Hyperuricemia

1
Hyperuricemia
Wednesday March 19, 2008

• Jennifer Chow (jennifer.chow_at_utoronto.ca)
• Jennifer Kwong (jennifer.kwong_at_utoronto.ca)
• Karen Li (karenhokyee.li_at_utoronto.ca)
• Melissa Tam (melly.tam_at_utoronto.ca)

2
Hyperuricemia

• The condition when there are high concentrations
  of uric acid in the blood.
• Serum levels of uric acid are gt7mg/dL (Normally,
  2.4-6mg/dL in females 3.4-7mg/dL in males)
• At such a high level, uric acid tends to
  aggregate and form crystals
• Primary Hyperuricemia an innate defect in purine
  metabolism and/or uric acid excretion
• Secondary Hyperuricemia high uric acid levels
  due to medications/medical conditions such as
  diabetic ketoacidosis, psoriasis, chronic lead
  poisoning
• Uric acid can accumulate due to
• Overproduction of purine nucleotides
• Enhanced cell turnover ( ? purine degradation)
• Decreased in purine salvage pathway
• Underexcretion of uric acid
• Predisposition to many diseases
• People may live with elevated uric acid levels
  without experiencing any symptoms

Source Rubin R, Strayer DS. 2007. Rubins
Pathology Clinicopathologic Foundations of
Medicine. 5th ed. USA Lippincott Williams
Wilkins p 1142
3
Uric Acid

• Uric acid is the end product in purine metabolism
• Excretion of uric acid removes nitrogenous wastes
  from body
• An effective scavenger of ROS maybe as
  effective as vitamin C as an antioxidant
• 2/3 of uric acid made is excreted via kidneys
  1/3 via GI tract
• Urate protonated form of uric acid
• Purine Metabolism
• De novo pathway synthesis of purines from
  nonpurine precursors
• Salvage pathway purines are reconverted to their
  corresponding nucleotides

Source http//www.med.unibs.it/marchesi/nucmetab
.html
4
What Causes Hyperuricemia?

• Overproduction of uric acid (10)

• Exogenous (diet rich in purines)
• Endogenous (accelerated purine degradation)
• a) rapid cell proliferation and turnover
  (leukemia,
• hemolytic anemia)
• b) cell death (cytotoxic therapy)
• Enzyme Activity
• A small percentage may be due to enzyme
  deficiency or mutations that are genetically
  determined PRPP Synthetase and HGPRT

5
What Causes Hyperuricemia?
PRPP Synthetase Overactivity

• X-linked enzyme disorder
• Intracellular concentrations of
  5-phosphoribosyl-1-pyrophosphate (PRPP) is the
  major rate-limiting step in uric acid synthesis
• Increased activity of PRPP Synthetase leads to an
  overproduction of PRPP, which accelerates purine
  biosynthesis (and subsequent degradation), which
  results in uric acid overproduction

Source http//seqcore.brcf.med.umich.edu/mcb500/n
ucsyl/nucmetab.html
6
What Causes Hyperuricemia?
Source http//www.macaulay.ac.uk/IFRU/iaeacd/html
/techdoc/html/02_2.htm
7
What Causes Hyperuricemia?
HGPRT (hypoxanthine guanine phosphoribosyl
transferase)

• X-linked enzyme disorder
• HGPRT catalyses conversion of hypoxanthine to
  inosine monophosphate (IMP), where PRPP is the
  phosphate donor
• Deficiency of HGPRT leads to accumulation of
  PRPP, which results in accelerated purine
  biosynthesis, and subsequently increased uric
  acid levels

(HGPRT)
IMP
Source http//seqcore.brcf.med.umich.edu/mcb500/n
ucsyl/nucmetab.html
8
What Causes Hyperuricemia?

