GOUT

                  GOUT

Gout or gouty arthritis/podagra is an metabolically mediated for of inflammatory arthritis which are characterized by deposition of uric acid crystals in between the joints leading to recurrent attacks of red, swollen and tender joint.

The commonest joints affected by this form of inflammations are the ball of the great toe, small joints of the fingers( meta tarso phalangeal joint), also involvement of heel, wrists, knee is also not uncommon.

 Classification of gouty arthritis

1.              Primary gout.

2.              Secondary gout.

1.              Primary gout: Whenever there seems no specific cause behind production of this metabolic issue, we address the person as suffering from a primary gout.

Here, in this type of gout there is an overproduction or underexcretion of uric acid in the body leading to increased uric acid levels,finally causing gouty deposits of monosodium urate/uric acid metabolite In the joints(Tophi) . However, there seems to be no specific cause to rule out the metabolic disorder in the body. Hence, it is called primary.

               

                This type of gout may also be associated or caused by consumption dietary food rich in purines, alcohol overconsumption and various other factors apart from the metabolic disorder.

2.                Secondary gout: A person suffers from secondary gout when there is an increase in the production or reduced excretion of uric acid due to some underlying medical or congenital disorder or disease, or as a result of certain medications . Here, as in case of primary gout the exact mechanism in production  of gout may not always be problems with uric acid metabolism.

The commonest medical condition associated with secondary gout are as follows:

1.       Renal causes like renal nephropathy, renal failure, Chronic kidney diseases, kindney stones(if left untreated) etc.

2.    Haemolytic anaemias. Haemolysis or RBC breakdown, will cause increased cell turnover due to rapid RBC destruction, leading to reticulocyte responsiveness to this destruction, so that, there is increase conversion of purines to uric acid by xanthine overproduction.

3.    Lymphoproliferative and myeloproliferative disorders, in which lymphocytes and myelocytes, a variant of wbc, are increased in the blood. The commonest disorders include leukemia(blood cancers), multiple myeloma, Wiskott-aldrich syndrome, autoimmune lymphoproliferative disorders etc. These diseases may destroy the kidneys leading to chronic kidney failure, or also trigger increased cell turnover by destruction of blood cells specially wbc variants.

Thus, this cause seems to be a combinations of both the causes enlisted above.

4.    Certain malignant cancers.

5.    Chronic lead poisoning.

6.    Endocrinopathies/ hormonal disorders like hyperthyroidism or hypoparathyroidism.

7.    Hyperparathyroidism may also lead to pseudogout or a condition or lesion which resembles gout, but is not a gout, due to overproduction of calcium.

 

Pathophysiology of gout.

Acute gout , triggered by various factors like increased cell turnover like wbc destruction secondary to disease, leads to sudden increased in uric acid levels in the blood. This reacts with the blood forming monosodium urate crystals. These uric acid crystal via complement activation and synovial lining cell activation activate mast cells with release of cytokines, which  are inflammatory cells. Thereby causing inflammation of the affected area.

In chronic gout the tophi/the crystals deposited in the joints, bones and soft tissues. Following the deposition of MSU crystals, the lesions are surrounded by granulomatous inflammations due to immune system mediated attack, leading to inflammation. Resulting in chronic gout.

THE PURINE METABOLISM: Here I would depict a diagram of the purine metabolism.

STEPS IN PURINE METABOLISM:

1.       The Ribose 5-phosphate/R5P, obtained as an end result from pentose phosphate pathway, is an active sugar, is used for preparation of purines for making DNA and RNA.

2.    Ultimately, R5P is converted to PHOSPHORIBOSYL PYROPHOSPHATE(PRPP).

3.    PRPP, after further metabolism, leads to formation of the main and the most important molecule in this reaction, IMP/INOSINE MONOPHOSPHATE.

4.    Now, the reaction is divided to three parts.

FORMATION OF ADENINE:

·      IMP is converted to AMP/ADENINE MONOPHOSPHATE in presence of enzyme Adenyl succinate.

