the USA
1700 Sugar Consumption1 lb
2000 Sugar Consumption70 lbs
1700 Sugar Consumption1 lb
diabetes+
hypertension+
obesity
sugar
and
fructose
sugarobesity
diabetes+
hypertension+
obesity
sugar
and
fructose
sugarobesity
coincidence or
causal?
diabetes+
hypertension+
obesity
kidney disease heart disease
diabetes+
hypertension+
obesity
kidney disease heart disease
diabetes+
hypertension+
obesity
fructose
kidney disease heart disease
diabetes+
hypertension+
obesity
fructose
fructose
uric acid
kidney disease heart disease
diabetes+
hypertension+
obesity
fructose
fructose
uric acid
Paging Dr. Stryer
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.
ADPATP
ADP
Glucose
Glucose-6-P
Fructose 6-P
Fructose 1,6 bisphosphate
Glyceraldehyde 3-PDihydroxyacetone P
1,3 Bisphosphoglycerate
3 Phosphoglycerate
2 Phosphoglycerate
Phosphoenolpyruvate
Pyruvate
hexokinase
phosphofructokinase
pyruvate kinase
ATPADP
ADP
ATP
ATP
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.
ADPATP
ADP
Glucose
Glucose-6-P
Fructose 6-P
Fructose 1,6 bisphosphate
Glyceraldehyde 3-PDihydroxyacetone P
1,3 Bisphosphoglycerate
3 Phosphoglycerate
2 Phosphoglycerate
Phosphoenolpyruvate
Pyruvate
hexokinase
phosphofructokinase
pyruvate kinase
ATPADP
ADP
ATP
ATP
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.
ADPATP
Fructose
Fructose-1-P
Glyceraldehyde+
Dihydroxyacetone-P
ADPATP
ADPATP
ADP
Glucose
Glucose-6-P
Fructose 6-P
Fructose 1,6 bisphosphate
Glyceraldehyde 3-PDihydroxyacetone P
1,3 Bisphosphoglycerate
3 Phosphoglycerate
2 Phosphoglycerate
Phosphoenolpyruvate
Pyruvate
hexokinase
phosphofructokinase
pyruvate kinase
ATPADP
ADP
ATP
ATP
In vitro: Fructose infusion for 70 minutes resulted in 22.5% decrease in ATP, glucose did not change ATP
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.
ADPATP
Fructose
Fructose-1-P
Glyceraldehyde+
Dihydroxyacetone-P
ADPATP
ADPATP
ADP
Glucose
Glucose-6-P
Fructose 6-P
Fructose 1,6 bisphosphate
Glyceraldehyde 3-PDihydroxyacetone P
1,3 Bisphosphoglycerate
3 Phosphoglycerate
2 Phosphoglycerate
Phosphoenolpyruvate
Pyruvate
hexokinase
phosphofructokinase
pyruvate kinase
ATPADP
ADP
ATP
ATP
In vitro: Fructose infusion for 70 minutes resulted in 22.5% decrease in ATP, glucose did not change ATP
In vivo: following a fructose load hepatic fructose-1-P rose 800% and ATP fell 75%
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.
ADPATP
Fructose
Fructose-1-P
Glyceraldehyde+
Dihydroxyacetone-P
ADPATP
ADPATP
ADP
Glucose
Glucose-6-P
Fructose 6-P
Fructose 1,6 bisphosphate
Glyceraldehyde 3-PDihydroxyacetone P
1,3 Bisphosphoglycerate
3 Phosphoglycerate
2 Phosphoglycerate
Phosphoenolpyruvate
Pyruvate
hexokinase
phosphofructokinase
pyruvate kinase
ATPADP
ADP
ATP
ATP
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
In vitro: Fructose infusion for 70 minutes resulted in 22.5% decrease in ATP, glucose did not change ATP
In vivo: following a fructose load hepatic fructose-1-P rose 800% and ATP 75%
21 men placed on a diet containing 25-30% of calories from sucrose developed increase in SGPT, SGOT within 18 days. Transaminases normalized with 10% of calories from sucrose
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.
Porikos KP, Van Itallie TB. Am J Med. 1983 Oct;75(4):624-30.
