Uric acid metabolism and its complication Gout Pseudogout

1. URIC ACID METABOLISM
&
GOUT
Moderator: Prof Santa Naorem
Presenter: Dr Supriya Jamatia

2. Uric acid metabolism
Uric acid is a end product of purine metabolism
• Endogenous uric acid:
- ~300 to 600mg derived from the endogenous source
- Excreted through the urine normally
• Exogenous uric acid:
- Diet with high purine and nucleic acid
Normal serum uric acid level ~3-6 mg/100ml

3. Purine biosynthesis

4. Uric acid synthesis and purine salvage

5. GOUT
• Metabolic disease
• Middle age or elderly men and post menopausal women
• Increased body pool of urate with hyperuricemia
• Characterised by episodic acute and chronic arthritis
• Deposition of monosodium urate(MSU) crystel in joints and
connective tissue

6. CLASSIFICATION
GOUT
Primary
Gout
Secondary
Gout
Due to abnormality of uric acid
production and metabolism.
Excess uric acid production due to
excessive breakdown of nuclei
secondary to some disease
(leukaemia, pernicious anemia,
hemolytic anemia and polycythemia.

7. PATHOGENESIS

8. PATHOPHYSIOLOGY

9. Initial phase of urate crystal
induced activation

10. Propagation of acute gouty response
by activated neutrophils

11. GOUT- Risk factor
• Demographics: sex, age, ethnicity
• Lifestyle factors:
i. Adiposity- strongest risk factor
ii. Meat and seafood- 41% and 51% increased risk respectively
iii. Dairy intake- 44% lower risk
Purine rich vegetable protein and cherries - not associated

12. IV. Alcoholic beverages
V. Sugar sweetened sodas and fructose rich food
VI. Coffee, teas, and caffeine
VII. Vitamin C
Medications
Increase Risk Decrease Risk
• Low dose salicylate
• Diuretics
• β Blockers
• ACE inhibitor
• ARB (except Losartan)
• Fenofibrate
• CCB
• Losartan

13. 1
METABOLIC DEFECT IN GOUT
(1) Defective excretion of urate by kidney (primary renal gout where there is
defect in renal tubule).
(2) Reduction in the enzyme hypoxyxanthine-guanine phosphoribosyl
tranferase (catalyses formation of necleotides from free purines)
(3) Reduced urate binding capacity of plasma.

14. CLINICAL FEATURES
• Referred as “Disease of the kings”
• Most common inflammatory arthritis in men > 40 yrs
 Stage 1: Asymptomatic hyperuricemia
 Stage 2: Acute gout attacks
 Stage 3: Intercritical period
 Stage 4: Chronic tophaceous gout
STAGES of Gout

15. Asymtomatic hyperuricemia
• Without sustained hyperuricemia gout cannot develop
• Hyperuricemia itself insufficient to cause the diseas & majority of
patients who have hyperuricemia never develop gout.
• Comorbidities associated with hyperuricemia include metabolic
syndrome, chronic kidney disease and congestive heart failure.
• Asymptomatic hyperuricemia ends with the first gout attack.

16. Acute gout
• Characterised by abrupt onset of severe pain and swelling
• Maximal inflammation occurs within 12 - 24 hours
• Attacks often come at night or early morning
• Most commonly monoarticular in men during first attack
• Joints are red, hot, swollen, and exqusitely tender

17. • Metatarsophalangeal joint is first
affected in 50% of cases
• Others commonly affected joints:
ankle, heel, knee, wrists, and hands
• Attacks resolve within days to weeks
without treatment
60% will experience second attack within 1 yr and 80% within 3 yrs

18. • Systemic symptoms and signs of fatigue , fever, and chills may accompany
• Its due to increased production of proinflammatory cytokines such as IL-1
• Local trauma, alcohol binges, overeating or fasting, weight changes, use of
diuretics and initiation of urate lowering therapy precipitate acute gouty
attack

19. Intercritical gout
• This is a period between attacks
• Clinically the disease seems quiscent, hyperuricemia still present ,
and MSU crystal formation and deposition may continue as ongoing
subclinical inflammation

20. Chronic tophaceous gout
• Gouty tophi are foreign body granulomas surrounding deposits of MSU
crystals.
• Chalk-like subcutaneous nodule(s) under transparent skin, often with
overlying vascularity. It develops 10 or more years after acute attacks
• Joints affected by OA are more predisposed to having MSU crystal
deposition in patients with gout.

