2. Purines (adenine and guanine) and
pyrimidines (cytosine, thymine, uracil) serve
fundamental roles in
in the replication of genetic material,
gene transcription,
protein synthesis,
cellular metabolism
3. hyperuricemia and gout
there is increased production or impaired
excretion of a metabolic end product of
purine metabolism (uric acid)
Understanding the biochemical pathways has
led to the development of specific forms of
treatment, such as the use of allopurinol, to
reduce uric acid production.
4. Uric acid is the final breakdown product of
purine degradation in humans.
It is a weak acid with pKas of 5.75 and 10.3.
Urates, the ionized forms of uric acid,
predominate in plasma extracellular fluid and
synovial fluid, with 98% existing as
monosodium urate at pH 7.4.
5. Plasma is saturated with monosodium urate
at a concentration of 405 mol/L (6.8 mg/dL)
at 37°C.
At higher concentrations, plasma is therefore
supersaturated, creating the potential for
urate crystal precipitation.
plasma urate concentrations can reach 4800
mol/L (80 mg/dL) without precipitation,
perhaps because of the presence of
solubilizing substances.
6. The pH of urine greatly influences the solubility
of uric acid.
At pH 5.0, urine is saturated with uric acid at
concentrations ranging from 360 to 900 mol/L
(6–15 mg/dL).
At pH 7, saturation is reached at concentrations
between 9480 and 12,000 mol/L (158 and 200
mg/dL).
Ionized forms of uric acid in urine include mono-
and disodium, potassium, ammonium, and
calcium urates
7. purine nucleotides are synthesized and
degraded in all tissues
urate is produced only in tissues that contain
xanthine oxidase, primarily the liver and small
intestine
Urate production varies with the purine content
of the diet and the rates of purine biosynthesis,
degradation, and salvage
Normally, two-thirds to three-fourths of urate is
excreted by the kidneys, and most of the
remainder is eliminated through the intestines.
8.
9. The kidneys clear urate from the plasma and
maintain physiologic balance by utilizing specific
organic anion transporters (OATs), including
urate transporter 1 (URAT1) and human uric acid
transporter (hUAT)
URAT1 and other OATs carry urate into the
tubular cells from the apical side of the lumen
Once inside the cell, urate must pass to the
basolateral side of the lumen in a process
controlled by the voltage-dependent carrier
hUAT.
10. the renal handling of urate/uric acid:
(1) glomerular filtration,
(2) tubular reabsorption,
(3) secretion
(4) postsecretory reabsorption
these processes have been considered
sequential, it is now apparent that they are
carried out in parallel
11.
12. . URAT1 is a novel transporter expressed at the apical
brush border of the proximal nephron
Uricosuric compounds directly inhibit URAT1 on the
apical side of the tubular cell (so-called cis-inhibition)
In contrast, antiuricosuric compounds (those that
promote hyperuricemia), such as nicotinate,
pyrazinoate, lactate, and other aromatic organic
acids, serve as the exchange anion inside the cell,
thereby stimulating anion exchange and urate
reabsorption (trans-stimulation).
The activities of URAT1, other OATs, and sodium
anion transporter result in 8–12% of the filtered urate
being excreted as uric acid.
15. Most children have serum urate concentrations
3–4 mg/dL
Levels begin to rise in males during puberty but
remain low in females until menopause
Mean serum urate values of adult men and
premenopausal women are (6.8 and 6 mg/dL),
respectively
After menopause, values for women increase to
approximate those of men
In adulthood, concentrations rise steadily over
time and vary with height, body weight, blood
pressure, renal function, and alcohol intake.
16. Hyperuricemia can result from increased
production or decreased excretion of uric acid
or from a combination of the two processes
Sustained hyperuricemia predisposes some
individuals to develop clinical manifestations
including :
gouty arthritis,
urolithiasis,
renal dysfunction
17. Hyperuricemia is defined as a serum urate
concentration 6.8 mg/dL.
The risk of developing gouty arthritis or
urolithiasis increases with higher urate levels
and escalates in proportion to the degree of
elevation.