ADPATP
Fructose
Fructose-1-P
Glyceraldehyde+
Dihydroxyacetone-P
ADPATP
ADPATP
ADP
Glucose
Glucose-6-P
Fructose 6-P
Fructose 1,6 bisphosphate
Glyceraldehyde 3-PDihydroxyacetone P
1,3 Bisphosphoglycerate
3 Phosphoglycerate
2 Phosphoglycerate
Phosphoenolpyruvate
Pyruvate
hexokinase
phosphofructokinase
pyruvate kinase
ATPADP
ADP
ATP
ATP
16-23% of Americans have non-alcoholic fatty liver disease
Fructose and 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.
Dai
ly f
ruct
ose
inta
ke (c
al/d
ay)
16-23% of Americans have non-alcoholic fatty liver disease
Fructose and 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.
Dai
ly f
ruct
ose
inta
ke (c
al/d
ay)
16-23% of Americans have non-alcoholic fatty liver disease
Fructose and non-alcoholic fatty liver disease
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.
Dai
ly f
ruct
ose
inta
ke (c
al/d
ay)
16-23% of Americans have non-alcoholic fatty liver disease
Fructose and non-alcoholic fatty liver disease
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.
Dai
ly f
ruct
ose
inta
ke (c
al/d
ay)
16-23% of Americans have non-alcoholic fatty liver disease
Fructose and non-alcoholic fatty liver disease
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.
Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, Johnson RJ, Abdelmalek MF. J Hepatol. 2008 June; 48(6): 993–999.
Consumption of ATP creates adenosine, a purine
All purines are metabolized to uric acid by xanthine oxidase
AMP
Adenosine
Inosine
Hypoxanthine
Xanthine
Uric Acid
GMP
Guanosine
Guanine
Xanthine oxidase
Xanthine oxidase
glycolysis Intermediates
PRPP
IMP
Consumption of ATP creates adenosine, a purine
All purines are metabolized to uric acid by xanthine oxidase
AMP
Adenosine
Inosine
Hypoxanthine
Xanthine
Uric Acid
GMP
Guanosine
Guanine
Xanthine oxidase
Xanthine oxidase
glycolysis Intermediates
PRPP
IMP
Stirpe et al. Fructose-induced hyperuricaemia. Lancet (1970) vol. 2 (7686) pp. 1310-1
fructose (g/kg) equal to a liter of pepsi for a 70 kg woman
4
5
6
0 30 60 120
5.75.9
5.6
4.4
Uric
Aci
d (m
g/dL
)
Time (minutes)
Stirpe et al. Fructose-induced hyperuricaemia. Lancet (1970) vol. 2 (7686) pp. 1310-1
Perheentupa and Raivio. Fructose-induced hyperuricaemia. Lancet (1967) vol. 2 (7515) pp. 528-31
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
If fructose increases uric acid, and fructose consumption has sky rocketed in the last few decades, are we seeing more gout?
