Uric Acid, Fructose and Hypertension

Gibbon Chimpanzees Humans Gorillas Old World Monkeys

Gibbon Chimpanzees Humans Gorillas Old World MonkeysGibbon Chimpanzees Humans Gorillas Old World Monkeys

25 million years ago

nonsense mutation at codon 33 of urate oxidase

Gibbon Chimpanzees Humans Gorillas Old World MonkeysGibbon Chimpanzees Humans Gorillas Old World Monkeys

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

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

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

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%

vol. 86 (4) pp. 899-906

hypertension

1907 1939 1975 1990 20040%

vol. 86 (4) pp. 899-906

140/90

hypertension

1907 1939 1975 1990 20040%

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

10,000

20,000

30,000

40,000

50,000

10,000

20,000

30,000

40,000

50,000

10,000

20,000

30,000

40,000

50,000

10,000

20,000

30,000

40,000

50,000

sugar and fructose

glucose

fructose

sucrose

high fructose corn syrup (HFCS)

lactose

galactose

glucose

sucrose

HFCS 42

fructose

0 50 100 150 200

relative sweetness

on this scale saccharine would be 30,000 and aspartame 18,000

Sucrose

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

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

fructose

sugarobesity

diabetes+

hypertension+

obesity

fructose

sugarobesity

coincidence or

causal?

diabetes+

hypertension+

obesity

kidney disease heart disease

diabetes+

hypertension+

obesity

diabetes+

hypertension+

obesity

fructose

diabetes+

hypertension+

obesity

fructose

uric acid

diabetes+

hypertension+

obesity

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

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

ADPATP

Glucose

Glucose-6-P

Fructose 6-P

3 Phosphoglycerate

2 Phosphoglycerate

Phosphoenolpyruvate

Pyruvate

hexokinase

phosphofructokinase

pyruvate kinase

ATPADP

ADPATP

Fructose

Fructose-1-P

Glyceraldehyde+

Dihydroxyacetone-P

ADPATP

Glucose

Glucose-6-P

Fructose 6-P

3 Phosphoglycerate

2 Phosphoglycerate

Phosphoenolpyruvate

Pyruvate

hexokinase

phosphofructokinase

pyruvate kinase

ATPADP

In vitro: Fructose infusion for 70 minutes resulted in 22.5% decrease in ATP, glucose did not change ATP

ADPATP

Fructose

Fructose-1-P

Glyceraldehyde+

Dihydroxyacetone-P

ADPATP

Glucose

Glucose-6-P

Fructose 6-P

3 Phosphoglycerate

2 Phosphoglycerate

Phosphoenolpyruvate

Pyruvate

hexokinase

phosphofructokinase

pyruvate kinase

ATPADP

In vivo: following a fructose load hepatic fructose-1-P rose 800% and ATP fell 75%

ADPATP

Fructose

Fructose-1-P

Glyceraldehyde+

Dihydroxyacetone-P

ADPATP

Glucose

Glucose-6-P

Fructose 6-P

3 Phosphoglycerate

2 Phosphoglycerate

Phosphoenolpyruvate

Pyruvate

hexokinase

phosphofructokinase

pyruvate kinase

ATPADP

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 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

Porikos KP, Van Itallie TB. Am J Med. 1983 Oct;75(4):624-30.

ADPATP

Fructose

Fructose-1-P

Glyceraldehyde+

Dihydroxyacetone-P

ADPATP

Glucose

Glucose-6-P

Fructose 6-P

3 Phosphoglycerate

2 Phosphoglycerate

Phosphoenolpyruvate

Pyruvate

hexokinase

phosphofructokinase

pyruvate kinase

ATPADP

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.

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.

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.

Consumption of ATP creates adenosine, a purine

All purines are metabolized to uric acid by xanthine oxidase

Adenosine

Inosine

Hypoxanthine

Xanthine

Uric Acid

Guanosine

Guanine

Xanthine oxidase

glycolysis Intermediates

Consumption of ATP creates adenosine, a purine

All purines are metabolized to uric acid by xanthine oxidase

Adenosine

Inosine

Hypoxanthine

Xanthine

Uric Acid

Guanosine

Guanine

Xanthine oxidase

glycolysis Intermediates

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

0 30 60 120

5.75.9

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

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

VERSUS

all cases no HCTZ

Annual Incidence

1977-78 1995-96

1977-78 1995-96 p

weight

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. 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

cause hypertension

cause hypertensionhypertension

kidney disease

increased uric acid

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

1st 2nd 3rd 4th

Developed Hypertension

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

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

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

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

Control Oxanic acidOxanic Acid + Benziodarone

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

10 mg/kg 15 mg/kg

Oxanic AcidOxanic Acid -> WithdrawlOxanic Acid ->Allopurinol

Correction of hyperuricemia after 7 weeks

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...

these low-grade but significant inflammatory and fibrotic changes.