21. Tophi on bilateral
Metatarsophalangeal joints
Tophi in hand with severe
tophaceous gout

22. • Pattern of symptoms changes: time
between attacks shortens; more
joints may be involved
• Tophaceous disease may result in a
destructive arthropathy and marked
reduction in quality of life
• Increased risk for nephrolithiasis

23. Laboratory diagnosis
• Presumptive diagnosis ideally should be confirmed by needle aspiration
of acutely or chronically involved joints or tophaceous deposits.
• Acute septic arthritis other crystal line associated arthropathies,
palindromic rheumatism, and psoriatic arthritis may present with similar
clinical features.
• Needle shaped MSU crystal typically seen both intracellularly and
extracellularly during acute attack.

24. • Crystals are “needle shaped negative
birefringent” in polarizing light
microscopy which firmly establish
diagnosis of gouty arthritis.
• Synovial fluid leukocyte counts elevated
from 2000 to 60,000/μL.
• Effusion appear cloudy due to increased
leukocytes
• Thick pasty or chalky joint fluid contains
large amount of crystal.

25. • Send for culture if septic arthritis suspected.
• MSU crystal can often demonstrated in first metatarsophalangeal joint and
knees during intercritical period.
• Serum uric acid can be normal or low during acute attack
• 24 hr urine collection for uric acid: For assessing risk of stones, elucidating
overproduction or underexcretion of uric acid.

26. Radiography findings
• Punched-out erosion or
lytic area with overhanging
edge
• Maintenance of joint space
• Absent of periarticular
osteopenia
• “double contour sign” in
USG

27. American college of Rheumatology diagnostic
criteria for gout
• Presence of characteristic urate crystal in the joint fluid
or
• Presence of tophus proven to contain urate crystal by chemical means or
polararized light microscopy
or
• Presence of six or more of the following clinical, laboratory, or radiologic
findings:

28. 1.Asymmetric swelling within a joint on radiography
2.Attack of monoarticular arthritis
3.Culture of joint fluid negative for microorganism during attack of joint
inflammation
4. Development of maximal inflammation within one day
5. Hyperuricemia
6. Joint redness
Diagnostic criteria – cont..

29. 7. More than one attack of acute arthritis
8. Pain or redness in the first meta-tarsophalangeal joint
9. Subcortical cyst without erosion on radiography
10. Suspected tophus
11. Unilateral attack involving first meta-tarsophalangeal joint
12. Unilateral attack involving tarsal joint
Diagnostic criteria – cont..

30. Management of gout and hyperuricemia
• Given full doses for 3 days then tapered until symptoms subsides.
• COX-non selective- Naproxen 750-1000mg PO divided doses,
Sulindac 300-400 mg/day divided doses for 7-10 days
Indomethacin , 150-200 mg PO daily for 3 days in divided doses then
100mg PO daily for 4-7days
• COX-2 selective- celecoxib 800mg; then 400mg on day 1 followed by 400
mg BID for 7 days
ACUTE GOUTY ARTHRITIS:
NSAIDS

31. • High starting doses needed for acute gout
 Prednisone, 30-60 mg/day for 3 days then taper every 3 days by 10-15
mg less until discontinuation
 Triamcinolone (60 mg IM once) or methylprednisolone dose pack can be
used
 Intra articular injection of depot corticosteroid for one or two large joint
can be tried
 Prophylactic daily low dose colchicine should be added to prevent gout
flare
SYSTEMIC CORTICOSTEROID

32. COLCHICINE
• Readily bioavailable after oral administration
• Eliminated by biliary and fecal excretion
• Acts by making tubulin-colchicine complex which bind with
microtubules.
• Regulates cell proliferation, signal transduction, gene expression,
chemotaxis, and neutrophil secretion of granules contents.
• Acts on high proliferating cell

33. • Dose- 1.2 mg once followed by 0.6 mg after one hr and then after 12 hr
oral low dose until gout flare resolves
• 0.5 mg TID - EULAR recommendation
• Side effect- gastrointestinal toxicity most frequent, bone marrow
depression, cardiac toxicity arrhythmia, hepatotoxic, alopecia and
colchicine myopathy.

