Crystal Arthropathies
Gout
Gout is a disease of urate burden. Gout is rare in men <25yrs and in premenopausal women;
when it occurs in these populations, it is often attributed to an inherited defect in purine
metabolism, alcohol use and/or renal insufficiency including familial juvenile hyperuricemic
nephropathy or medullary cystic kidney disease. The definition of hyperuricemia is urate
>6.8mg/dL because this level defines the saturation point of the sodium urate salt in biologic
fluids at physiologic pH and temperature. Women’s serum urate levels remain relatively low
throughout most of their adult lives because of the uricosuric effect of estrogens
Hyperuricemia is a necessary, but not sufficient risk factor in gout. Although only a
small proportion of individuals with hyperuricemia eventually develop gout (≈15%), the risk
increases to >20-30% in the context of marked hyperuricemia (>9mg/dL). The risk of gout
increases with advancing age. Asymptomatic hyperuricemia is associated with not crystal-
related manifestations, like hypertension, metabolic syndrome, ↑ CVD risk, CKD. U/S and
DECT studies show that 25% of patients with asymptomatic hyperuricemia have detectable
MSU crystal deposition, albeit with much lower volumes of deposition than in patients with
symptomatic gout.
Gout includes:
-Gouty arthritis
-Tophi (aggregated deposits of MSU occurring in articular, osseous, cartilaginous, or soft
tissue areas)
-Acute uric acid nephropathy
-Chronic urate nephropathy
-Uric acid nephrolithiasis
Epidemiology
The overall prevalence of gout in the US = 4% (affecting 6% of men and 2% of women and
affecting a total of 8.3 x106 individuals), representing by far the most common form of
inflammatory arthritis.
Risk factors + causes
Age, sex, race: urate concentration in men is 1mg/dL higher than in women in
adult life. This leads to a substantially higher risk for gout in men than in women, particularly
before menopause. Therefore, age appears to have an influence only in women, in whom
serum uric acid levels steadily increase with age. African Americans have higher levels than
European Americans. UA is also higher in certain aboriginal people (Maori, Taiwanese
aborigines).
Insulin resistance (and thus ↓ renal excretion of UA): gout and hyperuricemia are
considered a component of the insulin resistance syndrome.
Adiposity is one of the strongest risk factors, ↑ UA production and ↓ renal
excretion (by insulin resistance).
Dehydration
Surgery / trauma
Renal disease (including hereditary)
Food (however, the overall effect of diet on UA is moderate):
•Red meat: high purine content + saturated fat (→ insulin resistance →
reduced renal excretion of urate).
•Seafood + shells: high purine content
•Small fish (sardines, anchovies)
, •Purine-rich vegetables (asparagus, cauliflower, spinach, nuts, legumes):
contrary to traditional dietary approaches, consumption of these vegetables was not found
to be associated with risk for incident gout. The short-term impact of purine from plant
sources on risk for recurrent gout attacks was found to be minimal, which may be explained
by insufficient amounts or bioavailability of purine in these plants and by other healthy
constituents (fiber or healthy fat) that may reduce insulin resistance and, therefore, risk for
gout.
•Alcohol: increase of risk by dose-dependent manner. >30-50g of alcohol/d
(3-4 beers, glasses of wine or shots) increases gout risk by 2-2.5x.
Beer has high purine content, predominantly guanosine which is
converted to guanine and then directly to xanthine (while adenine converts to IMP via ADA).
i) ↑production: ethanol increases hepatic degradation of ATP to AMP
ii) ↓ excretion: competitive inhibition of secretion by the proximal tubule by
a) lactic acid (alcohol → lactic acidosis)
b) fasting-induced ketones
•Fructose-rich foods: fructose is the only common dietary sugar that directly
and significantly raises UA as it is rapidly phosphorylated by fructokinase (in the liver) and
this rapidly consumes ATP (producing AMP → IMP → […] → UA). Other sugars do not trigger
the same ATP-depletion and purine breakdown pathway. Also, fructose intake is associated
with increased insulin levels and insulin resistance.
