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Dr. MohdViquasuddin Saim
DNB General Medicine resident
Medwin hospital
 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
 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.
 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.
 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.
 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
 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.
 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.
 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
 . 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.
 ACTH
 Ascorbic acid
 Calcitonin
 Estrogens
 Glucocorticoids
 Losartan
 Probenicid
 Radiocontrast agents
 Salicylates >2gm/day
 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.
 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
 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.
 Urate over producers
 Under excretors
 Combination of both
 Primary idiopathic
 HPRT deficiency, PRPP synthetase overactivity
 Hemolytic processes
 Lymphoproliferative diseases,
Myeloproliferative diseases
 Polycythemia vera
 Psoriasis, Paget's disease
 Glycogenosis III,V, andVII
 Rhabdomyolysis
 Exercise
 Alcohol, Obesity
 Purine-rich diet
 Primary idiopathic
 Renal insufficiency, Polycystic kidney disease, Diabetes
insipidus, Hypertension
 Acidosis : Lactic acidosis, Diabetic ketoacidosis, Starvation
ketosis
 Berylliosis, Sarcoidosis,
 Lead intoxication
 Hyperparathyroidism, Hypothyroidism
 Toxemia of pregnancy
 Bartter's syndrome
 Down syndrome
 Drug ingestion : Salicylates (>2 g/d), Diuretics, Alcohol,
Levodopa, Ethambutol, Pyrazinamide, Nicotinic acid,
Cyclosporine
 Glucose-6-phosphatase deficiency
 Fructose-1-phosphate aldolase deficiency
 Alcohol
 Shock
 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.
 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).
 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
 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
 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.
 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.
 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
 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.
 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.
 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.
 Physiological : pregnancy
 Pathological : SIADH, Fanconi’s syndrome
 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
 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
 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
 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
 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
 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
 Problems of tophaceous gout
 cosmetic problems,
 ulceration and superimposed
 infection,
 mechanical obstruction of joint movement,
 Bone and cartilage damage
 musculoskeletal disability
 heavy alcohol intake,
 dehydration,
 joint trauma,
 medical illness,
 surgery,
 intake of high-purine diet
 Urate lower therapy
 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
 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
 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
 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
 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
 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
 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.
 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
 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
 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
 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
 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
 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
 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
 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
 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
 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
 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
Referrences
Harrison’s 18TH edition
Oxford’s rheumatology

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Hyperuricemia and gout

  • 1. Dr. MohdViquasuddin Saim DNB General Medicine resident Medwin hospital
  • 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.
  • 13.
  • 14.  ACTH  Ascorbic acid  Calcitonin  Estrogens  Glucocorticoids  Losartan  Probenicid  Radiocontrast agents  Salicylates >2gm/day
  • 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
  • 19.  Primary idiopathic  HPRT deficiency, PRPP synthetase overactivity  Hemolytic processes  Lymphoproliferative diseases, Myeloproliferative diseases  Polycythemia vera  Psoriasis, Paget's disease  Glycogenosis III,V, andVII  Rhabdomyolysis  Exercise  Alcohol, Obesity  Purine-rich diet
  • 20.  Primary idiopathic  Renal insufficiency, Polycystic kidney disease, Diabetes insipidus, Hypertension  Acidosis : Lactic acidosis, Diabetic ketoacidosis, Starvation ketosis  Berylliosis, Sarcoidosis,  Lead intoxication  Hyperparathyroidism, Hypothyroidism  Toxemia of pregnancy  Bartter's syndrome  Down syndrome  Drug ingestion : Salicylates (>2 g/d), Diuretics, Alcohol, Levodopa, Ethambutol, Pyrazinamide, Nicotinic acid, Cyclosporine
  • 21.  Glucose-6-phosphatase deficiency  Fructose-1-phosphate aldolase deficiency  Alcohol  Shock
  • 22.
  • 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.
  • 33.  Physiological : pregnancy  Pathological : SIADH, Fanconi’s syndrome
  • 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