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Chemical Pathology > Purin And Urate Metabolism > Flashcards

Purin And Urate Metabolism Flashcards

1
Q

What are purines and Pyrimidines?

A

They are nitrogenous bases that make up the two different nucleotides in DNA and RNA.

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2
Q

Structure of purines

A

imidazole ring fusing with a pyrimidine ring to make up
- nucleic acids (DNA and RNA)
- certain alkaloids (caffeine and theophylline).

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3
Q

Examples of purines?

A
  • nitrogenous bases (nucleobases) like adenine and guanine
  • caffeine
  • xanthine
  • hypoxanthine
  • uric acid
  • theobromine.
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4
Q

Adenine is a type of purine that pairs complementary with ?

A

DNA - Adenine complementary pairs with thymine
RNA - Adenine complementary pairs with uracil

Two hydrogen bonds.

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5
Q

Guanine is a purine that complementary pairs with?

A

Guanine to cytosine in both DNA and RNA

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6
Q

How to differentiate adenine from guanine based on structure?

A

Adenine can be distinguished from guanine by

  • its amine group at position 6
  • the presence of an additional double bond between N-1 and C-6 in its heterocyclic aromatic ring.
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7
Q

biosynthesis of purines occurs where?

A

in the cytosol of the liver cell.

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8
Q

Degradation of guanine process?

A
  • Guanine (via guanase) » xanthine
  • Xanthine (via xanthine oxidase) » uric acid
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9
Q

Degradation of Adenine steps?

A
  • Adenosine »» inosine (via purine nucleoside phosphorylase)
  • inosine » hypoxanthine
  • Hypoxanthine » xanthine (via **xanthine oxidase)
  • Xanthine » Uric acid (via xanthine oxidase)
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10
Q

Exogenous purines can be obtained from?

A

Dietary sources like
- meat and meat products
- seafood
- mushrooms
- spinach
- cauliflower
- wheat bran
- beans

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11
Q

The end product of purine metabolism is ?

A

The formation of urine acid

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12
Q

Functions of purines?

A
  • Purines serve as structural constituents of DNA and RNA.
  • They are also important components of certain proteins and starches
  • They are also involved in the regulation of enzymes and cell signaling
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13
Q

Why are humans prone to clinical effects of hyperuricemia?

A
  • Because humans lack Uricase, so they cannot breakdown Uric acid to allontoin
  • Also, because of the poor solubility of uric acid, it tends to accumulate and cause conditions like gout, and renal damage
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14
Q

What amount of purine is produced endogenously per day ?

A
  • About two-thirds of the body’s urate (3-4 mmol/day) is produced endogenously,
  • one-third coming from exogenous dietary purines (1-2 mmol/day)
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15
Q

The first step In the synthesis of purine is?

A

The condensation of
pyrophosphate + ribosephosphate
= Phosphoribose diphosphate

AKA Phosphoribosylpyrophosphate (PRPP)

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16
Q

After the formation of PRPP, what’s the next step ?

A

The Amino group of glutamine is incorporated into the ribose phosphate molecule and pyrophosphate is released.

phosphoribosylamine is formed

Then Glycine is added to this molecule

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17
Q

What enzyme catalyzes the rate limiting step

A

Amidophosphoribosyl transferase

  • Inhibited by purine nucleotides
  • purine ribonucleotides (purine ribose phosphates) are formed, which control this second step in the synthetic pathway
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18
Q

Rough summary of how gout develops based on your knowledge of the purine pathway?

A
  • control of the RLS is inhibited in gout, hence there’s no feedback inhibition and purines just keep on being produced and subsequently accumulates
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19
Q

What is the fate of purine in the body?

A

Purines gotten from;
- synthesis in the body
- those derived from the diet
- those liberated by endogenous catabolism of nucleic acids

may be
- oxidized to urate
- reused for nucleic acid synthesis ; Some xanthine, hypoxanthine and guanine can be resynthesized to purine

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20
Q

The formation of Uric acid (urate) depends on the activity of what enzyme?

A

xanthine oxidase activity:

The oxidation of both hypoxanthine and xanthine is catalysed by xanthine oxidase in the liver to Uric acid.

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21
Q

How is gout treated, based on your knowledge of the pathway now ?

A

inhibition of xanthine oxidase - Using allopurinol

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22
Q

Renal handling of urate ?

A
  • Urate is filtered through the glomeruli
  • most is reabsorbed in the proximal tubules.
  • More than 80% of that formed in urine is derived from more distal tubular secretion
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23
Q

Urinary excretion of urate is lower in which gender ? The hat is the implication?

