INTRODUCTION

Gout refers to disease that occurs in response to the presence of crystals of monosodium
urate (MSU) in joints, bones, and soft tissues. Both acute arthritis and chronic arthropathy
(tophaceous gout) are considered under the rubric of gout.
The mechanisms of crystal deposition, crystal-induced inflammation, and destructive lesions
of joints and bones associated with macroscopic collections of MSU (tophi) will be reviewed
here. The clinical features, diagnosis, and treatment of acute gout, prevention of recurrent
gout, asymptomatic hyperuricemia, and associated renal diseases are discussed elsewhere.
(See "Clinical manifestations and diagnosis of gout" and"Treatment of acute
gout" and "Prevention of recurrent gout" and "Asymptomatic hyperuricemia" and "Uric acid
nephrolithiasis" and "Uric acid renal diseases".)
HYPERURICEMIA AND GOUT
Hyperuricemia can be caused by underexcretion or overproduction of uric acid, and/or
overconsumption of purine-rich foods that are metabolized to urate. A detailed discussion of
the causes of hyperuricemia and of the normal mechanisms of urate handling are presented
separately. (See "Asymptomatic hyperuricemia" and"Uric acid balance".)
A causative relationship among hyperuricemia, deposition of urate crystals, and gout was
proposed by Garrod in 1859 and later [1]. However, injection of solutions of uric acid into
blood or joints failed to reproduce the clinical features of the disease, casting doubt on the
association. Freudweiler noted in 1899 that injection of tophaceous material caused
inflammation [2,3].
The identification of MSU crystals within phagocytes when synovial fluid was examined using
compensated polarized microscopy was an important advance in understanding the
pathogenesis of gout [4]. This was followed by the observation that injection of MSU
crystals into normal joints produced acute gout attacks, reestablishing the connection
between urate crystals and gout [5,6]. The outline of the pathophysiology of gout is as
follows: a period of hyperuricemia leads to MSU crystal deposition, reaction to which can
result in acute and/or chronic inflammation.

INTRODUCTION
Gout (monosodium urate crystal deposition disease) is characterized biochemically by
extracellular fluid urate saturation. The clinical manifestations include one or more of the
following:
O #ecurrent attacks of acute inflammatory arthritis
O Chronic arthropathy
O Accumulation of urate crystals in the form of tophaceous deposits
O Uric acid nephrolithiasis
O A chronic nephropathy that in gouty patients is most often due to comorbid states
All patients with gout have hyperuricemia (saturation of serum for urate) at some point in
their disease. (See"Uric acid balance".) However, most hyperuricemic individuals never
experience a clinical event resulting from urate crystal deposition. Thus, the diagnosis of
gout focuses on the fundamental pathophysiologic events defining the clinical state: tissue
deposition of urate crystals and the accompanying inflammatory and potentially destructive
consequences. Within this framework, hyperuricemia is viewed as a necessary but not
sufficient precondition for the development of urate crystal deposition disease and is to be
distinguished from gout, the clinical syndrome.
The clinical manifestations and diagnosis of gout will be reviewed here. Issues related to
asymptomatic hyperuricemia, the treatment of acute gout, and prevention of recurrent gout
are discussed separately. (See"Asymptomatic hyperuricemia" and "Treatment of acute
gout" and "Prevention of recurrent gout".)
HISTORICAL PERSPECTIVE
Descriptions of the epidemiology, clinical features, and natural history of gout evolved over
more than two millennia of study. The last half of the twentieth century produced
confirmation that the pathogenesis of gout involves urate crystal deposition. Pivotal in this
progress was the introduction of polarized light microscopy into clinical practice, providing
urate crystal identification in synovial fluid as the means to achieve rapid and definitive
diagnosis and to resolve the formerly ambiguous relationship between hyperuricemia and
gout [1].

