- Gout is a metabolic disease which is associated with overproduction of uric acid.
- Uric acid is found in a more soluble form as sodium urate at the physiological pH.
- Crystals of sodium urate get deposited in the soft tissues particularly in the joints in case of severe hyperuricemia.
- Such deposits are commonly called tophi.
- This leads to inflammation in the joints resulting in a painful gouty arthritis.
- Sodium urate or uric acid may also precipitate in kidney and ureters that result in renal damage and stone formation.
- Gout was found to be often associated with high living, over-eating and alcohol consumption.
- In the previous centuries, alcohol was contaminated with lead during its manufacture and storage.
- Lead poisoning leads to kidney damage and decreased uric acid excretion causing gout.
- The prevalence of gout is 3 per 1000 persons, mostly affecting males.
- Post-menopausal women are as susceptible as men for this disease.
- Gout is of two types. They are:
- It is an inborn error of metabolism due to overproduction of uric acid.
- This is mostly related to increased synthesis of purine nucleotides.
- The following are the important metabolic defects associated with primary gout.
- In normal circumstances, PRPP synthetase is under feedback control by purine nucleotides ADP and GDP.
- However, variant forms of PRPP synthetase which are not subjected to feedback regulation have been detected.
- This leads to increased production of purines.
- There is lack of feedback control of this enzyme by purine nucleotides which also leads to their elevated synthesis.
- This is an enzyme of purine salvage pathway which defect causes Lesch-Nyhan syndrome.
- This disorder increases the synthesis of purine nucleotides by a two-fold mechanism.
- Firstly, decreased utilization of purines (hypoxanthine and guanine) by salvage pathway, resulting in the accumulation and diversion of PRPP for purine nucleotides.
- Secondly, the defect in salvage pathway leads to decreased levels of IMP and GMP causing impairment in the tightly controlled feedback regulation of their production.
iv)Glucose 6-phosphatase deficiency
- In type I glycogen storage disease (von- Gierke’s), glucose 6-phosphate cannot be converted to glucose due to the deficiency of glucose 6-phosphatase.
- This leads to the increased utilization of glucose 6-phosphate by hexose-monophosphate shunt (HMP shunt) resulting in the elevated levels of ribose 5-phosphate and PRPP.
- This ultimately leads to purine overproduction.
- von-Gierke’s disease is also associated with increased activity of glycolysis.
- Due to this, lactic acid accumulates in the body which interferes with the uric acid excretion through renal tubules.
v)Elevation of glutathione reductase
- Increased glutathione reductase generates more NADP+ which is utilized by HMP shunt.
- This causes increased ribose 5-phospahte and PRPP synthesis.
- Among the five enzymes described, the first three are directly involved in purine synthesis.
- The remaining two indirectly regulate purine production.
- This is a good example to show how an abnormality in one metabolic pathway influences the other.
- Secondary hyperuricemia is due to various diseases causing increased synthesis or decreased excretion of uric acid.
- Increased degradation of nucleic acids (hence more uric acid formation) is observed in various cancers (leukemias, polycythemia, lymphomas, etc.), psoriasis and increased tissue breakdown (trauma, starvation, etc.).
- The disorders associated with impairment in renal function cause accumulation of uric acid which may lead to gout.
Gout and its types