1. Your Patient
50 years old male comes in the emergency complaining severe pain in his big toe and ankle for the last 12 hrs. On examination joint shows red, swollen and very tender

2. Lecture objectives At the end of the lecture students will be able to:
Define gout, its types and complications
Name the defective enzymes involved in purine nucleotide metabolism
Explain the causes of hyperuricemia

3. Uric Acid
Uric acid is formed from the breakdown of nucleic acids and is an end product of purine metabolism.
Uric acid is transported by the plasma from the liver to the kidney, where it is filtered and where about 70% is excreted in Urine.
The remainder of uric acid is excreted into the GI tract.

5. Catabolism of Purine Nucleotides

6. Uric acid
Normal serum uric acid concentration: 3-7mg/dl in males; 2-5 mg/dl in females
Excretion mg per day
Hyperuricemia: increased serum uric acid levels above 7mg/dl in men and above 6mg/dl in women

7. Gout
Gout is a metabolic disorder of purine catabolism resulting in hyperuricemia and crystallization of uric acid salts in joints, soft tissues, cartilages and kidneys.
The joints become inflamed, painful, and arthritic. The joint most commonly involved in gout is the first metatarsophalangeal joint (the big toe)
Renal stones
Tophus. 7

8. Types of Gout
Primary gout is inherited-90%, due to inborn error of metabolism and mainly affects men over 30
Secondary gout is associated with various diseases causing increased synthesis or decreased excretion of uric acid leukemia, polycythemia, HGPRT deficiency, renal insufficiency, radiotherapy, lifestyle (rich foods) 1 2 1 3
The advanced gout stage is often referred to as chronic tophaceous gout to indicate the presence of this clinical manifestation, which will remain unresolved in the absence of urate-lowering therapy.
Tophi are characterized by solid urate deposits in connective tissues that produce irregular nodularities and joint destruction. In addition, the skin overlying the tophi may become ulcerated and exude a white, chalky material.
Shown here are some common sites of tophi, including dermal tophi on the finger, periarticular tophi on the hands, and tophi on the helix of the ear.
The patient who was experiencing the intradermal tophi on the knees was diagnosed and treated by multiple generalists and specialists for osteoarthritis. This photo was taken during his self-referred first visit to a rheumatologist and reinforces the point that gout is a disease that is under-recognized.1 The patient with polyarticular involvement of his hands had been misdiagnosed and treated for rheumatoid arthritis for 8 years.2
The tophi exhibited on this slide are clinically apparent, but this may not always be the case, as was seen in the previous case study examples of the tophi that formed in the bone of the knee and the palm of the hand.
1. Patient case study courtesy of Brian Mandell, MD, PhD, Cleveland Clinic.
2. Patient case study courtesy of N. Lawrence Edwards, MD, University of Florida. 8

9. There are two pathways leading to nucleotides
De novo synthesis: The synthesis of nucleotides begins with their metabolic precursors: amino acids, ribose-5-phosphate, CO2, and one-carbon units.
Salvage pathways: The synthesis of nucleotide by recycle the free bases or nucleosides released from nucleic acid breakdown.

10. What happens in gout? PRPP
Inhibited by AMP
AMP
Ribose
5-phosphate
PRPP
Phosphoribosyl
amine
IMP
GMP
Inhibited by IMP,
AMP, and GMP
Inhibited by GMP
1. Negative regulation of PRPP Synthatase & PRPP Amidotransferase is lost
2. PRPP levels are increased because of defects in salvage pathways
Therefore, there is net increase in biosynthetic/degradation pathways!!

12. Risk Factors
High Purine Diet (Red Meat, Fatty Poultry, High Fat Dairy, Seafood)
Alcohol Consumption
Trauma
Osteoarthritis
Surgery
Starvation
Dehydration
Obesity
Drugs
Renal Impairment
Genetic Mutations
Mayo Clinic
Seafood high in purines: anchovies, herring, sardines, mussels, scallops, trout, haddock, mackerel and tuna.
Genetics: Glucose transporter (SLC22A9), uric acid transporter in kidney (SLC22A12), ATP binding cassette transporters (transport molecules across cell membranes)

13. Gout
Tophus or tophi in plural is a deposit in the elbow, toe, ankle, knee, ear, fingers or other joint in the body of monosodium urate crystals.
Inflammation of joints 
Acute gouty arthritis is a painful condition that often affects only one joint
Chronic gouty arthritis is a repeated episodes of pain and inflammation 13

14. Acute gout
Other common areas of affliction.

15. acute synovitis, ankle & first MTP joints
Gout - acute arthritis
acute synovitis, ankle & first MTP joints

16. acute olecranon bursitis
Gout - acute bursitis
acute olecranon bursitis

17. Monosodium urate crystals
polarized light
red compensator
needle shape
negative birefringence

18. Crystal-induced inflammation
crystal deposition
hyperuricemia
protein binding
receptor binding
cytokine release
influx of PMN’s
crystals engulfed
inflammation

19. Gouty arthritis - characteristics
sudden onset
middle aged males
severe pain
distal joints
intense inflammation
recurrent episodes
influenced by diet
bony erosions on Xray
hyperuricemia

20. Hyperuricemia Serum uric acid level dependent upon
Rate of uric acid production
Efficiency of renal uric acid excretion

21. Hyperuricemia results when production exceeds excretion

22. net uric acid loss results when excretion exceeds production
Hyperuricemia
production
excretion
net uric acid loss results when excretion exceeds production

23. Chronic tophaceous gout
tophus = localized deposit of monosodium urate crystals

24. classic location of tophi on helix of ear
Gout - tophus
classic location of tophi on helix of ear