A
  • Urinary excretion is slightly lower in males
  • which may contribute to the higher incidence of hyperuricaemia in men.
24
Q
A

Renal secretion may be enhanced by uricosuric drugs (e.g. probenecid or sulfinpyrazone), which block tubular urate reabsorption.
•Tubular secretion of urates is inhibited by organic acids, such as lactic and oxoacids, and by ketones and thiazide diuretics.

25
Q

About 75% of urate leaving the body is in urine. The remaining 25% ??

A
  • passes into the intestinal lumen, where it is broken down by intestinal bacteria, the process being known as uricolysis.
26
Q

Hyperuricemia is defined as?

A

serum urate concentration > 6.8 mg/dl

27
Q

Hyperuricemia causes?

A

can occur by two main mechanisms:
- Increased production (overproducers)
- Decreased excretion (underexcretors).

28
Q

Factors that can predispose to hyperuricemia ?

A
  • increased synthesis of purines
  • increased intake of purines
  • increased turnover of nucleic acids
  • increased rate of urate formation
  • reduced rate of urate excretion
29
Q

The most important mechanism causing primary hyperuricemia is ?

A

Increased synthesis due to impaired feedback control

whereas abnormalities of the other steps are causes of secondary hyperuricaemia

30
Q

Ionization of Urate ?

A
  • Urate is poorly soluble in plasma
  • At plasma pH, most urate is ionized at position 8 of the purine ring.
  • Ionization of uric acid decreases as the pH falls (at pH becomes acidic) and it therefore becomes less soluble;

at a urinary pH below about 6, uric acid may form renal calculi

31
Q

Consequences of hyperuricemia

A
  • Crystallization in joints, especially those of the feet, produces the classic picture of gout.
  • Urate precipitation at these sites causes an inflammatory response with leucocytic infiltration
  • It is thought that lactic acid production by these cells causes a local fall in pH (acidic): this converts urate to uric acid, which is less soluble than urate

A vicious circle is set up in which further precipitation, and therefore further inflammation, occurs.

32
Q

Plasma urate concentration is abnormal in acute attacks of gouty arthritis? T/F

A

False

It is normal

33
Q

What is gouty tophi?

A
  • Precipitation of urate may occur in subcutaneous tissues, especially of the ears, and in the olecranon and patellar bursae and tendons.
  • Deposits are called Gouty Tophi
34
Q

Can Uric acid deposit in the kidneys ?

A
  • A potentially serious effect of hyperuricaemia is precipitation of urate in the kidneys and renal calculi, causing progressive renal damage.
  • Thus, it has been recommended that even asymptomatic cases should probably be treated if the plasma urate concentration is consistently higher than 600 µmol/L.
35
Q

What is Gout - overview?

A
  • Gout is a form of arthritis.
  • It is a disease that occurs in response to the presence of monosodium urate crystals in joints, bones and soft tissues.
  • It causes pain and swelling in the joints.
  • Gout develops in some people with hyperuricaemia
  • Urate can form crystals that build up in different parts of the body, causing symptoms.
  • In some people, uric acid crystals may form that can lead to kidney stones and other problems with kidney function.
36
Q

Everyone with hyperuricemia will have gout?

A

False

  • Not everyone with hyperuricemia develops gout; up to two-thirds of people with hyperuricemia never have any symptoms
37
Q

The clinical manifestation of gout are ?

A
  • recurrent flares of inflammatory arthritis (a gout flare)
  • chronic arthritis (chronic gouty arthritis)
  • tophi ( tophaceous gout)
  • Uric acid nephrolithiasis.
38
Q

Gout usually develops in adulthood and is rare in children. T/F?

A

True

Gout usually develops in adulthood and is rare in children.
- It develops earlier in adult men (between the ages of 30 and 45) than in women (after age 55).
- It is particularly common in people older than 65 regardless of gender.

39
Q

Risk factors for Gout ?

A
  • Obesity
  • High blood pressure
  • Chronic kidney disease
  • Overeating or prolonged fasting
  • Consuming excessive amounts of alcohol (particularly beer, whiskey, gin, vodka, and rum and other spirits) on a regular basis
  • Consuming large amounts of meat or seafood
  • Consuming beverages containing high fructose corn syrup (such as non-diet sodas)
  • Taking medications that affect blood levels of urate (especially diuretics)
40
Q

Phases of Gout ?

A

There are three main phases of gout:
1) gout flare
2) intercritical gout
3) tophaceous gout.

