Uric Acid, Fructose and Hypertension

Gibbon Chimpanzees Humans Gorillas Old World Monkeys

nonsense mutation at codon 33 of urate oxidase


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
mammals and joined
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 hypertension
Joel M. Topf, MD

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.

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

24 million americans have
diabetes
prevalence 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

40%

hypertension
30%

20%

10%

6%

0%
1907 1939 1975 1990 2004

vol. 86 (4) pp. 899-906

40%

hypertension
30%

20%

10%
140/90
6%

0%
1907 1939 1975 1990 2004

vol. 86 (4) pp. 899-906

40%

hypertension
30% 31%
28%
25%

20%

10% 12%
140/90
6%

0%
1907 1939 1975 1990 2004

vol. 86 (4) pp. 899-906

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 Glomerulonephritis
Polycystic disease Other

15%

0%
100%

15%
1980
1981
1982
1983
1984
1985
Diabetes

1986
1987
1988
Polycystic disease

1989
1990
1991
Other

1992
1993
Hypertension

1994
1995
1996
1997
1998
1999
2000
2001
Glomerulonephritis

2002
2003
2004

Diabetes Hypertension Glomerulonephritis
Polycystic disease Other

0
10,000
20,000
30,000
40,000
50,000
1980
1981
1982
1983
1984
Diabetes

1985
1986
1987
Polycystic disease

1988
1989
1990
1991
Other

1992
1993
Hypertension

1994
1995
1996
1997
1998
1999
2000
2001
Glomerulonephritis

2002
2003
2004

Sucrose

glucose

fructose
relative sweetness

sucrose lactose 16

galactose 32

glucose 50

high fructose corn honey 97

sucrose 100
syrup (HFCS) HFCS 42 100

fructose 173

0 50 100 150 200
on this scale saccharine would be 30,000 and aspartame 18,000

Indians boil the cane juice and
500 B.C. produce crystal 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

1960s: glucose (D-Xylose)
isomerase is discovered. This
enzyme converts glucose to fructose
creating high fructose corn syrup

fructose compared to glucose

increases triglycerides metabolized in the liver

does not suppress appetite

does not stimulate insulin release

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

1700 Sugar Consumption
1 lb

1700 Sugar Consumption 2000 Sugar Consumption
1 lb 70 lbs

sugar
obesity

diabetes sugar
+
hypertension and
+
obesity fructose

coincidencesugar

or
obesity

diabetes sugar
+

causal?
hypertension and
+
obesity fructose

diabetes
+
hypertension
+
obesity

kidney disease heart disease

fructose

diabetes
+
hypertension
+
obesity


fructose

fructose
diabetes
+
uric acid hypertension
+
obesity


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.

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


ADP
ATP

3 Phosphoglycerate

2 Phosphoglycerate

Phosphoenolpyruvate
ADP
pyruvate kinase
ATP

May;35(3):245-51.
Radiol. 1986 Jul;59(703):695-9.

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
ATP +
phosphofructokinase
Dihydroxyacetone-P
ADP

ADP


ADP
ATP

3 Phosphoglycerate

2 Phosphoglycerate

Phosphoenolpyruvate
ADP
pyruvate kinase
ATP

May;35(3):245-51.
Radiol. 1986 Jul;59(703):695-9.

ATP hexokinase
ADP
ATP
not change ATP
ATP +
phosphofructokinase
ADP
Dihydroxyacetone-P
In vivo: following a fructose load
ADP hepatic fructose-1-P rose 800%
and ATP fell 75%

ADP
ATP

3 Phosphoglycerate

2 Phosphoglycerate

Phosphoenolpyruvate
ADP
pyruvate kinase
ATP

May;35(3):245-51.
Radiol. 1986 Jul;59(703):695-9.

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

ATP hexokinase
ADP
ATP
not change ATP
ATP +
phosphofructokinase
ADP
Dihydroxyacetone-P
In vivo: following a fructose load
ADP hepatic fructose-1-P rose 800%
and ATP 75%
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.
Radiol. 1986 Jul;59(703):695-9.
Porikos KP, Van Itallie TB. Am J Med. 1983 Oct;75(4):624-30.