Glucose & other sugars don’t do so because glucose metabolism
is tightly regulated by phosphofructokinase (doesn’t cause sudden ATP depletion) (it’s
muscle isoform is deficient in Tarui) and other sugars like galactose or sucrose (which
contains fructose, but also glucose) are metabolized more slowly or indirectly and don’t
trigger the same response unless the fructose content is high.
Diseases (with increased cell turnover): myeloproliferative (leukemia, lymphomas,
tumor lysis syndromes, polycythemia vera, sickle cell disease), psoriasis, hemolytic states,
lead toxicity (renal failure, cognitive impairment, neuropathy, anemia, pica eating),
preeclampsia, Down syndrome, genetic diseases with hyperuricemia.
Hypothyroidism: ↓ GFR
Medications:
Mnemonic: TA CAPELA
Thiazides (+ other diuretics)
ACEis/ARBs (except for losartan*)
CNIs (nephrotoxicity, hypertension, block UA excretion. TAC better)
Alcohol
Pyrazinamide
Ethambutol
Levodopa
Aspirin (low dose)
Also: β-blockers, nicotinic acid, theophylline (asthma), didanosine (reverse
transcriptase/HIV), lead intoxication (saturnine gout).
losartan: its uricosuric effects is maximal at 50mg/d, but even then, the
effect is transitory and mild, around 10%.
Alcohol UA raising pathophysiology
When alcohol is metabolized, it uses a lot of NAD⁺ and turns it into NADH.
1. Gluconeogenesis needs NAD⁺ to convert lactate → pyruvate, but since there’s
lack of it, lactate accumulates → lactic acidosis (competitive inhibition of UA excretion).
2. Ethanol detoxification uses ATP derivatives (so it consumes ATP → more AMP).
, 3. High NADH blocks the TCA cycle and oxidative phosphorylation → mitochondria
cannot efficiently regenerate ATP. Oxidative phosphorylation in mitochondria needs NADH
to donate electrons to the electron transport chain (ETC). As electrons move through the
ETC, protons are pumped across the inner mitochondrial membrane, creating a H⁺ gradient.
ATP synthase uses this gradient to generate ATP from ADP + Pi. NADH is reoxidized to NAD⁺
in this process. However, when there's too much of NADH, it can’t be reoxidized efficiently
as the ETC becomes saturated. This limits oxidative phosphorylation and reduces ATP and
NAD⁺ regeneration.
The TCA cycle needs NAD⁺, which it reduces to NADH. High NADH levels
slow the TCA cycle by negative feedback, further reducing production of substrates (NADH)
for ATP generation, so ATP generation is slowed down. As ATP is consumed, AMP levels rise.
So ATP is consumed more rapidly than it’s produced, leading to accumulating AMP.
Then, the adenylate kinase reaction helps regenerate ATP by converting
2ADP ⟷ ATP + AMP. This is a buffer system: when ATP is being consumed, ADP rises. To
prevent ADP from accumulating (which would stall many reactions), adenylate kinase
converts it to ATP. This gives the cell a little extra ATP, but at the cost of making AMP. So
AMP builds up when ATP regeneration is impaired. This enzyme can be defective in
myoadenylate kinase metabolic myopathy.
Genetic syndromes with hyperuricemia
•(in)complete HPRT deficiency: there’s no purine salvage so all hypoxanthine and
guanosine are metabolized to xanthine.
-Lesch-Nyhan syndrome: X-linked, recessive, complete deficiency of HPRT.
These boys develop gout and nephrolithiasis by the age of 10 if not treated very early. They
also develop severe neurologic manifestations in infancy or early childhood consisting of
variable mental retardation, dystonia and compulsive self-mutilating behavior.
-Kelley-Seegmiller syndrome: X-linked, recessive, partial deficiency of HPRT.
A milder phenotype that usually manifests as gout and nephrolithiasis in male teenagers
without neurologic abnormalities.
•PRPP synthetase overactivity: X-linked mutation in the PRPP synthetase gene that
makes it insensitive to downregulation by purine nucleotides, so it overproduces PRPP (PPP
pathway) which is used for de novo purine synthesis. One of the two phenotypes is the
infantile-onset form in which gout and uric acid nephrolithiasis are combined with
neurodevelopmental impairment, including sensorineural hearing loss. The milder
phenotype can be seen in older children, who have gout, nephrolithiasis and either mild or
no neurologic impairment. This form of PRPP synthetase overactivity is caused by
overexpression of a normal (non-mutated) PRPP synthetase gene.