gout in England
0
2.5
5.0
7.5
10.0
1970/71 1981/82 1991
gout
/100
0 pa
tient
s
Harris et al. The prevalence and prophylaxis of gout in England. J Clin Epidemiol (1995) vol. 48 (9) pp. 1153-8
Arromdee et al. Epidemiology of gout: is the incidence rising?. J Rheumatol (2002) vol. 29 (11) pp. 2403-6
Arromdee et al. Epidemiology of gout: is the incidence rising?. J Rheumatol (2002) vol. 29 (11) pp. 2403-6
Arromdee et al. Epidemiology of gout: is the incidence rising?. J Rheumatol (2002) vol. 29 (11) pp. 2403-6
1977
1995
VERSUS
0
17.5
35.0
52.5
70.0
all cases no HCTZ
42
62
16
45
Annual Incidence
New
cas
es/1
00,0
00
1977-78 1995-96
1977-78 1995-96 p
age
weight
BMI
uric acid
43.5 53.5 0.07
84.5 85.5 0.50
28.8 29.8 0.36
8.3 8.4 0.28
1.Fructose increases uric acid
2.Uric acid and gout are increasing increasing
3.Uric acid causes hypertension
circumstantial
animal
interventional
Uric acid causes hypertension
Uric acid is associated but doesn’t
cause hypertension
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 significantCulleton 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
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
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
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
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
Fang and Alderman. JAMA (2000) vol. 283 (18) pp. 2404-10
For each increase in the uric acid of one
MENDeath from CVD rose 9%Fatal MI increased 17%
WOMENDeath from CVD rose 26%
Fatal MI increased 30%
Fang and Alderman. JAMA (2000) vol. 283 (18) pp. 2404-10
For each increase in the uric acid of one
Uric acid causes hypertension
Uric acid is associated but doesn’t
cause hypertension
Uric acid causes hypertension
Uric acid is associated but doesn’t
cause hypertensionhypertension
kidney disease
increased uric acid
Uric acid causes hypertension
Uric acid is associated but doesn’t
cause hypertensionhypertension
kidney disease
increased uric acid hypertension
kidney disease
increased uric acid
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
0
5
10
15
20
1st 2nd 3rd 4th
Developed Hypertension
20
25
30
35
40
1st 2nd 3rd 4th
Worsening Hypertension
An increase in the uric acid of 1.2 mg/dL increased risk of worsening hypertension by 27%
Sundström et al. Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension (2005) vol. 45 (1) pp. 28-33
1.Fructose increases uric acid
2.Uric acid and gout are increasing increasing
3.Uric acid causes hypertension
circumstantial
animal
interventional
The problem with animal models: uricase or urate oxidase
Normal rat uric acid is 1 mg/dL
Uric acid + O2 + H2O → 5-hydroxyisourate + H2O2→ allantoin + CO2
The problem with animal models: uricase or urate oxidase
Normal rat uric acid is 1 mg/dL
Uric acid + O2 + H2O → 5-hydroxyisourate + H2O2→ allantoin + CO2
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
p=0.05p=0.05
109
130
151
Bas
elin
e
4 w
eeks
7 w
eeks
Sys
tolic
BP
Control Oxanic acid
normal salt diet
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
Mice randomized to control diet or oxanic acid
Oxanic acid doubles the serum uric acid
Within a month, a significant increase in blood pressure
Control Oxanic acidOxanic Acid + Allopurinol
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
All mice are fed a low salt diet
Then randomized to diet alone, oxanic acid or oxanic acid plus allopuriniol
If the culprit is uric acid, allopurinol should neutralize it
Bas
elin
e
wee
k 2
wee
k 4
wee
k 5
wee
k 7
109
130
151
Sys
tolic
BP
Control Oxanic acidOxanic Acid + Allopurinol
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
All mice are fed a low salt diet
Then randomized to diet alone, oxanic acid or oxanic acid plus allopuriniol
If the culprit is uric acid, allopurinol should neutralize it
Bas
elin
e
wee
k 2
wee
k 4
wee
k 5
wee
k 7
109
130
151
Sys
tolic
BP
Control Oxanic acidOxanic Acid + Allopurinol
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
All mice are fed a low salt diet