Renin % +JGANOS1 cells/100 Glom

hypertension driven by Renin NO

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?

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

4.3 3.5 3.6

uric acid levels by diagnosis

3.5 3.6

uric acid levels by diagnosisessential hypertension

normal (control or white coat)

uric acid > 5.5

uric acid ≤ 5.5

100% specific62

88% sensitive56

100% ppv

5656+0

89% npv

6262+7

4.3 3.5 3.6

3.5 3.6

4.3 3.5 3.6

100% specific62

65% sensitive68

pathology (1° or 2°)

normal (control or white coat)

uric acid > 5.5

uric acid ≤ 5.5

100% ppv

6868+0

63% npv

6262+36

3.5 3.6

essential hypertension

secondary hypertension

uric acid > 5.5

uric acid ≤ 5.5

70% specific28

88% sensitive56

82% ppv

5656+12

80% npv

2828+7

essential hypertension

secondary hypertension

uric acid > 5.5

uric acid ≤ 5.5

70% specific28

88% sensitive56

82% ppv

5656+12

80% npv

2828+7

renal ultrasound with DopplerDMSA renal perfusion scanrenin and aldosterone levelsrenal angiogramUrinary 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

Allopurinol200 mg bid placebo

73% over weight or obese

30% met criteria for metabolic syndrome

73% over weight or obese

30% met criteria for metabolic syndrome

uric acid

in-clinic 24-hr

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

Urate oxidase genes

nonsense: codon 33

nonsense: codon 187

aberrant splice

13-bp deletion

Urate oxidase genes

nonsense: codon 33

nonsense: codon 187

aberrant splice

13-bp deletion

Urate oxidase genes

nonsense: codon 33

nonsense: codon 187

aberrant splice

13-bp deletion

Urate oxidase genes

nonsense: codon 33

nonsense: codon 187

aberrant splice

13-bp deletion

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

23% lower

mortality

allopurinol

thankspbfluids.com

Uric Acid, Fructose and Hypertension

Health & Medicine

Natural sweeteners: health benefits of stevia - hypertension... · 2019. 7. 16. · is sweetness. Honey, coconut sugar, blackstrap molasses, table sugar, agave, high fructose, corn

صفحه نخست / وب سایت زر فروکتوزzarfructose.com/Content/Download/Catalouge2.pdf · Fructose Zar Fructose . Fructose Zar Fructose . Created Date: 20180925071551Z

Uric acid and gout

Uric Acid Production

Ketohexokinase C Blockade Ameliorates …...degradation pathway resulting in increased uric acid (Fig. 1a). After an acute exposure of mice to fructose (1 g/kg for 90 min), the livers

Uric Acid - Gout - Reduce High Uric Acid

Presentation - Uric Acid

Article- Uric Acid

Oxidative Stress, Uric Acid, Vascular Inflammation in Non ...hypertension and diabetes is the endothelial malfunction which may severely disrupt the body’s homeostasis by generating

Fructose Metabolism. Catabolism of Fructose Considerable quantity of fructose is taken as sucrose (glucose- fructose), fruit juice and honey. This sugar

THE PALEO DIET THE INSIDER · 2016-04-07 · ultimately converted to uric acid by the liver, thereby elevating plasma uric acid levels. 24,25 Only fructose causes this effect, as

Fructose, Uric Acid and Hypertension in Children and ...htpaediatrics.com/wp-content/uploads/2018/02/1100-Feig.pdf · Fructose, Uric Acid and Hypertension in ... by 1mg/dL. Baseline

Urea and Uric acid

Sucrose, High-Fructose Corn Syrup, and Fructose, Their Metabolism

Uric Acid and Hypertension Oussama Hassan, MD ERA-EDTRA Fellow Royal London Hospital - Barts Health NHS Trust, London, UK

Fructose: Metabolic, Hedonic, and Societal Parallels …podcast.uctv.tv/webdocuments/Fructose-and-Ethanol.pdf · Fructose: Metabolic, Hedonic, and Societal ... reduce fructose consumption

Maternal fructose drives placental uric acid …pages.ucsd.edu/~mboyle/COGS163/pdf-files/Maternal fructose drives... · Maternal fructose drives placental uric acid production leading

Uric a & kidney

Fructose metabolism

Introduction Metabolism Fructose Malabsorption Diagnosismedicalexposedownloads.com/W/Fructose Malabsorption hereditary... · Fructose Malabsorption ... Assessment of Dietary Fructose