Metabolism of uric acid

&
Gouty arthritis

Albiner Siagian
Topik
Untuk Mengetahui:
1. Uric acid
2. Lintas Uric acid
3. Hypouricemia
4. Hyperuricemia
5. Gout
Uric acid
 Produk akhir pemecahan purin

 Urates, bentuk terionisasi dari uric acid, terutama

berada di cairan ekstraseluler plasma, sebagai
monosodium urate pada pH 7.4.
 Plasma jenuh dengan monosodium urate.

 Pada konsentrasi yang lebih tinggi, plasma yang

superjenuh, mengakibatkan potensi untuk
pengendapan kristal urate (urate crystal precipitation).
 pH of urine sangat mempengaruhi solubilitas uric acid.
Uric acid
 Bentuk terionisasi dari uric acid dalam urine termasuk
mono- and disodium, potassium, ammonium, and
calcium urates.
 Purine nucleotida disintesis dan didegradasi pada
semua jaringan
 urate dihasilkan hanya pada jaringan yang
mengandung xanthin oksidase, terutama di hati dan
usus halus
 Produksi urate bervariasi dalam kandungan purin
dalam diet, laju biosintesis purin, degradasinya.
Uric acid
 Daily synthesis 400mg

 Dietary sources 300mg

 Normal uric acid pool: 1200mg pada pria and 600mg

pada wanita, 75% diekskresi melalui urin
 Pria: 3.4–8 mg/dL Wanita: 2.4–6 mg/dL

 Peningkatan uric acid dikaitkan dengan peningkatan

katabolisme purin dan sintesis nukleoprotein ,
penurunan pencucian renal terhadap uric acid
(misalanya pada kasus gagal ginjal)
Purine biosynthesis
Purine catabolism pathway
 Uric acid
 Ginjal membersihkan urates dari plasma dan mempertahankan
keseimbangan fisiologis dengan menggunakan pengangkut anion
organik khusus (specific organic anion transporters (OATs))
termasuk urate transporter 1 (URAT1) and human uric acid
transporter (hUAT).
 Empat komponen model digunakan untuk menggambarkan
penanganan urate/uric acid oleh ginjal.
(1) Penyaringan glomelural (glomerular filtration),
(2) Reabsorbsi tubular (tubular reabsorption),
(3) Sekresi (secretion), and
(4) Reabsorbsi pascasekresi (Postsecretory reabsorption).
 HYPOURICEMIA
 Didefinisikan sebagai keadaan dengan konsentrasi urate
serum <120 mol/L (2.0 mg/dL).
 Keadaan ini dapat dihasilkan oleh penurunan produksi
urate, peningkatan sekresi uric acid, atau kombinasi
keduanya.
Penyebab:
 Hepatocellular disease with reduced purine synthesis
 Defective tubular reabsorption
 Over treatment
 Deficiency of xanthine oxidase( xanthinuria also present)
Most hypouricemia results from increased renal uric acid
excretion.
HYPOURICEMIA

 Penyebab lain, termasuk hepatic cirrhosis dan

diabetes mellitus
 Kerusakan pada renal tubular transport dan heavy
metal toxicity;
 HYPERURICEMIA
 Diartikan sebagai keadaan dengan konsentrasi plasma urate
>408 mol/L (6.8 mg/dL).
 Dapat dihasilkan dari peningkatan produksi atau penurunan
ekskresi uric acid atau kombinasi keduanya.
 Hyperuricemia yang berlanjut memprediksi untuk timbulnya
manifestasi klinis termasuk gouty arthritis, and renal
dysfunction
 Hyperuricemia hadir pada antara 2.0 dan 13.2% pada pasien
dewasa rawat jalan (ambulatory adults) dan bahkan lebih
sering pada individu yang rawat inap.
Penyebab Hyperuricemia

Dapat diklasifikasikan sebagai penyebab

primer dan sekunder bergantung pada
apakah penyebanya innate atau hasil dari
acquired disorder
 Penyebab Hyperuricemia (cont..)
1. Elevated 5-phosphoribosyl-1-pyrophosphate
synthetase (PRPP synthetase) activity.
 PRPP synthetase is responsible for the synthesis of PRPP
(activated ribose) necessary for de novo synthesis of purine
nucleotides

2. Hypoxanthine-guanine phosphoribosyl transferase

(HGPRT) deficiency.
 HGPRT enzyme involved in salvage of purine nucleotides
 Decrease salvage leads to increased metabolism
 Increased production of uric acid HGPRT, PRPP synthetase
RENAL DYSFUNCTION THAT RESULTS IN
DECREASED IN URIC ACID EXCRETION
 Uric Acid Transporter (URAT1) :

 Organic anion transporter (OAT).

