SUMMARY OF GOUT DISEASE

Summary

Gout is a metabolic disorder which causes inflammation of the joints. Gout attacks often
begin at night or in the early morning with sudden, very painful joint swelling. Gout may
arise from too much uric acid in the bloodstream. It's estimated that only about one in three
people with high uric acid levels develop gout, though. Anything that increases uric acid
levels can also increase the risk of gout. People who have already had a gout attack are at
greater risk of having more attacks. Gout is the most common inflammatory joint disease
(arthritis) in industrialized countries. It is estimated that 1 to 2 % of the population are
affected. Men are a lot more likely to get it than women. If the gout becomes chronic and
damages the joints, it restricts mobility and can also weaken the muscles. Doctors are often
able to recognize gout based on its typical symptoms and risk factors. Painful, reddened
swelling at the base or the final joint of the big toe is a fairly sure sign of gout.Gout attacks
are treated with anti-inflammatory medications. These include anti-inflammatory
painkillers, such as ibuprofen, indometacine or naproxen,steroid medicines (usually tablets
with prednisolone), as well as the gout medicine colchicine. Because colchicine is slow to
start working and has certain possible side effects, it is no longer used very often.

History:

First identified by the Egyptians in 2640 BC, podagra (acute gout occurring in the first
metatarsophalangeal joint) was later recognized by Hippocrates in the fifth century BC, who
referred to it as ‘the unwalkable disease’. The term is derived from the Latin word gutta (or
‘drop’), and referred to the prevailing medieval belief that an excess of one of the four
‘humors’ – which in equilibrium were thought to maintain health – would, under certain
circumstances, ‘drop’ or flow into a joint, causing pain and inflammation. Throughout
history, gout has been associated with rich foods and excessive alcohol consumption.
Because it is clearly associated with a lifestyle that, at least in the past, could only be
afforded by the affluent, gout has been referred to as the ‘disease of kings’. Although there
is evidence that colchicine, an alkaloid derived from the autumn crocus (Colchicum
autumnale), was used as a powerful purgative in ancient Greece more than 2000 years ago,
its first use as a selective and specific treatment for gout is attributed to the Byzantine
Christian physician Alexander of Tralles in the sixth century AD. Uricosuric agents were first
used at the end of the 19th century. In the modern era, nonsteroidal antiinflammatory
drugs are usually the drugs of choice for treating acute gout. Perhaps the most important
historical advance in the treatment of hyperuricemia was the development of xanthine
oxidase inhibitors, which are effective in reducing plasma and urinary urate levels and have
been shown to reverse the development of tophaceous deposits. (Nuki, Simkin et al. 2006)

Introduction

Gout is the most prevalent form of inflammatory arthritis and is associated with impaired
quality of life. Elevation of serum uric acid (SUA) levels, or hyper uricaemia, is an essential
prerequisite for the development of gout. As SUA levels rise and the physiological saturation
threshold for uric acid is exceeded in body fluids, the formation and deposition of
monosodium urate (MSU) crystals occurs in and around joints. Clinical manifestations of
MSU crystal deposition include acute attacks of severe pain and inflammation affecting
peripheral joints, most commonly the first metatarsophalangeal (MTP) joint, chronic joint
damage, and tophaceous deposits of MSU crystals in the joints and skin. (Cronstein,
Terkeltaub et al. 2006)

Prevalence of gout

Epidemiological evidence from New Zealand, the USA, the UK and China suggests that gout
is becoming more prevalent. The findings of three similarly conducted successive surveys
from New Zealand show an increase in the prevalence of gout, diagnosed by interview and
physical examination, in both European US. In the USA, the prevalence of gout in a
managed-care administrative claims database increased in most notably in men aged over
75 years.

Risk factors for the development of gout

1. Hyperuricaemia
2. Genetic factors
3. Dietary factors
4. Alcohol consumption
 5. Metabolic syndrome
6. Diuretic use
7. Renal disease
8. Osteoarthritis
(Roddy, Doherty et al. 2010)

Co-morbidities

Gout often occurs in the presence of other conditions, such as hypertension, renal
impairment, diabetes mellitus and cardiovascular disease. Hyperuricaemia may actually be
an independent risk factor for some of these conditions. Likewise, some of these conditions
and their associated treatments can influence SUA levels.In this sense gout truly is
about‘more than joints’ and can having wide-ranging health implications. .

Hypertension

Hypertension is a common co-morbidity of gout and hyperuricaemia, with around 40% of

gout patients also having hypertension . Hyperuricaemia may actually itself contribute to
hypertension, with raised SUA levels being predictive of the development of hypertension
and ULTs such as allopurinol being shown to reduce blood pressure.

Renal impairment

While chronic kidney disease has long been identified as a common co-morbidity of gout,
the nature of this association has been debated. Hyperuricaemia is a recognised risk factor
for the development of urate kidney stones. Recent animal and epidemiologic studies
suggest that hyperuricaemia may independently lead to kidney disease and renal failure.