• Underexcretion of uric acid (90)

• Accounts for most causes of hyperuricemia
• Normally
• 98 - 100 of uric acid is reabsorbed in the
  proximal region of the proximal convoluted tubule
• 50 of the original amount is secreted into the
  distal portion of the proximal convoluted tubule,
  but 40 - 44 is subsequently reabsorbed, and 6 -
  12 of the original glomerular filtrate
  eventually excreted

9
What Causes Hyperuricemia?

• Underexcretion of Uric Acid
• Impaired renal function reduced clearance or
  reduced fractional excretion by kidneys
• Result from decreased glomerular filtration,
  decreased tubular secretion, or enhanced tubular
  reabsorption
• Urate transporters in kidney
• URAT1 urate/anion exchanger in brush-border
  membrane of kidney
• hOAT1 human organic anion transporter
  (inhibited by uricosuric
  
  drugs)
• UAT urate transporter that facilitates
  urate efflux out of cells
• These transporters may account for the renal
  reabsorption and
• secretion of urate
• Decreased secretion of urate occurs in patients
  with acidosis (ie. diabetic ketoacidosis, ethanol
  intoxication, starvation ketosis) because the
  organic acids that accumulate in these conditions
  compete with urate for tubular secretion

10
What Causes Hyperuricemia?
Alcohol consumption

• Ethanol
• Enhanced adenine nucleotide degradation
• Increased hypoxanthine levels increased uric
  acid production
• Increased lactic acid levels
• Decreased uric acid excretion
• Lactic acid competitively competes with urate for
  renal tubular secretion

11
What Causes Hyperuricemia?
Aldolase-B Enzyme Deficiency

• Aldolase B is responsible for the formation of
  dihydroxyacetone-P and glyderaldehyde from
  fructose-1 phosphate in glycolysis
• Aldolase B deficiency leads to accumulation of
  fructose-1 phosphate, hence the trapping of
  phosphate, making it unavailable to form ATP from
  ADP therefore AMP accumulates
• Excess AMP is broken down to uric acid

12
What Causes Hyperuricemia?
Source http//www.macaulay.ac.uk/IFRU/iaeacd/html
/techdoc/html/02_2.htm

• AMP ? Inosine ? Hypoxanthine ? Xanthine ? Uric
  acid
• GMP ? Guanosine ? Guanine ? Xanthine ? Uric acid

13
What Causes Hyperuricemia?

• Glucose-6-phosphatase enzymatic deficiency
• Glycogenosis type 1, von Gierkes diseases
• Decreased renal urate secretion as a consequence
  of lactic acidosis
• Increased de novo synthesis of purines because of
  excessive production of ribose-5-phosphate (due
  to shunting of glucose-6-phosphate through the
  pentose phosphate pathway)
• Accelerated ATP degradation uric acid
  overproduction

PRPP Synthetase
ribose-5-phosphate ATP -------------------------
-----? PRPP AMP
14
Related Conditions

• Gout
• Kidney Stones
• Lesch-Nyhan Syndrome

Source http//en.wikipedia.org/wiki/Gout
15
Related Conditions

• Gout
• An extremely painful condition of the joints
• Symptoms
• Most common in the big toe (affects gt90 of
  people affected, at some time)
• Other locations such as ankles, knees, wrists,
  fingers, and elbows are commonly involved as
  well.
• The area is red, swollen, and warm.
• Cause
• Monosodium urate crystals are deposited in the
  joints. This produces an immune response that
  results in inflammation and pain.

16
Related Conditions

• Gout
• Diagnosis is confirmed by the discovery of urate
  crystals in the synovial fluid of the joint
  crystals are needle-shaped
• Gout is easily diagnosed by light microscopy, and
  is readily treatable

Source http//www.nlm.nih.gov/medlineplus/ency/im
agepages/1222.htm
17
Related Conditions

• Kidney Stones
• An accumulation of urate salt in the kidneys
• Symptoms
• Its presence may be asymptomatic until a stone
  causes pain as it begins to travel down the
  ureter during urination.
• Abdominal pain, back pain, blood in the urine,
  frequent urination, and fever may also occur.
• Cause
• When uric acid is present in high concentrations
  in the blood, it may precipitate as a salt in the
  kidneys. The salt can form stones, which can in
  turn cause pain, infection, and kidney damage.