Then randomized to diet alone, oxanic acid or oxanic acid plus allopuriniol
If the culprit is uric acid, allopurinol should neutralize it
Bas
elin
e
wee
k 2
wee
k 4
wee
k 5
wee
k 7
109
130
151
Sys
tolic
BP
Control Oxanic acidOxanic Acid + Allopurinol
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
All mice are fed a low salt diet
Then randomized to diet alone, oxanic acid or oxanic acid plus allopuriniol
If the culprit is uric acid, allopurinol should neutralize it
Bas
elin
e
wee
k 2
wee
k 4
wee
k 5
wee
k 7
109
130
151
Sys
tolic
BP
Control Oxanic acidOxanic Acid + Allopurinol
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
Control Oxanic acidOxanic Acid + Benziodarone
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
Mice randomized to control, oxanic acid or oxanic acid + benziodarone
benziodarone is a uricosuric agent so it can decrease uric acid without affecting xanthine oxidase
Control Oxanic acidOxanic Acid + Benziodarone
Bas
elin
e
wee
k 2
wee
k 3
wee
k 4
wee
k 5
wee
k 6
wee
k7
100
135
170
Sys
tolic
BP
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
Mice randomized to control, oxanic acid or oxanic acid + benziodarone
benziodarone is a uricosuric agent so it can decrease uric acid without affecting xanthine oxidase
Control Oxanic acidOxanic Acid + Benziodarone
Bas
elin
e
wee
k 2
wee
k 3
wee
k 4
wee
k 5
wee
k 6
wee
k7
100
135
170
Sys
tolic
BP
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
Mice randomized to control, oxanic acid or oxanic acid + benziodarone
benziodarone is a uricosuric agent so it can decrease uric acid without affecting xanthine oxidase
Control Oxanic acidOxanic Acid + Benziodarone
Bas
elin
e
wee
k 2
wee
k 3
wee
k 4
wee
k 5
wee
k 6
wee
k7
100
135
170
Sys
tolic
BP
10 mg/kg 15 mg/kg
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
Oxanic AcidOxanic Acid -> WithdrawlOxanic Acid ->Allopurinol
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
Correction of hyperuricemia after 7 weeks
Oxanic AcidOxanic Acid -> WithdrawlOxanic Acid ->Allopurinol
Bas
elin
e
wee
k 2
wee
k 4
wee
k 6
wee
k 7
wee
k 8
wee
k 9
wee
k 10
wee
k 11
100
135
170
Sys
tolic
BP
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
Correction of hyperuricemia after 7 weeks
Oxanic AcidOxanic Acid -> WithdrawlOxanic Acid ->Allopurinol
Bas
elin
e
wee
k 2
wee
k 4
wee
k 6
wee
k 7
wee
k 8
wee
k 9
wee
k 10
wee
k 11
100
135
170
Sys
tolic
BP
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
Correction of hyperuricemia after 7 weeks
Oxanic AcidOxanic Acid -> WithdrawlOxanic Acid ->Allopurinol
Bas
elin
e
wee
k 2
wee
k 4
wee
k 6
wee
k 7
wee
k 8
wee
k 9
wee
k 10
wee
k 11
100
135
170
Sys
tolic
BP
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
Correction of hyperuricemia after 7 weeks
uric acid can account 56% of the variability in blood pressure
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
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...
these low-grade but significant inflammatory and fibrotic changes.
Mazzali et al. Hypertension (2001) vol. 38 (5) pp. 1101-6
0
30
60
90
120
Con
trol
Oxa
nic
Aci
d
Oxa
lani
c ac
id w
ithdr
awal
Oxa
nic
Aci
d +
Allo
purin
ol
Renin % +JGANOS1 cells/100 Glom
0
40
80
120
160C
ontr
ol
Oxa
nic
Aci
d
Oxa
nic
Aci
d +
Allo
purin
ol
Renin % +JGANOS1 cells/100 Glom
0
30
60
90
120
Con
trol
Oxa
nic
Aci
d
Oxa
lani
c ac
id w
ithdr
awal
Oxa
nic
Aci
d +
Allo
purin
ol
Renin % +JGANOS1 cells/100 Glom
0
40
80
120
160C
ontr
ol
Oxa
nic
Aci
d
Oxa
nic
Aci
d +
Allo
purin
ol
Renin % +JGANOS1 cells/100 Glom
hypertension driven by Renin NO
1.Fructose increases uric acid
2.Uric acid and gout are increasing increasing
3.Uric acid causes hypertension
circumstantial
animal
interventional
Ideal test subjects
Homogenous population
No comorbidities to complicate interpretation
New onset disease without end-organ damage
Human interventional data
What disease is the type I diabetes of hypertension?
What disease is the type I diabetes of hypertension?
What disease is the type I diabetes of hypertension?
