Monday, March 29, 2021

Gout Case File

Posted By: Medical Group - 3/29/2021 Post Author : Medical Group Post Date : Monday, March 29, 2021 Post Time : 3/29/2021
Gout Case File
Eugene C.Toy, MD, William E. Seifert, Jr., PHD, Henry W. Strobel, PHD, Konrad P. Harms, MD

CASE 43
A 46-year-old male presents to the emergency department with severe right toe pain. The patient was in usual state of health until early in the morning when he woke up with severe pain in his right big toe. The patient denies any trauma to the toe and no previous history of such pain in other joints. He did say that he had a “few too many” beers with the guys last night. On examination, he was found to have a temperature of 38.2°C (100.8°F) and in moderate distress secondary to the pain in his right toe. The right big toe was swollen, warm, red, and exquisitely tender. The remainder of the examination was normal. Synovial fluid was obtained and revealed rod- or needle-shaped crystals that were negatively birefringent under polarizing microscopy, consistent with gout.

◆ What is the likely diagnosis?

◆ How would you make a definite diagnosis?

◆ What is the pathophysiology of this disorder?


ANSWERS TO CASE 43: GOUT

Summary: A 47-year-old male presents with an acute onset of right toe pain in the middle of night after drinking alcohol and no history of trauma or any other joint pain.

Diagnosis: Gouty arthritis.

Confirming diagnosis: Demonstration of the presence of the monosodium urate crystals within the synovial leukocytes or in material derived from tophi under polarizing microscopy.

Pathophysiology: Increased conversion of purine bases to uric acid or a decreased excretion of uric acid by the kidney. Elevated levels of the insoluble uric acid result in precipitation of urate crystals in the joints.


CLINICAL CORRELATION
Gout is a disorder that occurs when uric acid crystallizes in the joints of the body, usually the great toe or large joints. Hyperuricemia is a clinical condition characterized by elevated levels of uric acid. This leads to the formation of sodium urate crystals, which are found primarily in the joints of the extremities and in the renal interstitium. The presence of urate crystals is associated with extreme swelling and tenderness in the joints of the extremities. This condition is often referred to as gout or gouty arthritis. In this condition, elevated levels of uric acid are detectable in the blood and urine, and definitive diagnosis can be made by observing the presence of urate crystals in synovial fluid removed from affected joints. The preference of urate crystal formation in the joints of the extremities, such as the big toe, is thought to be associated with the decreased temperature of the extremities that aids in urate crystal formation when levels exceed solubility.


APPROACH TO URIC ACID CRYSTALLIZATION

Objectives

1. Be familiar with the uric acid pathway.
2. Know about purine base metabolism.
3. Be aware of treatment of gout with allopurinol and colchicine.


Definitions

Allopurinol: An inhibitor of the enzyme xanthine oxidase used to treat gout to decrease the amount of sodium urate in the blood and thus prevent its crystallization in the joints.
Colchicine: A tricyclic, water-soluble alkaloid isolated from the autumn crocus. Colchicine will inhibit microtubule formation and inhibit phagocytosis of urate crystals, thus preventing the inflammatory events associated with a gouty attack.
Gout: An inflammatory event triggered by the crystallization of sodium urate crystals in the joints as a result of increased levels of sodium urate in the blood.
HGPRT: Hypoxanthine-guanine phosphoribosyltransferase; the enzyme that catalyzes the synthesis of inosine monophosphate (IMP) and guanosine monophosphate (GMP) from hypoxanthine and guanine, respectively. It makes up part of the purine salvage pathway, a way of recycling purine bases back to the nucleotides.
Lesch-Nyhan syndrome: A genetic disease caused by a deficiency in HGPRT that is characterized by mental retardation and self-destructive behavior. Lesch-Nyhan patients have increased levels of uric acid and sodium urate that lead to gout and kidney stones.
Purine salvage pathway: The synthesis of purine nucleotides by the condensation of the purine bases with phosphoribosyl pyrophosphate. As the name suggests, it is a way in which purine bases can be recycled back to nucleotides. The purine salvage pathway consists of two enzymes, HGPRT and adenine phosphoribosyltransferase (APRT).
Uric acid: The final product in the degradation of purine nucleotides in human metabolism. The salt form of uric acid, sodium urate, is present at about saturation levels in the bloodstream. When sodium urate levels increase above this point, it can crystallize into sharp crystals, usually in the joints where the temperature is lower.
Xanthine oxidase: The enzyme that catalyzes the final steps in purine degradation to produce urate. This enzyme is inhibited by compounds such as allopurinol in treatment regimens designed to decrease sodium urate concentrations in the blood.