25. Gout - X-ray changes
DIP joint destruction
phalangeal bone cysts

26. Gout - X-ray changes
bony erosions

27. Gout - cardinal manifestations
arthritis
tophi
acute & chronic
HYPERURICEMIA
nephrolithiasis
nephropathy

28. Gout: kidney stones
The kidneys are also affected, because excess uric acid is deposited in the kidney tubules.
Other complications like urolithiasis and renal damage 28

29. Uric acid metabolism
cell breakdown
dietary intake
purine bases
hypoxanthine
xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid
xanthine
uric acid

30. Hyperuricemia - mechanisms
excessive production
inadequate excretion

31. Drugs used to treat gout
Acute Arthritis Drugs
Urate Lowering Drugs
steroids
NSAID’s
colchicine
allopurinol
probenecid
febuxostat?
rest + analgesia + time

32. Drugs used to treat gout
Acute Arthritis Drugs
allopurinol
probenecid
febuxostat?
steroids
NSAID’s
colchicine
Urate Lowering Drugs
rest + analgesia + time

33. allopurinol inhibits xanthine oxidase
Uric acid metabolism
cell breakdown
dietary intake
purine bases
hypoxanthine
oxypurinol
xanthine
allopurinol inhibits xanthine oxidase
allopurinol
uric acid

34. Lesch-Nyhan Syndrom
Inherited X linked recessive disorder caused by a deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT).
Characterized by excess production of uric acid leads to Gout
Loss of HGPRT leads to elevated PRPP levels and stimulation of de novo purine synthesis.
Decrease salvage pathway - decrease IMP & GMP – impairs feedback regulation of de novo
purine synthesis – leads to overproduction purines 34

36. Lesch-Nyhan syndrome Symptoms: Nephrolitiasis- leads to renal failure
Mental retardation, aggressive behaviour
Self-mutilation – bite their fingers and lips

37. PRACTICE QUESTIONS

38. a. Wrong because Organism in culture is negative
Q.1 A 24 year old man woke up at night with severe pain and swelling in his right big toe. There is no history of trauma. His joint aspirate shows negatively birefringent crystals and no organisms detected on culture. Rheumatic Factor is negative in blood test. What is the most likely diagnosis?
Septic arthritis
Rheumatoid arthritis
Gout
Osteoarthrosis
Key: C
a. Wrong because Organism in culture is negative
b. Wrong because RF is negative
c. Right because of negatively birefringent crystals and typical symptoms.
d. Wrong because Osteoarthrosis occurs in old age and also affects on big joints

39. c. Wrong because it does not suppress Adenosine deaminase
Q.2 A 63-year-old male presents with severe pain in his left wrist and a nodular swelling is observed on the wrist which is red and tender to touch. Aspiration reveals fine needle shaped yellow birefringent crystals. Allopurinol is most likely to help this patient because:
It suppresses Xanthine oxidase
It increases the excretion of uric acid
It suppresses Adenosine deaminase
It Increases the degradation of Purines
Key: A
a. Right because it suppresses Xanthine oxidase which reduces the generation of uric acid.
b. Wrong because allopurinol has no effect on the excretion of uric acid
c. Wrong because it does not suppress Adenosine deaminase
d. Wrong because it does not Increases the degradation of Purines

40. Q. 3. Which is the correct statement regarding gout
Q.3. Which is the correct statement regarding gout? a) Only about 5% of hyperuricemic patients develop gout b) Monosodium urate crystals are demonstrable in synovial fluid leukocytes c) May occur as a result of PRPP synthetase deficiency d) The great toe is the site of first attack in 90% of cases

41. Key: D
Primary gout is a biochemically and genetically heterogeneous disorder resulting from inborn metabolic errors that alter uric acid homeostasis.
About 5- 10% of people with hyperuricemia develop gout at some point in their lifetimes.
One of the inherited defects that lead to early development of severe hyperuricemia and gout is elevated 5'-phosphoribosyl-1'-pyrophosphate synthetase (PRPP synthetase) activity.
Gout is defined by: an increase in the serum urate concentration; characteristic, recurrent, acute arthritic attacks, with monosodium urate monohydrate crystals demonstrable in synovial fluid leukocytes; renal disease, often accompanied by hypertension with glomerular, tubular, interstitial, and vascular involvement; and uric acid nephrolithiasis.

42. Q. 4 Treatment of an acute gout attack is achieved by
Q.4 Treatment of an acute gout attack is achieved by? a) Colchicine b) Allopurinol c) Uricosuric agents d) Methorexate Key: A NSAIDs are the most commonly used drugs in acute gout. Over the long term, gout is treated by decreasing tissue stores of uric acid with the xanthine oxidase inhibitors allopurinol or febuxostat or with the uricosuric agent probenecid.

43. Q. 5 Which of the following statement is correct in Pseudogout
Q.5 Which of the following statement is correct in Pseudogout? a) It occurs as a result of calcium pyrophosphate deposition b) It usually affects younger individuals c) It cannot be associated with hyperthyroidism, ochronosis and Wilson’s disease d) It occurs due to uric acid deposition

44. Key: A
Pseudogout, also known as calcium pyrophosphate deposition (CPPD) disease, is a type of arthritis that causes spontaneous, painful swelling in your joints.  
an analysis of joint fluid to look for calcium pyrophosphate crystals
Pseudogout is more common in older adults
Pseudogout can sometimes be associated with other illnesses, such as:
hemophilia (a hereditary bleeding disorder that prevents the blood from clotting normally)
ochronosis (a condition causing the deposit of a dark pigment in the cartilage and other connective tissues)
amyloidosis (an abnormal buildup of protein in the tissues)
hemochromatosis (an abnormally high level of iron in the blood)
Uric acid is not deposited in Pseudogout
X-rays of the joints to check for any damage to the joint, calcification (calcium buildup) of the cartilage, and deposits of calcium in the joint cavities