Pediatric primary hypertension
Secondary hypertension
renal disease
cardiac disease
endocrine disease
represents 30-60% of pediatric hypertension
Primary Secondary
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
PrimarySecondaryWhite Coat Hypertension
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
6.7
4.3 3.5 3.6
uric acid levels by diagnosis
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
6.7
3.5 3.6
uric acid levels by diagnosis
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
6.7
3.5 3.6
uric acid levels by diagnosisessential hypertension
normal (control or white coat)
uric acid > 5.5
uric acid ≤ 5.5
56 0
7 62
100% specific62
62+0
88% sensitive56
56+7
100% ppv
5656+0
89% npv
6262+7
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
6.7
4.3 3.5 3.6
uric acid levels by diagnosis
6.7
3.5 3.6
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
6.7
4.3 3.5 3.6
uric acid levels by diagnosis
100% specific62
62+0
65% sensitive68
68+36
pathology (1° or 2°)
normal (control or white coat)
uric acid > 5.5
uric acid ≤ 5.5
68 0
36 62
100% ppv
6868+0
63% npv
6262+36
6.7
3.5 3.6
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
6.7
4.3
uric acid levels by diagnosis
6.7
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
6.7
4.3
uric acid levels by diagnosis
6.7
essential hypertension
secondary hypertension
uric acid > 5.5
uric acid ≤ 5.5
56 12
7 28
70% specific28
28+12
88% sensitive56
56+7
82% ppv
5656+12
80% npv
2828+7
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
6.7
4.3
uric acid levels by diagnosis
6.7
essential hypertension
secondary hypertension
uric acid > 5.5
uric acid ≤ 5.5
56 12
7 28
70% specific28
28+12
88% sensitive56
56+7
82% ppv
5656+12
80% npv
2828+7
renal ultrasound with DopplerDMSA renal perfusion scanrenin and aldosterone levelsrenal angiogramUrinary catecholamines
Feig and Johnson. Hypertension (2003) vol. 42 (3) pp. 247-52
allopurinol to treat hypertension
if uric acid causes hypertension then reducing uric acid should treat hypertension
that’s impossible allopurinol can’t treat hypertension
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
Allopurinol200 mg bid placebo
4 w
eeks
4 w
eeks
73% over weight or obese
30% met criteria for metabolic syndrome
73% over weight or obese
30% met criteria for metabolic syndrome
0
3
6
9
enro
llmen
t
begi
n pl
aceb
o
end
plac
ebo
begi
n al
lopu
rinol
end
allo
purin
ol
uric acid
115
125
135
145
enro
llmen
t
begi
n pl
aceb
o
end
plac
ebo
begi
n al
lopu
rinol
end
allo
purin
ol
in-clinic 24-hr
60
70
80
90
enro
llmen
t
begi
n pl
aceb
o
end
plac
ebo
begi
n al
lopu
rinol
end
allo
purin
ol
in clinic 24-hr
systolics diastolics
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.
The new normal
if uric acid is so bad for us, why are we among the only mammals without uricase?
Urate oxidase genes
nonsense: codon 33
nonsense: codon 187
aberrant splice
13-bp deletion
Gibbon Chimpanzees Humans Gorillas Old World MonkeysOrangutans
Urate oxidase genes
nonsense: codon 33
nonsense: codon 187
aberrant splice
13-bp deletion
Gibbon Chimpanzees Humans Gorillas Old World MonkeysOrangutans
Urate oxidase genes
nonsense: codon 33
nonsense: codon 187
aberrant splice
13-bp deletion
Gibbon Chimpanzees Humans Gorillas Old World MonkeysOrangutans
Urate oxidase genes
nonsense: codon 33
nonsense: codon 187
aberrant splice
13-bp deletion
Gibbon Chimpanzees Humans Gorillas Old World MonkeysOrangutans
Urate oxidase genes
nonsense: codon 33
nonsense: codon 187
aberrant splice
13-bp deletion
Gibbon Chimpanzees Humans Gorillas Old World MonkeysOrangutans
Urate oxidase genes
nonsense: codon 33
nonsense: codon 187
aberrant splice
13-bp deletion
Gibbon Chimpanzees Humans Gorillas Old World MonkeysOrangutans
Urate oxidase genes
nonsense: codon 33
nonsense: codon 187
aberrant splice
13-bp deletion
Gibbon Chimpanzees Humans Gorillas Old World MonkeysOrangutans
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.
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
addendum
what should we do about asymptomatic hyperuricemia?
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
23% lower
mortality
allopurinol
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