 Uric acid reabsorption

 URAT 1 exchange uric acid with endogenous and

exogenous anions : e.g Lactic acid, Butyric acid,
Nicotinic acid, PZA- Polymorphisms or mutations of
the URAT1
 Uricosuric drugs: Probenecid, Benzbromarone,
Sulfinpyrazone, and losartan inhibit the uptake of
uric acid by inhibiting URAT 1
Renal insufficiency
 Gagal ginjal (renal failure) adalah salah satu penyebab
umum hiperurisemia.
 Pada kelainan ginjal tertentu, seperti medullary cystic
disease and chronic lead nephropathy, hiperurisemia
lazim terjadi meskipun pada keadaan renal insufficiency
minimal.
 Syndrome X atau sindrom metabolik yang dicirikan oleh
hipertensi, obesitas, resistnasi insulin, dislipidemia, and
hiperurisemia. Ini berkaitan dengan penurunan fraksi urat
urate yang diekskresikan oleh ginjal.
Obat-obatan
 Obat-obatan kausatif termasuk diuretik, low-dose
salicylate, cyclosporine, pyrazinamide, ethambutol,
nicotinic acid, and methoxyflurane.
 Hypertension Acidosis: Tipe yang menyebabkan
hiperurisemia termasuk lactic acidosis, diabetic
ketoacidosis, alcoholic ketoacidosis, and starvation
ketoacidosis.
 Preeclampsia and eclampsia: Peningkatan asam urat
berkaitan dengan preeclamsia dan eclamsia merupakan
tanda-tanda kunci adanya hiperuricemia karena kadar
asam urat adalah rendah pada masa hamil normal.
Overproduction :
 Idiopathic HGPRT(hypoxanthine-guanine phosphoribosyl
transferase) deficiency (Lesch-Nyhan syndrome):
 This is an inherited X-linked disorder.
 HGRPT catalyzes the conversion of hypoxanthine to inosinic
acid, in which PRPP serves as the phosphate donor. The
deficiency of HGPRT results in accumulation of PRPP, which
accelerates purine biosynthesis with a resultant increase in uric
acid production.
 In addition to gout and uric acid nephrolithiasis, these patients
develop a neurologic disorder that is characterized by
choreoathetosis, spasticity, growth, mental function retardation,
and, occasionally, self-mutilation.
 Partial deficiency of HGPRT (Kelley-Seegmiller syndrome): This
is also an X-linked disorder. Patients typically develop gouty
arthritis in the second or third decade of life, have a high
incidence of uric acid nephrolithiasis, and may have mild
neurologic deficits.
 Increased activity of PRPP synthetase:
 This is a rare X-linked disorder in which patients make mutated
PRPP synthetase enzymes with increased activity.
 These patients develop gout when aged 15-30 years and have
a high incidence of uric acid renal stones.
 Purine-rich diet: A diet rich in meats, organ foods, alcohol, and
legumes can result in an overproduction of uric acid.
 Increased nucleic acid turnover: This may be observed in
persons with hemolytic anemia and hematologic malignancies
such as lymphoma, myeloma, or leukemia.
 Tumor lysis syndrome: This may produce the most serious
complications of hyperuricemia. Glycogenoses III, V, and VII
 Ethanol increases the production of uric acid by causing increased
turnover of adenine nucleotides. It also decreases uric acid
excretion by the kidneys, which is partially due to the production of
lactic acid.
 Exercise: Exercise may result in enhanced tissue breakdown and
decreased renal excretion due to mild volume depletion.
 Deficiency of aldolase B (fructose-1-phosphate aldolase): This is a
fairly common inherited disorder, often resulting in gout.
 Glucose-6-phosphatase deficiency (glycogenosis type I, von Gierke
disease): This is an autosomal recessive disorder characterized by
the development of symptomatic hypoglycemia and hepatomegaly
within the first 12 months of life.
 Additional findings include short stature, delayed adolescence,
enlarged kidneys, hepatic adenoma, hyperuricemia, hyperlipidemia,
and increased serum lactate levels
 FRUCTOSE INDUCES AN INCREASE IN URIC
ACID :Fructose rapidly raises uric acid as a
consequence of activation of fructokinase with
ATP consumption, resulting in intracellular
phosphate depletion.
 AMP deaminase activity is stimulated by low
levels of phosphorus, resulting in greater
degradation of AMP to uric acid
 Fructose also competes for uric acid excretion
 GOUT: THE PROTOTYPICAL CRYSTAL
DEPOSITION ARTHROPATHY
Monosodium
Urate
Crystal
Gout arthritis:
 Classic example of crystal-induced inflammation
of synovial joints.
 It is a common condition, presenting in 1–4% of
adult men.
 precipitation of monosodium urate in tissues
and joints eliciting an intense inflammatory
response.
 Gout
 Elevated uric acid levels in the blood

 Uric acid crystals will form in the extremities

with a surrounding area of inflammation. This is
called a tophus and is often described as an
arthritic “great toe”.
 Can be caused by a defect in an enzyme of
purine metabolism or by reduced secretion of
uric acid into the urinary tract.
 Deposition of monosodium urate crystals in the
joint space leads to episodes of severe acute
joint pain and swelling (particularly in the great
toe, midfoot, ankle, and knee). These episodes
tend to resolve completely and spontaneously tophus
within a week even without treatment.
 Gouty arthritis
 Crystals of monosodium urate free in the joint
activate a number of inflammatory pathways.
 The crystals are coated with immunoglobin G
(IgG), which activates complement. Similarly, the
kallikrein system is activated. As a result, there is
vasodilatation and influx of neutrophils.
 Phagocytosed uric acid crystals stimulate
neutrophils to release prostaglandins and
lysosomal enzymes and induce oxidant
production.
 Gouty Arthritis
 Further, neutrophils are unable to digest the
phagocytosed urate crystal, which ultimately results in
lysosomal rupture, cell death, and spillage of cellular
contents extracellularly.
 Simultaneously, free uric acid crystals activate
mononuclear cells and synoviocytes with the
production of inflammatory cytokines, including
interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha,
which account for some of the systemic symptoms seen
particularly in recurrent attacks of gout.
 Factors posited as reasons for
involvement of the lower extremity
 Uric acid solubility is temperature dependent and
thus colder peripheral joints would be less likely to
maintain its solubility. Further, hyaluronic acid, a
major component of articular cartilage, increases
the solubility of uric acid.
 Finally, it has been suggested that, with ambulation,
the simple trauma causes fluid to enter the joint. At
night, water is more rapidly absorbed from the joint
than uric acid, increasing the concentration of uric
acid, thus potentially causing its precipitation and
triggering an attack.