DISCUSSION

Purine bases are used in many important biological processes including the formation of nucleic acids (ribonucleic acid [RNA] and deoxyribonucleic acid [DNA]), energy currency (adenosine triphosphate [ATP]), cofactors (nicotinamide adenine dinucleotide [NAD], flavin adenine dinucleotide [FAD]), and cellular signaling (guanosine triphosphate [GTP], ATP, adenosine). Purines are both synthesized de novo and taken in through the diet. Their degradation is a ubiquitous process; however, increased levels of the enzymes that carry out the metabolism of purine bases suggest that purine catabolism is higher in the liver and the gastrointestinal tract. Abnormalities in purine biosynthesis and degradation are associated with numerous disorders suggesting that the regulation of purine levels is essential.

Degradation of purine nucleotides, nucleosides and bases follow a common pathway (Figure 43-1). During purine catabolism, the purine nucleotides

Purine catabolic pathway

Figure 43-1. Purine catabolic pathway. The enzyme steps inhibited by allopurinol are indicated.

adenosine monophosphate (AMP) and GMP are generated from the dephosphorylation of ATP and GTP, respectively. AMP is then deaminated to IMP by AMP deaminase. Subsequently, GMP and IMP are dephosphorylated by specific nucleotidases to produce the nucleosides inosine and guanosine. Alternatively, AMP can be dephosphorylated to form adenosine, which is then deaminated by adenosine deaminase (ADA) to form inosine. Inosine and guanosine are further broken down by the cleavage of the purine base from the ribose sugar to yield ribose 1-phosphate and hypoxanthine and guanine, respectively. Similar reactions are carried out for the degradation of purine deoxyribonucleotides and deoxyribonucleosides. Guanine is deaminated to form xanthine, whereas hypoxanthine is oxidized to form xanthine by the enzyme xanthine oxidase. Xanthine is further oxidized, again by xanthine oxidase, to form uric acid, which is excreted in the urine. Uric acid has a pKa of 5.4 and is in the ionized urate form at physiologic pH. Urate is not very soluble in an aqueous environment and the concentration of urate in human blood is very close to saturation. Therefore, conditions that lead to excessive degradation of purine bases can lead to the formation of urate crystals.

Metabolic abnormalities that lead to the overproduction of purine nucleotides through the de novo pathway lead to increased purine degradation and subsequent hyperuricemia. An example of this is an increase in the activity of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase. This enzyme is
responsible for the production of PRPP, which is an important precursor of both purine and pyrimidine de novo biosynthesis. Elevations in PRPP lead to increased purine nucleotide production that can in turn increase the rate of degradation and hence increased uric acid production. Hyperuricemia can also result from defects in the purine salvage pathway. The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is responsible for reforming IMP and GMP from hypoxanthine and guanine, respectively. In this manner purine bases are salvaged back into the purine nucleotide pool. Lesch-Nyhan syndrome results,from an inherited deficiency in HGPRT. This syndrome is associated with mental retardation and self-destructive behavior, which may be associated with inadequate
production of purine nucleotides through the salvage pathway in certain neuronal cells. In addition, Lesch-Nyhan patients have gout resulting from the inability to salvage purine bases, which leads to increased levels of uric acid. Hyperuricemia and gout can also arise from numerous undefined mechanisms that include dietary issues.