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.

disease
Daily fructose intake (cal/day)


disease

NHANES 1999-2000


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,

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

Stirpe et al. Fructose-induced hyperuricaemia. Lancet (1970) vol. 2 (7686) pp. 1310-1

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

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?

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

Arromdee et al. Epidemiology of gout: is the incidence rising?.
J Rheumatol (2002) vol. 29 (11) pp. 2403-6

1977
VERSUS

1995
Arromdee et al. Epidemiology of gout: is the incidence rising?.
J Rheumatol (2002) vol. 29 (11) pp. 2403-6

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

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 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

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

For each increase in the uric acid of one

Fang and Alderman. JAMA (2000) vol. 283 (18) pp. 2404-10

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

increased uric acid
Uric acid causes
hypertension

kidney disease

Uric acid is
cause hypertension
hypertension

increased uric acid hypertension
Uric acid causes
hypertension

kidney disease kidney disease

Uric acid is
cause hypertension
hypertension 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

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

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

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

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

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


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

Control Oxanic acid
Oxanic Acid + Allopurinol
151

Systolic BP
130

109
Baseline

week 2

week 4

week 5

week 7

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


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


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

Correction of hyperuricemia after 7 weeks
Oxanic Acid
Oxanic Acid -> Withdrawl
Oxanic Acid ->Allopurinol


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

uric acid can account 56% of
the variability in blood pressure


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

0
40
80
120
160
Control
Renin % +JGA

Oxanic Acid
NOS1 cells/100 Glom


0
30
60
90
120

Control

Oxanic Acid
Renin % +JGA

Oxalanic acid withdrawal
NOS1 cells/100 Glom


Renin % +JGA Renin % +JGA
NOS1 cells/100 Glom NOS1 cells/100 Glom

160 120

120 hypertension driven by 90

Renin
80 60

40 30

NO
0 0
Control

Oxanic Acid


Control

Oxanic Acid

Oxalanic acid withdrawal


Human interventional data

Ideal test subjects
Homogenous population
No comorbidities to complicate interpretation
New onset disease without end-organ damage

What disease is the type I
diabetes of hypertension?

What disease is the type I
diabetes of hypertension?

Pediatric primary hypertension

Secondary hypertension Primary Secondary

renal disease

cardiac disease

endocrine disease

represents 30-60% of
pediatric hypertension

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

uric acid levels by diagnosis

6.7

4.3 3.5 3.6



6.7

3.5 3.6


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


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
68 62
68+36 62+0

6.7

4.3 3.5 3.6



6.7

4.3


essential secondary
hypertension hypertension
82% 56
uric acid > 5.5 56 12 ppv 56+12
80% 28
uric acid ≤ 5.5 7 28 npv 28+7

56 28
56+7 28+12

6.7

4.3


essential secondary
hypertension hypertension
82% 56
uric acid > 5.5 56 12 ppv 56+12
80% 28
uric acid ≤ 5.5 7 28 npv 28+7

56 28
56+7 28+12

6.7

4.3

renal ultrasound with Doppler
DMSA renal perfusion scan
renin and aldosterone levels
renal angiogram
Urinary catecholamines

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

Allopurinol
200 mg bid placebo
4 weeks
4 weeks

73% over weight or obese

30% met criteria for metabolic syndrome

0
3
6
9

enrollment

begin placebo

end placebo
uric acid

begin allopurinol

end allopurinol

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

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.

if uric acid is so bad for us,
why are we among the only
mammals without uricase?

Gibbon Chimpanzees Humans Gorillas Orangutans Old World Monkeys

Urate oxidase genes

nonsense: codon 33

nonsense: codon 187

aberrant splice

13-bp deletion

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

allopurinol

23%
lower
mortality

Uric Acid, Fructose and Hypertension

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