Hyperuricemia is present in between 2 and
13.2% of ambulatory adults
more frequent in hospitalized individuals.
18. Urate over producers
Under excretors
Combination of both
23. Diet contributes to the serum urate in
proportion to its purine content.
Strict restriction of purine intake reduces the
mean serum urate level by about 1 mg/dL and
urinary uric acid excretion by 200 mg/dL
Foods high in nucleic acid content include
liver, "sweetbreads" (i.e., thymus and
pancreas), kidney, and anchovy.
24. Endogenous sources of purine production also influence the serum
urate level.
De novo purine biosynthesis is an 11-step process that forms
inosine monophosphate (IMP)
The rates of purine biosynthesis and urate production are
determined, for the most part, by
amidophosphoribosyltransferase (amidoPRT), which combines
phosphoribosylpyrophosphate (PRPP) and glutamine.
A secondary regulatory pathway is the salvage of purine bases by
hypoxanthine phosphoribosyltransferase (HPRT).
HPRT catalyzes the combination of the purine bases hypoxanthine
and guanine with PRPP to form the respective ribonucleotides IMP
and guanosine monophosphate (GMP).
25. Serum urate levels are closely coupled to the
rates of de novo purine biosynthesis, which is
driven in part by the level of PRPP
Both increased PRPP synthetase activity and
HPRT deficiency are associated with
overproduction of purines, hyperuricemia,
and hyperuricaciduria
26. Accelerated purine nucleotide degradation can
also cause hyperuricemia
Hyperuricemia can result from excessive
degradation of skeletal muscle ATP after
strenuous physical exercise or status epilepticus
and in glycogen storage diseases types III,V, and
VII
The hyperuricemia of myocardial infarction,
smoke inhalation, and acute respiratory failure
may also be related to accelerated breakdown of
ATP
27. More than 90% of individuals with sustained
hyperuricemia have a defect in the renal
handling of uric acid.
Gouty individuals excrete 40% less uric acid than
nongouty individuals for any given plasma urate
concentration.
Uric acid excretion increases in gouty and
nongouty individuals when plasma urate levels
are raised by purine ingestion or infusion, but in
those with gout, plasma urate concentrations
must be 1–2 mg/dL higher than normal to
achieve equivalent uric acid excretion rates.
28. Altered uric acid excretion results from decreased
glomerular filtration, decreased tubular secretion, or
enhanced tubular reabsorption.
Decreased urate filtration does not appear to cause
primary hyperuricemia but does contribute to the
hyperuricemia of renal insufficiency.
hyperuricemia is invariably present in chronic renal disease
Uric acid excretion per unit of glomerular filtration rate
increases progressively with chronic renal insufficiency,
but tubular secretory capacity tends to be preserved,
tubular reabsorptive capacity is reduced, and extrarenal
clearance of uric acid increases as renal damage becomes
more severe.
29. Many agents that cause hyperuricemia exert their
effects by stimulating reabsorption rather than
inhibiting secretion.
This appears to occur through a process of "priming"
renal urate reabsorption through the sodium-
dependent loading of proximal tubular epithelial cells
with anions capable of trans-stimulating urate
reabsorption
carboxylates are well known to cause hyperuricemia,
including pyrazinoate (from pyrazinamide treatment),
nicotinate (from niacin therapy), and the organic acids
lactate,beta -hydroxybutyrate, and acetoacetate
30. Alcohol promotes hyperuricemia because of
increased urate production and decreased uric
acid excretion.
Excessive alcohol consumption accelerates
hepatic breakdown of ATP to increase urate
production.
Alcohol consumption can also induce
hyperlacticacidemia, which blocks uric acid
secretion.
The higher purine content in some alcoholic
beverages such as beer may also be a factor.
31. Hyperuricemia does not necessarily represent a disease,
nor is it a specific indication for therapy.
The decision to treat depends on the cause and the potential
consequences of the hyperuricemia in each individual.