One approach for the treatment of gout is to decrease the production of uric acid to prevent the development of urate crystals. Allopurinol is an inhibitor of xanthine oxidase enzymatic activity (see Figure 43-1). The administration of allopurinol is an effective treatment of gout because it decreases the amount of uric acid produced, which in turn alleviates the amount of sodium urate crystals that are formed. Additional drugs used for the treatment of gout include alloxanthine, another inhibitor of xanthine oxidase, and colchicine, which inhibits microtubule formation and prevents phagocytic cells from engulfing the urate crystals. This prevents the urate crystals from rupturing the phagocytes and causing inflammation in the joints.


COMPREHENSION QUESTIONS

[43.1] A patient presents with extreme swelling and tenderness in the joints of the extremities. Examination of synovial fluid extracted from the big toe reveals the presence of urate crystals and confirms the diagnosis of gouty arthritis. The drug allopurinol is prescribed to inhibit which of the following enzymes?
A. Adenosine deaminase
B. AMP deaminase
C. Nucleoside phosphorylase
D. Uricase
E. Xanthine oxidase

[43.2] Hyperuricemia (gout) is a clinical condition characterized by elevated levels of uric acid that lead to the formation of sodium urate crystals that are found primarily in the joints of the extremities. Which of the following factors contributes most to the formation of urate crystals in the extremities?
A. Decreased blood flow
B. Decreased temperature
C. Exposure to sunlight
D. Increased blood flow
E. Increased mobility

[43.3] Inherited defects in components of purine catabolism and salvage are associated with various conditions and syndromes. The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a key enzyme in the purine salvage pathway. It is responsible for reforming IMP and GMP from hypoxanthine and guanine, respectively. In this manner purine bases are salvaged back into the purine nucleotide pool. Genetic defects that lead to the loss of HGPRT activity are the primary cause for which of the following conditions?
A. Gout
B. Lesch-Nyhan syndrome
C. Orotic aciduria
D. Severe combined immunodeficiency syndrome
E. Tay-Sachs disease


Answers

[43.1] E. One approach for the treatment of gout is to decrease the levels of uric acid production to prevent the development of urate crystals. Allopurinol is an inhibitor of xanthine oxidase enzymatic activity. The administration of allopurinol is an effective treatment of gout because it decreases the amount of uric acid produced, which in turn alleviates the formation of sodium urate crystals.

[43.2] B. Uric acid has a pKa of 5.4 and is ionized in the body to form urate. Urate is not very soluble in an aqueous environment, and the quantity of urate in human blood is very close to the solubility range. Therefore, situations that lead to excessive degradation of purine bases can increase the urate concentration past the solubility point and lead to the formation of urate crystals. The decreased body temperature found in the joints contributes to the formation of urate crystals under these conditions.

[43.3] B. Lesch-Nyhan syndrome results from an inherited deficiency in HGPRT. This syndrome is associated with mental retardation and self-destructive behavior, which may be associated with inadequate production of purine nucleotides through the salvage pathway in certain neuronal cells. In addition, Lesch-Nyhan patients have gout resulting from the inability to salvage purine bases, which leads to increased levels of uric acid. However, most patients with gout do not have a defect in HGPRT but have hyperuricemia resulting from a number of factors, including diet.


BIOCHEMISTRY PEARLS

❖ Purine bases are used in many important biologic processes including the formation of nucleic acids.

❖ Because urate is not very soluble in an aqueous environment and the concentration of urate in human blood is very close to saturation, conditions that lead to excessive degradation of purine bases can lead to the formation of urate crystals.

❖ Allopurinol is an inhibitor of xanthine oxidase enzymatic activity.

❖ Colchicine inhibits microtubule formation and prevents phagocytic cells from engulfing the urate crystals.

References

Becker MA. Hyperuricemia and gout. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic and Molecular Basis of Inherited Disease, 8th ed. New York: McGraw-Hill, 2001:2513–35. 

Marks DB, Marks AD, Smith CM, eds. Basic Medical Biochemistry. Baltimore, MD: Lippincott Williams & Wilkins, 1996:633–5.

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