Diabetes mellitus

diabetes is common in gout patients , although the nature of this association is complex.
Choi and colleagues reported that individuals with moderately elevated HbA1c levels had an
increased risk of gout but as HbA1c or fasting serum glucose rose the level of serum urate
fell.

. Cardiovascular disease
As with hypertension, hyperuricaemia has been associated with increased cardiovascular
morbidity and mortality. It appears that gout may increase the risk of CVD mortality
independently of hyperuricaemia, although even in gout patients higher levels of SUA
increase the risk of CVD mortality.

Optimising therapy

The associations between gout and other chronic diseases are important to consider in
their own right. But regardless of the nature of these associations, the chronic nature of
these diseases means that a significant number of patients in middle to later life will be
affected by gout and one (if not several) of the diseases listed above. It is therefore
important to appreciate that the pharmacological treatments for one can affect the other.
Certain antihypertensives can influence SUA levels; beta blockers, loop and thiazide
diuretics have been shown to increase SUA levels, while ACE inhibitors and calcium channel
blockers reduce SUA levels. Likewise, the lipid-lowering drugs atorvastatin and fenofibrate
decrease SUA levels. Conversely, allopurinol has been found to reduce blood pressure in
hypertensive patients, as well as reduce CVD morbidity and mortality. It can also improve
renal function in patients with gout and has been shown to slow progression of renal
disease . The appropriate choice of medications is clearly important in optimising the
potential benefits pharmacological treatment of gout patients with co-morbidities

Clinical features and impact of gout

Some individuals may only have one to two attacks of gout, or have extremely intermittent
attacks months apart, but the majority will suffer from increasingly frequent attacks.
Subsequent attacks commonly involve additional joints such as the knee and as gout
progresses it can cause polyarticular attacks and tophus development, although tophi can
also be the first presentation of disease. Gout can eventually progress to a chronic phase
whereby there is persisting inflammation in joints. The characteristic of attacks is a rapid
onset (over 12–24 h) of acute pain, which can be associated with overlying joint erythema
and swelling.(Robinson and Horsburgh 2014)

Uric Acid Crystals and the Mechanism of Inflammatory

uric acid crystals can precipitate out of serum and into tissues (typically, into joints), where
they induce inflammation via complement activation and subsequent neutrophilic
infiltration. However, neutrophil egress from the vasculature first requires endothelial cell
activation, which is induced by synovial macrophage-derived cytokines such as interleukin
(IL)-1.. How that first crucial step of gouty inflammation occurs—uric acid crystal activation
of macrophages—had remained unclear until very recently, when it was discovered that uric
acid activates macrophages via stimulation of the NALP3 inflammasome. Inflammasomes
are structures that mediate the activation of IL-1, that cause inflamation.(Abeles, Park et al.
2007)

DIAGNOSIS OF GOUT

Diagnosis of gout comprises

1. nosologic diagnosis (is it true gout?),

2. evaluation of the burden of the deposition (how great and extensive is the
deposition and how much is the structural damage induced?)
3. differentialdiagnosis.(Perez-Ruiz, Castillo et al. 2014)

Gout therapy:

Acute attacks of gout

 Acute attacks of gout are usually treated with high doses of NSAIDs such as
diclofenac sodium, diclofenac potassium , etoricoxib, indometacin , ketoprofen ,
naproxen.
 Colchicine below is an alternative in patients in whom NSAIDs are contra-indicated.
 Aspirin is not indicated in gout.
 Allopurinol, febuxostat , and uricosurics are not effective in treating an acute attack
and may prolong it indefinitely if started during the acute episode.

Long-term control of gout

Frequent recurrence of acute attacks of gout, the presence of tophi, or signs of

chronic gouty arthritis may call for the initiation of long-term (‘interval’) treatment.
For long-term control of gout
  the formation of uric acid from purines may be reduced with the xanthine-oxidase
inhibitors allopurinol or febuxostat alternatively the uricosuric drug sulfinpyrazone
may be used to increase the excretion of uric acid in the urine. Treatment should be
continued indefinitely to prevent further attacks of gout by correcting the
hyperuricaemia.
 These drugs should never be started during an acute attack; they are usually started
1–2 weeks after the attack has settled. (Britain 2009)

References
Abeles, A. M., et al. (2007). "Update on gout: Pathophysiology and potential treatments." 11(6):
440-446.

Britain, R. P. S. o. G. (2009). British National Formulary 58, Royal Pharmaceutical Society.

Cronstein, B. N., et al. (2006). "The inflammatory process of gout and its treatment." 8(1): S3.

Nuki, G., et al. (2006). "A concise history of gout and hyperuricemia and their treatment." 8(S1): S1.

Perez-Ruiz, F., et al. (2014). "Clinical manifestations and diagnosis of gout." 40(2): 193-206.

Robinson, P. C. and S. J. M. Horsburgh (2014). "Gout: joints and beyond, epidemiology, clinical
features, treatment and co-morbidities." 78(4): 245-251.

Roddy, E., et al. (2010). "Gout. Epidemiology of gout." 12(6): 223.