Quantification of uric acid excretion can be used to determine
whether hyperuricemia is caused by overproduction or decreased
excretion.
On a purine-free diet, men with normal renal function excrete <3.6
mmol/d (600 mg/d).
Thus, the hyperuricemia of individuals who excrete uric acid
above this level while on a purine-free diet is due to purine
overproduction; for those who excrete lower amounts on the
purine-free diet, it is due to decreased excretion.
32. gouty arthritis
Nephrolithiasis
urate nephropathy :a rare cause of renal
insufficiency attributed to monosodium urate
crystal deposition in the renal interstitium
uric acid nephropathy : a reversible cause of
acute renal failure resulting from deposition
of large amounts of uric acid crystals in the
renal collecting ducts, pelvis, and ureters.
34. One of the earliest diseases to be recognized
in humans
first described in ancient Egypt in 2640 B.C
known as "the disease of kings
fifth century B.C.,Hippocrates described gout
as unwalkable disease
sixth century A.D. colchicine recognised as
gout remedy
35. is the most common inflammatory arthritis
affecting men
most often presents as recurrent, self-
limiting episodes of severe acute arthritis
central feature of gout is deposition of MSU
crystals
The gold standard for diagnosis of gout is
identification of MSU crystals within tissue or
synovial fluid
36. male sex, increasing age, socio-economic
deprivation,
Polynesian ethnicity
obesity,
chronic renal impairment, renal
transplantation
cardiovascular disease, type 2 diabetes,
hypertension, heart failure,
hypertriglyceridaemia, and psoriasis
Diuretic and cyclosporine usage
37. high intake of beer and spirits, sugar-
sweetened soft drinks, fructose, meat, and
seafood
Weight gain and obesity in younger life are
strongly associated with development of
gout
low-fat dairy products, coffee, and vitamin C
are associated with reduced risk
38. first attack of gout most often presents as rapid
onset of acute inflammation affecting the first
metatarsophalangeal (MTP) joint or other joint
in the lower limb
Patients describe severe joint pain with difficulty
walking and performing daily activities
Examination of the affected joint shows the
cardinal features of inflammation; erythema,
heat, tenderness, swelling, and loss of joint
mobility
39. severe gout attack, patients may also be
systemically unwell with fever.
The acute gout attack typically resolves
spontaneously after 7–10 days
In the presence of persistent hyperuricaemia,
recurrent flares occur, with increasingly
frequent and prolonged attacks which may
affect numerous joints including those in the
upper limbs
40. Problems of tophaceous gout
cosmetic problems,
ulceration and superimposed
infection,
mechanical obstruction of joint movement,
Bone and cartilage damage
musculoskeletal disability
41. heavy alcohol intake,
dehydration,
joint trauma,
medical illness,
surgery,
intake of high-purine diet
Urate lower therapy
42. Chronic gout has an important impact on health-
related quality of life and musculoskeletal
function.
In particular, recurrent gout flares, the presence
of joint inflammation and tophi are associated
with disability and poor health-related quality of
life.
Work productivity is also reduced in patients of
working age with severe gout, with an estimated
mean work day loss of 25.1 days per year
43. thiazide diuretic use in patients with
hypertension may increase serum urate
concentrations
chronic kidney disease may limit the use of non-
steroidal anti-inflammatory drugs (NSAIDs)
and/or colchicine for management of acute
flares
blood sugar control may be difficult in patients
with coexistent diabetes receiving
corticosteroids
44. confirmed by identification of MSU crystals in
synovial fluid or tophus
synovial fluid analysis typically shows an
inflammatory picture with high
concentrations of neutrophils
Blood testing typically shows signs of acute
infl ammation with neutrophil leucocytosis
and high acute phase reactants
Low complement levels common
45. during an acute gout flare, serum urate
concentration drops into the normal range in
approximately 40% of patients
repeat measurement of the serum urate
concentration in the convalescent period is
required
46. plain radiographs are normal in patients with
recent presentation of gout
In patients with established disease, typical
plain radiographic features are asymmetric
soft -tissue masses (tophi) and well-
corticated bone erosions with overhanging
edge
Dual energy CT (DECT) for non-invasive
diagnosis of gout
47. Three therapeutic goals
1. treatment of acute gout flares
2.prophylaxis against acute gout flares
(usually at the time of initiating ULT)
3. long-term preventive treatment of chronic
gout with ULT
48. goal of treating acute gout is resolution of
pain and inflammation
Treatment should be commenced as soon as
possible after development of symptoms
includes rest, icing of the affected joint, and
Analgesia
NSAIDs are first-line treatment in patients
without contraindications.