·      When in need of preparing DNA and RNA AMP is converted to adenosine triphosphate(ATP) for preparing RNA and dATP(deoxyadenosine triphosphate) for DNA production.

·      However, if there is no need of DNA/RNA synthesis, this reaction is inhibited.

·      Subsequently, AMP is converted to ADENOSINE and finally to ADENINE.

FORMATION OF XANTHINE:

·      The second half of IMP is converted to hypoxanthine in presence of enzyme PNP/purine nucleoside phosphorylase.

·      This hypoxanthine is further broken down to xanthine in presence of enzyme XANTHINE OXIDASE. Which is again further broken down to uric acid in presence of the same enzyme.

·      Finally, this uric acid is excreted out via kidneys.

FORMATION OF GUANINE:

·      As in case of Adenine, Guanine is also required for DNA and RNA synthesis.

·      Guanine, like Adenine, is synthesized from IMP. IMP, is converted to XANTHINE MONOPHOSPHATE/XMP in presence of IMP DEHYDROGENASE.

·      XMP is converted to GUANOSINE MONOPHOSPHATE/GMP.

·      As in Adenine, if DNA/RNA synthesis is required, then GMP is converted to GUANOSINE TRIPHOSPHATE/GTP and later to DEOXYGUANOSINE TRIPHOSPHATE/dGTP for RNA and DNA synthesis.

·      If there is no need of DNA/RNA synthesis then GMP is converted to GUANOSINE in presence of enzyme PMP and later to GUANINE. GUANINE can further be converted to XANTHINE and finally to URIC ACID.

5.   SALVAGE PATHWAY.

·       Salvage pathway, as the name suggests is a proctective response in which the end products of the metabolism are converted back to their precursor form to prevent over production.

·      Hence, ADENINE is converted to AMP in presence of APRT enzyme(ADENINE PHOSPHORIBOSYL TRANFERASE)

·      GUANINE is converted to GMP, and hypoxanthine is converted IMP in presence of HGRPT enzyme(hypoxanthine/guanine phophoribosyl transferase).

·      Hence, it can be seen as a protective response,which prevents excessive uric acid production and thereby preventing gout.

CLINICAL APPLICATION OF THE BIOCHEMISTRY OF PURINE METABOLISM:

1.       SULPHA DRUGS AND CYTOTOXIC DRUGS like METHOTRAXATE and MYCOPHENOLASE may disrupt the conversion of IMP from PRPP, and conversion of XMP from IMP respectively.

2.     XANTHINE OXIDASE INHIBITORS like ALLUPURINOL, FEBRUXOSTAT etc, suppress XANTHINE OXIDASE enzyme therefor prevent conversion of XANTHINE and HYPOXANTHINE to URIC ACID and so helpful in treating gout.

Signs and symptoms:

1.       Hot, tender swelling with redness of the affected joint. Attacks of pain may be chronic or episodic. It may affect many different joints, but the commonest joint includes the ball of the great toe.

2.    Nodules called tophi, may be seen in people with long continued and profoundly elevated levels of uric acid. Extemsive tophi may lead to chronic gout.

3.    Rarely, bodyache, fatigue and sometimes fever may accompany the joint pains.

4.    Urine may be hot and offensive in some cases due to increased uric acid filtration. And sometimes uric acid calculus may form due to urate nephropathy.

5.    In case of secondary gout, constitutional symptoms of the affected symptoms may accompany joint pains.

DIAGNOSIS:

1.      Elevated levels of serum uric acid may be seen.

2.   Chronic cases may exhibit deformities of the finger, while x-rays may confirm the presence of nodules(tophi) in the joint.

3.   Synovial fluid aspiration and its subsequent examination under microscope shows the presence of needle like uric acid crystal.

4.   Clinical correlation must be carefully assessed.

SOME HOMOEOPATHIC DRUGS USED IN THERAPEUTICS:

        An in depth analysis and selection of an accurate constitutional remedy may be of great help in curing gout. However some medicines for gout includes.

Calcarea carb, calcarea flour, ledum pal, ammonium benzoicum, causticum, benzoic acid, etc.