1. Introduction

2. What is Gout?
Gout is defined as a peripheral arthritis, resulting from the deposition of MSU crystals at one or more joints.
Characterized by Hyperuricemia
Known as:
Rich man’s Disease / Disease of Kings
Poor man’s Gout

3. Uric acid  Product of purine catabolism
Ionized forms of uric acid readily form salt.
98% of Uric acid forms monosodium salts
MSU crystals form in synovial fluid when solubility limit are exceeded.
These crystals provoke an inflammatory reaction.

5. Classifications: Progression Primary Gout – 90% Secondary Gout – 10%
Overproduction
Under excretion
Secondary Gout – 10%
Progression
Asymptomatic Hyperuricemia
Acute gouty arthritis
Intercritical Gout
Chronic / Tophaceous Gout

6. Epidemiology

7. There is an increased incidence of gout among:
Research has shown that risk factors for development of gout can be attributed to the increasing longevity, dietary and lifestyle changes and a history of comorbidities.
There is an increased incidence of gout among:
Males between the ages of 20 – 40.
Men have higher serum urate levels.
Post menopausal women
Patients on diuretics.
Such medication increase reabsorption of uric acid in kidneys hence increasing the risk of developing gout.
Patients with hypertension, diabetes, hyperlipidemia, chronic kidney disease, or the metabolic syndrome.
Studies show that more than 60% of patients with gout have the metabolic syndrome.

8. Both incidence and Prevalence of Gout is increasing.
Diet :
Beer drinking, High red meat and seafood consumption increases risk.
Purine-rich vegetable consumption does not notably increase risk of hyperuricemia and development of gout.
Both incidence and Prevalence of Gout is increasing.
For example, Data from US managed care reflected an increase in gout prevalence from 2.9 cases per 1000 persons in 1990 to 5.2 cases per 1000 in 1999.
Societies such as New Zealand, Taiwan and USA show increasing prevalence.
More prevalent among African American Males than European American males.

12. Etiology

13. Causes of Gout (Etiology)
High levels of uric acid circulating in the blood, which can cause needle-shaped urate crystals to settle in the tissues of the joints as well as the kidneys.
These crystals are sodium urate crystals which are the end products of purine metabolism.
this deposition first causes acute then chronic gouty arthritis.

14. Causes of Gout (Etiology)
Inheritance of certain genes
This inherited gene causes an abnormality in the enzyme of purine metabolism (primary gout).
Several X-linked mutations have been identified in the PRPP synthetase gene which results in the enzyme having either:
Increased Vmax for the production of PRPP
A lower Km for ribose 5-phosphate
Decreased sensitivity to its purine nucleotide inhibitors
The overall result is increased purine production resulting in high levels of plasma uric acid.

15. Causes of Gout (Etiology)

16. Causes of Gout (Etiology)
Secondary Gout may be caused from cancer, chronic renal failure or any of the following:
From being overweight and eating a rich diet.
Lymphoma: a usually malignant tumor of lymphoid tissue
Leukemia: an acute or chronic disease characterized by an abnormal increase in the number of white blood cells in bodily tissues
hemolytic anemia: anemia caused by excessive destruction of red blood cells.
The latter three may be the underlying cause of the uric acid buildup that results in gout.

17. Causes of Gout (Etiology)
Chronic exposure to high levels of lead decreases the body’s excretion of urates, allowing uric acid to accumulate in the blood.

18. Pathophysiology

19. Any metabolic aberration which reduces the rate of synthesis of AMP or GMP from IMP, or from purine bases by the salvage mechanism, or which accelerates the removal of nucleotides into macromolecules or through increased catabolism, may in theory result in reduced intracellular concentrations of regulatory nucleotides and release of the aminotransferase from inhibition. This would permit excessive synthesis of phosphoribosylamine and ultimately of uric acid.
The turnover of nucleic acids and coenzymes ultimately results
in production of free purine bases, chiefly adenine, hypoxanthine and
guanine, which are largely recycled into purine ribonucleotides and nucleic
acid once again, by reactions sometimes referred to as salvage
pathways. A fraction of hypoxanthine and guanine is further oxidized
to uric acid, which is a biologically inert end product excreted largely
in the urine.

20. Studies of the rates of production of uric acid in subjects with primary gout have disclosed evidence of excessive synthesis of purines in a large percentage of patients. On a diet very low in purines, 24 per cent excreted quantities of urate in urine in excess of 590 mg per day, the upper limit of the normal range. Uric acid is produced by xanthine oxidase from xanthine and hypoxanthine, which in turn are produced from purine. Uric acid is more toxic to tissues than either xanthine or hypoxanthine.