49. These drugs are most effective when used in
a fast-acting preparation and at full dose
naproxen 500 mg twice daily, indomethacin
50 mg three times daily
give major clinical response within 2 days
COX-2 inhibitors such as etoricoxib (120 mg
daily) and lumiracoxib (400 mg daily) have
similar efficacy in treating acute gout
COX-2 inhibitors better tolerated
50. has been used for centuries for treatment of
acute gout
a low dose of colchicine (1.8 mg total over 1
hour) was as effective as a high dose (4.8 mg
total over 6 hours)
clinical response in 38% of patients within 24
hours
FDA recommends that colchicine dosing for
acute gout should be 1.2 mg stat followed by 0.6
mg in 1 hour
51. may cause severe drug interactions with
CYP3A4 inhibitors
(ciclosporin, clarithromycin, ketoconazole,
verapamil, diltiazem, erythromycin)
dose of colchicine should also be reduced in
patients with renal or liver disease
Loperamide best antidote for colchicine
induced diarrhea
52. Intra-articular corticosteroid injection of the aff
ected joint leads to rapid improvement in pain
and inflammation
Oral prednisolone is useful in patients where the
use of NSAIDs and colchicine is harmful
Adrenocorticotropic hormone (ACTH) injection
is also effective, typical doses are 40 IU
M.O.A : adrenal corticosteroid release and also
activation of the melanocortin type 3 receptor
53. use of anti-inflammatory agents to prevent
flares in patients with intercurrent or chronic
gout
relevant when commencing urate lowering
therapy
Low-dose colchicine (0.5–1.5 mg daily) is the
most frequently used prophylactic treatment
for gout
Regular use of NSAIDs to be avoided due to
renal impairment and hypertension in gout
54. Recommended for :
Recurrent gout flares (more than one fl are
per year),
gouty tophi,
Chronic gouty arthropathy
radiographic erosions
serum urate concentration (6 mg/dL) is
recommended
55. three main groups
1. the xanthine oxidase inhibitors,
2. uricosuric agents
3. recombinant uricase
VitaminC at 500mg-1000 mg daily has a
modest urate-lowering eff ect
56. Xanthine oxidase is a critical enzyme in the
metabolism of purines to urate,
catalyses the conversion of hypoxanthine to
xanthine and xanthine to urate
Allopurinol and febuxostat are two agents
currently used
allopurinol hypersensitivity syndrome can
cause progressive renal failure
Dose reduction needed when patient on
azathioprine
57. Approved by the FDA in 2009 upto dose of
80mg daily
febuxostat has superior urate-lowering
efficacy compared allopurinol
well tolerated
does not require dose adjustment in patients
with mild–moderate renal or hepatic
impairment
58. these drugs have the potential to promote
urate stone formation
should be avoided in patients with
nephrolithiasis
Liberal fl uid intake is recommended
urine alkalinization should be considered by
using sodium bicarbonate (3–7.5 g daily) or
potassium citrate (7.5g daily)
Probenicid, Sulphinpyrazone,
Benzbromarone are the drugs
59. Uricase (urate oxidase) converts urate to 5-
hydroxy isourate and H 2 O 2 , with
subsequent formation of allantoin
Allantoin is soluble and is readily eliminated
by the kidney
humans lack a functional uricase gene
profound reductions in serum urate
concentrations often to undetectable levels
Eg. Rasburicase, Pegloticase