1) Gout flare: Initial gout flares usually involve a single joint, most often the big toe or knee.
- Overtime, flares can begin to involve multiple joints at once and may be accompanied by fever.
- People with osteoarthritis in their fingers may experience their first gout flares in the fingers rather than the toes or knees.

2) Intercritical gout: The time between gout flares is known as an “intercritical” period.
- A second gout flare typically occurs within two years, and additional gout flares may occur thereafter.
- If gout is untreated over a period of several years, the time between gout flares may shorten, and gout flares may become increasingly severe and prolonged and involve multiple joints.

3) Tophaceous gout: People who have repeated gout flares or persistent hyperuricemia for many years can develop tophaceous rate Crystals in masses called ophi
- This term describes the accumulation of large numbers

  • People with this form of gout develop tophi in joints, bursae (the fluid-filled sacs that cushion and protect tissues), bones and cartilage, or under the skin.
  • Tophi may cause erosion of the bone and eventually joint damage and deformity (called gouty arthropathy).
41
Q

Gout diagnosis?

A
  • Gout is strongly suspected if a person has one or more acute attacks of intermittent and sudden joint pain, followed by a period in which there are no symptoms but there is persistent hyperuricaemia.
  • Examination of the synovial fluid from the lining of the affected joint under a microscope to look for urate crystals.
  • Tophi located just beneath the skin can also be sampled with a needle to diagnose tophaceous gout.
  • If it is not possible to do a synovial fluid analysis;

patient’s symptoms, physical exam, and blood test results should be used for diagnosis.

42
Q

Treatment of Gout??

A
  • NSAIDS
  • glucocorticoid
  • colchicine
  • Allupurinol
43
Q

Primary Hyperuricemia

A

INCIDENCE
- Familial incidence: involving abnormalities of urate metabolic pathways.
- Sex and age incidence: Primary hyperuricaemia and gout are very rare in children and unusual in women of child-bearing age.

  • Plasma urate concentrations are low in children and rise in both sexes at puberty.
  • concentrations are higher in males.
  • Women become more prone to hyperuricaemia and gout in the post-menopausal period.

Precipitating factors:
- A high-meat diet contains a relatively high proportion of purines.
- Alcohol has been shown to decrease renal excretion of urate. This may be because it increases lactic acid

44
Q

BIOCHEMICAL DEFECTS IN PRIMARY HYPERURICAEMIA

A
  • Purine synthesis is increased in about 25% of cases of primary hyperuricaemia due to overactivity of amidophosphoribosyl transferase, which controls the formation of phosphoribosylamine
  • Reduced renal tubular secretion of urate has also been demonstrated in other cases of primary hyperuricaemia.
  • Many subjects may have both increased synthesis and decreased excretion
45
Q

JUVENILE HYPERURICAEMIA

A
  • Lesch–Nyhan syndrome: is a rare X-linked, recessively inherited disorder of urate metabolism caused by a reduced activity of HGPRT.
    •Severe hyperuricaemia occurs in young male children.
  • Hypoxanthine and other purines cannot be recycled to form purine nucleotides, and probably produce more urate.
  • The syndrome is associated with mental deficiency, a tendency to self-mutilation, aggressive behaviour, athetosis and spastic paraplegia.
  • Hyperuricaemia can also occur with increased 5-PRPP synthase activity
46
Q

SECONDARY HYPERURICAEMIA

A

High plasma urate concentrations may be secondary to the following:
1) Increased turnover of nucleic acids due to:
- rapidly growing malignant tissue, especially in leukaemias, lymphomas and polycythaemia rubra vera.
- psoriasis, when turnover of skin cells is increased.
- following increased tissue breakdown – after treatment of large malignant tumors with radiotherapy or cytotoxic drugs (tumor lysis syndrome).
This can cause massive sudden release of urate, which may crystallize in and block renal tubules causing acute oliguric renal dysfunction. During such treatment, allopurinol should be given.

47
Q

Familial juvenile gouty nephropathy?

A
  • is a rare autosomal dominant condition leading to progressive renal failure.
48
Q

Kelley–Seegmiller syndrome causes ?

A

Partial deficiency of HGPRT

49
Q

Causes of secondary hyperuricemia?

A

Starvation or prolonged fasting: the patient’s own tissues may be used as an energy source, with increased urate release.
- Starvation may be associated with mild ketoacidosis and protein catabolism releases acidic amino acid residues.
- The acidosis by inhibiting the secretion of urate, may aggravate the hyperuricaemia.
- During prolonged fasting, plasma urate concentrations may rise.