21. In human blood plasma, the reference range of uric acid is between 3
In human blood plasma, the reference range of uric acid is between 3.6 mg/dl and 8.3 mg/dl
Purines are found in high amounts in animal internal organ food products, such as liver. A moderate amount of purine is also contained in beef, pork, poultry, fish and seafood, asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat bran and wheat germ.
Examples of high purine sources include: sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts (e.g. Oxo, Bovril), herring, mackerel, scallops, game meats, and gravy.

22. Turnover of nucleic acid and coenzymes results in the production of free purine bases (Adenine, hypoxantine and guanine). These bases go to the salvage pathways.
Decreased activity of HGPRT which catalyzes a reaction of hypoxantine, guanine and adenosine with PRPP to give IMP, GMP and AMP results in the build-up of PRPP and reduced levels of IMP,GMP and AMP.
Hence hypoxanthine, guanine and adenine would go towards the production of xanthine which is oxidised to uric acid – leading to hyperuricemia.
N.B. In Von Gierke Disease, G6P is shunted to the HMP pathway – lead to the increased production of R5P – leading to the increased production of PRPP.

26. Signs & Symptoms

27. Acute gout attacks: a rapid onset of pain in the affected joint followed by warmth, swelling, reddish discoloration, and marked tenderness.
Bursitis
The small joint at the base of the big toe is the most common site of an acute gout attack. Other joints that can be affected include the ankles, knees, wrists, fingers, and elbows.
Intense tenderness - even a blanket touching the skin over the affected joint can be unbearable

28. These painful attacks usually subside in hours to days, with or without medication
Symptoms related to Chronic Gout
Chronic (tophaceous) gout: nodular masses of uric acid crystals (tophi) deposit in different soft tissue areas of the body
Such as: fingers, at the tips of the elbows, and around the big toe;
Rarely in ears, vocal cords and around the spinal cord

32. Diagnosis

33. *Physical examination and medical history
*Measuring blood uric acid levels
*Examination and analysis of synovial fluid
*Radiography

34. Physical examination and medical history
patient’s description of symptoms
Gout is more likely if:
Arthritis first appears in the big toe than if it first appears elsewhere
Onset of symptoms (pain and swelling) takes days or weeks .symptoms which take hours to develop probably indicate a disorder other than gout.
Abnormal enlargements in joints that had been affected by previous injury or osteoarthritis are possible signs of gout

35. Measuring blood uric acid levels
A blood test is usually given for measuring uric acid and detecting hyperuricemia. A low level of uric acid in the blood makes a diagnosis of gout much less probable, and a very high level increases the likelihood of gout.
Uric acid levels in the blood during an attack of gout can lie within or below the normal range or
Hyperuricemia may be prevalent in population and doesn’t necessarily indicate gout.

36. Examination of synovial fluid
Examination of synovial fluid is the most accurate method for diagnosing gout.
Synovial fluid analysis
The sample is examined through a microscope under polarized light. This special light will reveal the presence of monosodium urate (MSU) crystals, which will nearly always confirm a diagnosis of gout.
Examination of aspirated joint fluid can rule out other disorders that mimic gout, such as septic arthritis and pseudogout.

37. Uric acid crystals under polarized light
DIAGNOSIS
Uric acid crystals under polarized light

38. Occasionally, patients with gout may present without uric acid crystals in the synovial fluid aspirate. However, aspiration repeated five hours to one day later shows crystals in the synovial fluid of most of these patients

39. Radiography
is not very useful in diagnosing initial attacks of acute gouty arthritis. The radiographic findings are generally nonspecific, consisting of soft tissue swelling around a joint.
Bony abnormalities indicate the presence of chronic gout.
In general, gout must be untreated or inadequately treated for approximately 12 years before chronic arthritis and bony erosions are seen on radiographs.

40. Radiograph showing sharply "punched-out" bony defects of the distal radius and proximal phalange of the middle finger

41. Treatment

42. There are two essential concepts behind the treatment of Gout:
Its is critical in stopping the inflammation caused by the gouty arthritis.
It is vital in addressing the long term management of the disease in order to prevent further attacks and shrink crystal deposits.

43. There are basically three ways of treating Gout:
Self Care
Medications
Surgery

44. Self Care Take medications as prescribed.
While a joint is hot and swollen, aggravation should be prevented to so as to reduce further discomfort. The following would be helpful:
Using of a cane or similar support to keep your weight off that joint.
Keep the swollen joint elevated above your chest as much as possible.
Ice packs can be helpful in relieving pain and reducing inflammation.
Maintaining adequate hydration is key for minimizing attacks and decreasing the formation of kidney stones.