18
Related Conditions

• Kidney Stones

• The stones do not normally cause any damage, but
  in serious cases, may need to be removed
  surgically
• It is important to determine the cause of
  hyperuricemia, and to treat the cause, or the
  kidney stones will recur

Source http//www.nlm.nih.gov/medlineplus/ency/im
agepages/17091.htm
19
Related Conditions

• Lesch-Nyhan Syndrome
• A genetic, sex-linked condition
• Symptoms
• Characterized by mental deficiency, aggression,
  and compulsive, self-destructive behaviour
• Affected children will begin to chew their
  fingers and lips beginning around the age of 2 or
  3 years, and unless restrained, will chew them
  off
• Cause
• An almost total lack of hypoxanthine-guanine
  phosphoribosyltransferase leads to an increased
  concentration of PRPP.
• This increases purine synthesis, which leads to
  an increase in uric acid production. The reason
  for the resulting behaviour is unknown.
• Since high urate levels are present in the
  blood, individuals with this condition are also
  prone to gout and kidney stones.

20
Pharmacologic Therapy for Hyperuricemia

• Drugs are the mainstay in the treatment of
  hyperuricemia
• Effects are to reduce the level of uric acid
• Indicated when
• The cause of hyperuricemia cannot be corrected.
  Even if corrected, does not lower the serum urate
  concentration to lt 7mg/dL
• Patient has had 2-3 attacks of gout or has tophi

21
Pharmacologic Therapy for Hyperuricemia
Uricosurics

• eg. probenecid (Benemid) and sulfinpyrazone
  (Anturane)
• Block uric acid reabsorption at the proximal
  convoluted tubule, thereby increasing the rate of
  uric acid excretion
• Contraindicated in patients with urinary tract
  stones
• Aspirin and other salicylates antagonize the
  action of uricosurics
• Adverse effects GI upset, renal dysfunction,
  hypersensitivity reactions

Source Golan DE. 2007. Physiology of Purine
Metabolism. Principles of Pharmacology The
Pathophysiologic Basis of Drug Therapy. 2nd
Edition. Lippincott Williams Wilkins
22
Pharmacologic Therapy for Hyperuricemia
Xanthine Oxidase Inhibitors

• Only one available on the US market is
  allopurinol
• Reduces uric acid production
• Xanthine oxidase catalyzes the final step in the
  degradation of purines to uric acid
• Allopurinol and its long-acting metabolite,
  oxypurinol, block the conversion of xanthine to
  uric acid by inhibiting xanthine oxidase
• Most common adverse effect is rash (2)
  increases to 20 if patient is taking ampicillin
  at the same time

Source Golan DE. 2007. Physiology of Purine
Metabolism. Principles of Pharmacology The
Pathophysiologic Basis of Drug Therapy. 2nd
Edition. Lippincott Williams Wilkins
23
Non-Pharmacologic Therapy for Hyperuricemia

• Low purine diet is commonly recommended
• Avoid caffeine and alcohol
• Foods that are high in purine include
• Red meat and organ meats (eg. liver)
• Yeasts and yeast extracts (eg. beer and alcoholic
  beverages)
• Asparagus, spinach, beans, peas, lentils,
  oatmeal, cauliflower and mushrooms
• Foods that are low in purine include
• Refined cereals - bread, pasta, flour, cakes
• Milk and milk products, eggs
• Lettuce, tomatoes, green vegetables
• Cream soups without meat stock

24
Counseling the Patient

• Keep well hydrated, drink 2 to 3 liters of water
  per day
• Take medications for hyperuricemia as directed
• Avoid the use of diuretics (eg.
  hydrochlorothiazide, furosemide)
• Caution patients who are taking niacin and low
  doses of aspirin (lt 3g per day) since these drugs
  can aggravate uric acid levels

25
Summary

• Hyperuricemia occurs when serum levels of uric
  acid exceeds 7mg/dL
• Many people may live many years with elevated
  uric acid levels without ever experiencing
  symptoms
• Hyperuricemia can be caused by
• Overproduction of Uric Acid (10) enzymatic
  deficiencies in PRPP Synthetase and HGPRT
• Underexcretion of Uric Acid (90) renal
  impairment
• Alcohol Consumption
• Aldolase-B Enzyme Deficiency
• Accelerated ATP breakdown glucose-6-phosphatase
  deficiency
• Hyperuricemia increases the risk of gout, kidney
  stones and Lesch-Nyhan Syndrome
• Pharmacologic treatments of hyperuricemia act to
  lower uric acid levels
• Uricosurics enhance uric acid excretion
• Xanthine Oxidase Inhibitors decrease uric acid
  production by blocking the conversion of xanthine
  to uric acid
• Non-pharmacologic treatments include following a
  low purine diet and avoiding caffeine and alcohol

26
References

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