34. • ACTH: not only induces adrenal glucocorticoid production has peripheral
anti-inflammatory effect via melanocortin receptor signaling. 25 USP unit
SC for less flare 40 USP IM or IV once for more severe flares
• IL-1antagonism- off level use anakinra 100 mg/day SC for 3 days,
canakinumab single dose 150 mg SC

35. Treatment of hyperuricemia in gout
• NONPHARMACOLOGIC MEASURES:
- Weight reduction, reduction of dietary excesses eg. Refined sugar, high
purine intake from animal sources, limiting alcohol consumption
especialy beer, fructose-sweetened beverages.
- Taking care of comorbid condition such as obesity, DM, atherosclerosis,
HTN, CKD .

36. Indication for pharmacologic serum urate
lowering treatment
• Minimum Sr. urate target  6.0 mg/dl
• Symptomatic gouty arthritis and one or more following-
1. Frequent attack of gout flares(≥2/yrs)
2. CKD
3. Overproduction of uric acid
4. Urolithiasis
5. Palpable tophi
6. Severe, difficult to treat acute attacks
7. Chronic tophaceous gouty arthritis

37.  oxypurinol active metabolite
 dose 300mg/day.
 Lower s.urate not only by inhibiting xanthine oxidase also by competing
for phospho-ribosylpyrophosphate in the salvage pathway
 Nonselectively interferes with pyrimidine metabolism
First line: Start potent oral urate lowering monotherapy and
titrate dose to appropriate maximum
Xanthine oxidase inhibitor (XOI)
ALLOPURINOL

38. • Side effect: nausea or diarrhea, elevated liver transaminases, hepatic
disease (granulomatous hepatitis,cholestatic jaundice, advanced liver
necrosis, pruritis rash
• Bone marrow suppression in advanced CKD
• Major drug interaction with azathioprine, 6-mercaptopurine and
theophylline
• Amoxicillin and ampicillin trigger rash
• Allopurinol hypersensitivity syndrome
• CKD dose adjustment needed- GFR<30 , 50mg/day

39. Febuxostat
• Selective inhibitor of xanthine oxidase
• Metabolised by oxidation and glucoronidation in liver
• Pyrimidine metabolism not affected
• Dose- 40 mg OD after 2weeks if urate level not decreased increase doses
to 80 mg/day maximum dose 300mg/day
• Side effect- rash, elevation of hepatic enzyme, diarrhea
• Major drug interaction with azathioprine and 6-mercaptopurine

40. Uricosurics
• Inhibit the urate anion
exchanger URAT1 (encoded by
SLC22A12) interfere in urate
reabsorption from the lumen.
• Probenecid acid 250mg BD
titrated up to 1000mg BD
3g/day if tolerated.
• Uricosurics
- probenecid
- benzbromarone
- lesinurad
• Low uricosuric activity
- losartan,
- high-dose salicylates)

41. • Oral hydration and alkalization to prevent urolithiasis
• lesinurad single dose of 200 mg OD and only as add-on therapy with an
XOI drug to constitute combination treatment.
• Acute kidney insufficiency is a potential side effect of lesinurad
• Should not be prescribed in those with GFR below 45 mL/min

42. THE URICASE PEGLOTICASE FOR REFRACTORY
HYPERURICEMIA IN PATIENTS WITH SEVERE,
CHRONIC GOUT
• Uricases directly degrade relatively insoluble uric acid by catalyzing its
conversion to highly soluble allantoin
• Administer Iv infusion
• Preinfusion of an antihistamine, acetaminophen, and a corticosteroid
decrease infusion reactions to pegloticase
• G6PD deficiency can induce methemoglobinemia or hemolysis so
screening is necessary

43. 1. Rasburicase(biosynthesized recombinant Aspergillus flavus uricase)
2. Pegloticase (pegylated, recombinant porcine-baboon uricase)
• Use strictly limited to gout or hyperuricemia from tumor lysis
syndrome(quick onset), extremely resistant gout/hyperuricemia
• Factors limiting use is exorbitant cost, anaphylactic reaction, hemolysis
in G6PD deficiency
Recombinent Uricase

44. Recent development
• “treat to target” ULT strategy
• Newer drugs (all are in phase І to III trial):
– Arhalofenate,
– bucillamine,
– levotofisopam,
– ulodesine,
– Verinuard
– tranilast

45. References
• Kelley 10th ed textbook of rheumatology
• Rheumatology Hochberg 7th edition
• Harrison’s 20th edition
• Progress in Medicine 2019

46. THANK YOU