Let's learn about the relevant anatomy, physiology, pathology, and pharmacology associated with uric acid and gout.

1. GOUT

2. Contents
• Introduction
• Basic science
 Metabolism of uric acid (Biochemistry)
 Pathogenesis of gout (Pathology)
 Treatment of gout (Pharmacology)
• Interesting info related to gout
 Is gout the disease of kings ?
 Why 1st metatarsophalangeal joint common in gout ?
 Higher uric acid in human than other mammals (Evolution)
 Is low uric acid level beneficial or harmful ?
 Fructose Vs Hyperuricemia ?
 Gender bias by gout ?
 Purine rich food source ( Plant Vs Animal )
Are legumes risk factor for hyperuricemia ?

3. Gout Timeline
• 2640 BC : 1st identified by Egyptians
(one of the oldest recognized diseases)
• 400 BC : Hippocrates described it as “arthritis of the rich”
due to association with certain foods & excessive alcohol.
(Disease of kings)
He believed that gout developed after accumulation of
bodily humors, such as “phlegm” which resulted in painful
distension of joints
• 13th century : Term “gout” used, derived from Latin “gutta”
(a drop) which reflects the notion that gout resulted from a
local instillation of malevolent humor.
• 17th & 18th centuries : Identification of crystals as urate &
demonstration of urate in tophi.
• 20th century : Many advances in the understanding &
therapy of gout emerged.

4. Introduction
• Metabolic disorder (of purine metabolism)
• Characterized by
 Hyperuricaemia
(Serum UA >= 7 mg/dL in male & 6 mg/dL in female)
 Deposition of monosodium urate crystals (MSU) in
joints & peri-articular tissues
 Recurrent attacks of acute synovitis
• Solubility limit of uric acid is 6.8 mg/dL
• UA at physiological pH breaks down forming urate ion in
ECF that binds Na forming MSU.

6. Classification of Gout

7. Purine synthesis

8. Purine synthesis

9. Purine excretion

10. Uric acid metabolism

11. Pathogenesis of Gout

12. Pathogenesis of gout
• Urate over-production -10%
(Lesch-Nyhan syndrome due to HGPRT deficiency)
• Urate under-excretion - 90%
(a relative deficit in the renal excretion)
• Combined overproduction and under-excretion
(Alcohol)

13. Clinical features
Four clinical stages are recognized :
• Asymptomatic hyperuricemia
• Acute arthritis
 Sudden onset of excruciating joint pain associated with
localized hyperemia, warmth, mild fever
 Untreated acute gouty arthritis may last for hours to weeks,
but gradually there is complete resolution
• Asymptomatic intercritical period
The period between attacks when the patients are
asymptomatic has been termed intercritical gout
 Most experience 2nd acute episode within months to few yrs
• Chronic tophaceous gout
 Develops on average about 12 years after initial acute attack
& appearance of chronic tophaceous arthritis
Radiographs show characteristic juxta-articular bone erosion
caused by osteoclastic bone resorption & loss of joint space.

14. Factors favoring Gout
Many factors contribute to the conversion of asymptomatic
hyperuricemia into primary gout, including the following:
• Age of the individual & duration of the hyperuricemia.
Gout usually appears after 20 to 30 years of hyperuricemia.
• Genetic predisposition
X-linked abnormalities of HGPRT
primary gout follow multifactorial inheritance, run in family
Polymorphisms in genes regulating URAT1 and GLUT9
• Heavy alcohol consumption
• Obesity
• Drugs (e.g. thiazides) that reduce excretion of urate
• Lead toxicity (so-called saturnine gout)

15. Treatment of Gout
Acute gout
• NSAIDS (Indomethacin, Naproxen, Diclofenac)
• Colchicine
 prevents release of chemotactic factors & inhibit
neutrophil chemotaxis
 S/E- NVD, abdominal pain; Chronic use-myopathy,
alopecia, aplastic anemia, agranulocytosis
• Glucocorticoid (Systemic-Prednisolone, methylprednisolone;
Intrarticular- triamcinolone)
Chronic gout
• Uricosuric drugs (Probenecid; High fluid intake advised to
prevent formation of urate crystals in urine)
• Uric acid synthesis inhibitors (Allopurinol, Febuxostat)
• Rasburicase (Urate oxidase, convert UA to soluble allantoin)

17. Why 1st metatarsophalangeal joint ?

18. Higher uric acid in humans ?
• Loss of uricase activity
• 90% of UA filtered by kidney reabsorbed
(instead of being excreted)
But WHY ?
• Evolutionally & physiologically, UA not treated as a harmful
waste product but something beneficial that has to be kept.
 Powerful antioxidant - 2/3 of total plasma antioxidant
activity (increased life expectancy & intelligence)
 A mechanism to maintain BP in times of very low salt
ingestion (inhibit bioavailability of NO)
 Protective effect against severe neurodegenerative
disease (Parkinson, Alzheimer, Multiple sclerosis)

19. Low uric acid level beneficial / harmful ?
• Low levels of UA detrimental to neurons (due to impaired
antioxidant capacity)
• Low serum UA associated with neurodegenerative diseases
 Multiple sclerosis
 Alzheimer’s disease
 Parkinson disease
(Optimizing serum UA level by supplying purine rich foods might
contribute favorably to Parkinson disease treatment)

20. Fructose Vs Hyperuricemia

21. Purine rich food sources
• Purine naturally occurs in all plant foods.
• Animal source (Meat-red meat, organ meat, fish, seafoods) –
higher purine content than plants
 Vegetarians have low mean serum UA concentration
than non vegetarians
 Some animal based foods (Low fat dairy products)
protective – Milk proteins lactalbumin, casein have
uricosuric action
• Purine rich plant source
 High (sea weeds)
 Moderate (Soybeans)
 Low (broccoli, cauliflower, beans, oats, spinach)
 Very low (peanuts, walnuts, almond)

22. Legumes: Risk factor for hyperuricemia ?
• High purine vegetables, no apparent association with
hyperuricemia/gout development
• But rather a negative association with gout development risk.
 Naturally low in fat
 Practically free of saturated fat & dietary cholesterol
 Low glycemic index
 Has significant portion of fiber, Vitamin B, Fe, Zn
• But if patient already has advanced kidney disease/gout, eat
high purine vegetables with caution or replace with lower
content

23. References
• Roddy E. Revisiting the pathogenesis of podagra: why does
gout target the foot?. J Foot Ankle Res. 2011;4(1):13.
• R Marcolongo. Gout: The King of Diseases and the Disease
of Kings. Journal of the Siena Academy of Sciences. 2012.
Vol 4.
• Jakše B, Jakše B, Pajek M, Pajek J. Uric Acid and Plant-
Based Nutrition. Nutrients. 2019;11(8):1736.
• Caliceti C, Calabria D, Roda A, Cicero AFG. Fructose
Intake, Serum Uric Acid, and Cardiometabolic Disorders: A
Critical Review. Nutrients. 2017;9(4):395.
• Robbins and Cotran Pathologic Basis of Disease.
• Kaplan’s Biochemistry Lecture notes.

24. THANK YOU!