2) Reduced excretion of urate: which may be due to medication use like thiazide diuretics, ciclosporin, nicotinic acid, methoxyflurane, levodopa, ethambutol and pyrazinamide

➢Renal glomerular dysfunction
➢Prolonged metabolic acidosis
➢Chronic lead intoxication.

50
Q

Combined (both increased production and reduced excretion)
causes

A
  • High alcohol intake.
  • Prolonged and severe exercise.
  • Dyslipidaemia and impaired glucose tolerance or type 2 diabetes mellitus.
  • Hyperuricaemia is associated with insulin resistance and the metabolic syndrome.
  • Glucose-6-phosphatase deficiency or von Gierke’s disease.
51
Q

PRINCIPLES OF TREATMENT OF HYPERURICAEMIA

A
  • Reducing dietary purine intake for example red meats. This treatment is rarely effective by itself.
  • An **acute attack of gout can be treated with a nonsteroidal anti-inflammatory drug (NSAID) **or sometimes steroids.
  • Colchicine, which has an anti-inflammatory effect and inhibits neutrophil activation, can be used in acute gouty arthritis but does not affect urate metabolism. It is sometimes used if NSAIDs are contraindicated.
    •Reducing urate production by using drugs that inhibit xanthine oxidase activity, such as allopurinol
  • Febuxostat is a noncompetitive inhibitor of xanthine oxidase
    and may have a place in those intolerant to allopurinol.

These drugs may be effective if renal function is normal, but are less so if there is renal glomerular dystunction. Fluid intake is usually kept high. Low doses ot most uricosuric drugs reduce rate secretion; they are rarely used unless allopurinol is contraindicated.

52
Q

INVESTIGATION OF HYPERURICAEMIA

A
  • A careful drug history is important, as various drugs such as thiazide diuretics, can evoke hyperuricaemia, as well as a high alcohol intake.
  • A family history may reveal a primary hereditary form of gout or hyperuricaemia.
  • Renal function is assessed by assaying plasma urea and creatinine, as renal impairment is a common cause of hyperuricaemia.
  • A spot urinary urate to creatinine concentration ratio may help to distinguish hyperuricaemia due to reduced renal excretion from renal impairment secondary to hyperuricaemia.
  • A 24-h urine analysis for urate excretion on and off a low-purine diet may give an indication of whether the patient is an overproducer or underexcretor of urate.
53
Q

CAUSES OF LOW PLASMA URATE CONCENTRATIONS (HYPOURICAEMIA)?

A
  • This is rare
  • it is the result of the treatment of hyperuricaemia with eg allopurinol or probenecid
  • It is associated with proximal renal tubular damage, in which the reabsorption of urate is reduced, and can be seen in Fanconi’s syndrome.
  • Hypouricaemia is also a finding in some patients receiving parenteral nutrition and in pregnancy, the syndrome of inappropriate antidiuretic hormone (SIADH) and type 1 diabetes mellitus.
54
Q

XANTHINURIA

A
  • This is a very rare inborn error of purine metabolism, inherited as an autosomal recessive disorder, in which there is a deficiency of xanthine oxidase in the liver.
  • Purine breakdown stops at the xanthine–hypoxanthine stage
  • plasma and urinary urate concentrations are very low
  • Increased xanthine excretion may lead to the formation of xanthine stones.
  • This does not occur during the treatment of gout with xanthine oxidase inhibitors because the drugs also inhibit purine synthesis
55
Q

MOA of allopurinol

A

hydroxypyrazolopyrimidine), which is structurally similar to hypoxanthine, so acting as a competitive inhibitor of the enzyme. De novo synthesis may also be decreased by this drug.
- However, allopurinol may worsen an acute attack of gout.
- Initiation of allopurinol should be made a few weeks after the acute attack under the cover of an NSAID, assuming that it is not contraindicated.

56
Q

Glucose-6-phosphatase deficiency causes hyperuricemia how?

A
  • The tendency to hyperuricaemia in these patients may be directly related to the inability to convert glucose-6- phosphate (G6P) to glucose. More G6P is available for metabolism through other intracellular pathways like:
    a) the pentose phosphate pathway which increases ribose phosphate (phosphoribose) synthesis;
    this may accelerate the first step in purine synthesis, with consequent urate overproduction.
    b) glycolysis which causes increased lactic acid production and lactic acid may reduce renal urate excretion.

Chemical Pathology (8 decks)

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