45. Reduce the consumption of alcohol since:
It is known to have a diuretic effects and can contribute to dehydration and precipitate the acute gout attack.
Affects uric acid metabolism resulting in hyperuricemia.
Dietary changes can help reduce the amount of uric acid in the blood;
Purine rich food should be avoided (shellfish and organ meats such as liver, brains, kidneys, and sweetbreads)

46. Medication
There are three aspects/lines of treatment of gout with medication:
Pain relievers such as acetaminophen (Tylenol) or other more potent analgesics are used to manage pain.
The exact mechanism of action of acetaminophen is not known. Acetaminophen relieves pain by elevating the pain threshold, that is, by requiring a greater amount of pain to develop before a person feels it.

47. Anti-inflammatory agents such as NSAIDS, colchicine, and corticosteroids, used to decrease joint inflammation.
NSAIDS such as: diclofenac, etoricoxib, indomethacin, ketoprofen and naproxen.
Most of these drugs function by inhibiting the COX-2 resulting in the reduction of prostaglandins production.

48. Colchicine is useful in suppressing the inflammation
Colchicine is useful in suppressing the inflammation. The exact mechanism of action of colchicine is not known but is speculated that it impairs the motility of granulocytes and hence prevent the inflammatory phenomena that initiate an attack or it may involve reduction in uric acid deposition leading to a reduction in the inflammatory response. Colchicine is not an analgesic (pain killer), but it reduces pain in acute gouty arthritis.

49. Corticosteroids such as prednisone a synthetic corticosteroids mimic the action of cortisol (hydrocortisone), the naturally-occurring corticosteroid produced in the body by the adrenal glands. Corticosteroids are potent anti-inflammatory effectors.
Prednisone is inactive in the body and, in order to be effective, first must be converted to prednisolone by enzymes in the liver. Therefore, prednisone may not work as effectively in people with liver disease whose ability to convert prednisone to prednisolone is impaired.
They function by inhibiting phospholipase A2 the enzyme responsible for the release of Archidonic acid from membrane phospholipids – the precursor for prostaglandins.

50. Medications for managing the chronic underlying metabolic derangement that causes hyperuricemia and gout. That is, medications that reduce the elevated levels of uric acid in the blood.
These medication are taken over prolonged periods to lower blood uric acid level.
Medicines used to lower blood uric acid level work either by increasing the kidney's excretion of uric acid or by decreasing the body's production of uric acid from the purines in foods.
These medicines are generally not started until after the inflammation from acute gouty arthritis has subsided because they can worsen the attack. If they are already being taken prior to the attack, they are continued and only adjusted after the attack has resolved.

51. Allopurinol lowers the blood uric acid level by preventing uric acid production. It acts by blocks the metabolic conversion from purines by inhibiting xanthine oxidase, the enzyme responsible for the conversion of xanthine to uric acid.
Probenecid (Benemid) and sulfinpyrazone (Anturane) are medications that are commonly used to decrease uric acid blood levels by increasing the excretion of uric acid into the urine.
These act by preventing the reabsorption of uric acid by the kidney and hence increasing its excretion from the body in the urine

52. Surgery
Surgery is rarely needed for gout unless significant joint damage has occurred from lack of effective treatment

53. Prevention

54. The key to prevent gout is to maintain the
concentration of uric acid within the normal
range (7.0 mg/dl),this can be achieved by:
Avoiding excessive intake of purine rich food such as those high in proteins and fats e.g. seafood, beef, poultry
Maintain a healthy body weight via proper diet and exercise.

55. Avoid foods rich in fructose, sucrose (glucose and fructose) especially high fructose corn syrup (a common sweetener in soft drinks which results in hyperuricemia), and diuretic foods or drugs( increases urination).
Restrict your intake of alcohol, especially beer(high in guanosine), on the basis that brewer’s yeast are very rich in purine, beer also can inhibit the elimination of uric acid and can cause dehydration which may lead to gout.

56. Avoid diet low in potassium(good sources: tomatoes, potatoes, bananas, soybeans, brown rice) since a deficiency increases urate in blood.
Avoid consuming too much acid containing substances
Drink plenty of liquids, especially water, to dilute and assist excretion of urates

57. Maintain an adequate intake of Vitamin C since it has been demonstrated to increase excretion on uric acid and in turn lower serum urate levels by dissolving the needle-like crystals that deposit themselves between the joints and connective tissue.
Avoid prolonged exposure to low temperature.

58. Prognosis/Outlook

59. It is excellent is you are properly diagnosed and treated.
The optimal regimens for the treatment of acute gout attacks and chronic gout conditions still require further long-term studies. Research scientists will continue to develop less toxic and more effective medications to battle this "scourge of the ages”.

60. Primary Gout is almost exclusively a disease of adult men because their kidneys excrete uric acid less well, and return more to blood, than do the kidneys of women and children.
In adult men urate already circulates at levels close to the maximum before crystals will form

61. References