INTRODUCTION
Acute gout is an intensely painful inflammatory arthritis that typically involves a single joint,
but can affect multiple joints. The goal of therapy in an acute gout attack is prompt and safe
termination of pain and disability. (See "Clinical manifestations and diagnosis of gout",
section on 'Acute gouty arthritis'.)
Without therapy, acute gouty arthritis usually resolves within a few days to several weeks.
However, symptoms improve more quickly with administration of any of a broad array of
antiinflammatory drugs (figure 1) [1]. Symptom resolution is more prompt and complete
with early initiation of therapy.
A number of drugs have been used for the treatment of acute gout, although randomized
trial data is surprisingly limited [2]:
O onsteroidal antiinflammatory drugs
O Colchicine
O Intraarticular or systemic glucocorticoids
O Interleukin 1 beta inhibition (investigational)
Upon resolution of the acute attack, the patient is said to have entered the intercritical
(between attacks) period, which may or may not require prophylactic therapy to prevent
recurrent gout and chronic tophaceous disease.

INTRODUCTION
Pharmacologic modalities employed in the treatment of gout can be classified as
antiinflammatory, prophylactic, and antihyperuricemic. These designations reflect the three
distinctive aims of treatment:
O Antiinflammatory therapy for prompt and safe termination of the acute arthritic
attack
O Antiinflammatory prophylaxis for prevention of recurrences of acute gouty arthritis
O Antihyperuricemic (urate-lowering) therapy for prevention and reversal of the
consequences of urate crystal deposition in joints (gouty arthropathy), urinary tract
(nephrolithiasis), renal interstitium (rarely producing renal failure due to urate
nephropathy), and tissues and parenchymal organs (tophi)
Upon resolution of an acute gouty attack, the patient is said to have entered an intercritical
(between attacks) period. Intervals between attacks of acute gouty arthritis are of variable
duration. Most untreated patients with gout will experience a second episode within two
years. (See "Clinical manifestations and diagnosis of gout", section on 'Intercritical gout and
recurrent gouty arthritis'.)
The following preventive issues should be addressed during the intercritical period:
O ifestyle modification and agents for risk reduction
O Comorbid disease management
O The need for pharmacologic urate-lowering therapy
O Prophylactic nonsteroidal antiinflammatory drug or colchicine therapy, primarily to
reduce the recurrence of acute attacks of gout during initiation of urate-lowering
therapy
INTRODUCTION
Asymptomatic hyperuricemia is the term applied to settings in which the serum urate
concentration is elevated, but neither symptoms nor signs of urate crystal deposition (gout)
have occurred. Although gout may develop in a hyperuricemic individual at any point, it is
likely that two-thirds or more of hyperuricemic individuals will remain asymptomatic [1-5].
The implications of hyperuricemia may be broadly regarded as those related to urate or uric
acid crystal deposition and those emerging from crystal deposition-unrelated associations of
hyperuricemia with important disorders, including hypertension, chronic kidney disease,
cardiovascular disease, and the insulin resistance syndrome.
The etiology and management of asymptomatic hyperuricemia will be reviewed here. Gout,
uric acid renal diseases, and uric acid nephrolithiasis are discussed separately. (See "Clinical
manifestations and diagnosis of gout" and "Treatment of acute gout" and "Prevention of
recurrent gout" and "Uric acid renal diseases" and"Uric acid nephrolithiasis".)
DEFINITIONS
The statistical definition of hyperuricemia is difficult to accept because of non-normal
distribution of serum urate concentrations in most populations. For purposes relating to
urate crystal deposition, a definition of hyperuricemia based on the solubility limit of urate
in body fluids (ie, the concentration at which a state of supersaturation for urate is reached
in the serum) is appropriate. This physicochemical definition corresponds to urate
concentrations exceeding about 7.0 mg/d (416 micromol/), as measured by automated
enzymatic (uricase) methods in routine clinical laboratory use. These values are
approximately 1 mg/d (60 micromol/) lower than those obtained with colorimetric
methods.
A definition of hyperuricemia appropriate to the non-crystal deposition-associations of
hyperuricemia with the conditions listed above is more problematic for two reasons: first,
the high prevalence of urate values exceeding saturation but within 2 standard deviations of
the population mean (for example, an estimated 5 to 8 percent in adult white males in the
US and 25 percent in Taiwan Chinese males [6]); and second, the fact that associations of
serum urate levels with cardiovascular and other disorders are manifested at concentrations
that are clearly subsaturating [7].
Classification - Persistent hyperuricemia is a common biochemical abnormality that
results from excessive urate production and/or diminished renal uric acid excretion [8].

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