•Glycogen storage disease types I, III, V, VII, IX: autosomal recessive. Early-onset
gout.
-Von Gierke disease (type IA) or glucose-6-phosphatase deficiency (= can't
convert G6P → glucose), childhood hyperuricemia can lead to acute and chronic gout in the
adolescent years, short stature, hepatomegaly, hypertriglyceridemia and fasting, non-ketotic
hypoglycemia. The reason for hyperuricemia in these children is an accelerated degradation
of ATP in the liver as excess G6P is shunted to PPP (which leads to ↑ purine synthesis).
Once glycogen is broken down to G6P, the cell has a choice either to directly convert
it to Glu (via glucose-6-phosphatase) [happens in liver & kidney, not in muscle]and release it
into the blood or initiate glycolysis. Muscles don’t have glucose-6-phosphatase, so it can only
send G6P into glycolysis. Without glucose-6-phosphatase, G6P is trapped inside hepatocytes
and cannot be released as free Glu into the blood, but it can still enter glycolysis. That means
hepatocytes can generate ATP for themselves via glycolysis, but the problem in Von Gierke
Gout
Gout is a disease of urate burden. Gout is rare in men <25yrs and in premenopausal women;
when it occurs in these populations, it is often attributed to an inherited defect in purine
metabolism, alcohol use and/or renal insufficiency including familial juvenile hyperuricemic
nephropathy or medullary cystic kidney disease. The definition of hyperuricemia is urate
>6.8mg/dL because this level defines the saturation point of the sodium urate salt in biologic
fluids at physiologic pH and temperature. Women’s serum urate levels remain relatively low
throughout most of their adult lives because of the uricosuric effect of estrogens
Hyperuricemia is a necessary, but not sufficient risk factor in gout. Although only a
small proportion of individuals with hyperuricemia eventually develop gout (≈15%), the risk
increases to >20-30% in the context of marked hyperuricemia (>9mg/dL). The risk of gout
increases with advancing age. Asymptomatic hyperuricemia is associated with not crystal-
related manifestations, like hypertension, metabolic syndrome, ↑ CVD risk, CKD. U/S and
DECT studies show that 25% of patients with asymptomatic hyperuricemia have detectable
MSU crystal deposition, albeit with much lower volumes of deposition than in patients with
symptomatic gout.
Gout includes:
-Gouty arthritis
-Tophi (aggregated deposits of MSU occurring in articular, osseous, cartilaginous, or soft
tissue areas)
-Acute uric acid nephropathy
-Chronic urate nephropathy
-Uric acid nephrolithiasis
Epidemiology
The overall prevalence of gout in the US = 4% (affecting 6% of men and 2% of women and
affecting a total of 8.3 x106 individuals), representing by far the most common form of
inflammatory arthritis.
Risk factors + causes
Age, sex, race: urate concentration in men is 1mg/dL higher than in women in
adult life. This leads to a substantially higher risk for gout in men than in women, particularly
before menopause. Therefore, age appears to have an influence only in women, in whom
serum uric acid levels steadily increase with age. African Americans have higher levels than
European Americans. UA is also higher in certain aboriginal people (Maori, Taiwanese
aborigines).
Insulin resistance (and thus ↓ renal excretion of UA): gout and hyperuricemia are
considered a component of the insulin resistance syndrome.
Adiposity is one of the strongest risk factors, ↑ UA production and ↓ renal
excretion (by insulin resistance).
Dehydration
Surgery / trauma
Renal disease (including hereditary)
Food (however, the overall effect of diet on UA is moderate):
•Red meat: high purine content + saturated fat (→ insulin resistance →
reduced renal excretion of urate).
•Seafood + shells: high purine content
•Small fish (sardines, anchovies)
, •Purine-rich vegetables (asparagus, cauliflower, spinach, nuts, legumes):
contrary to traditional dietary approaches, consumption of these vegetables was not found
to be associated with risk for incident gout. The short-term impact of purine from plant
sources on risk for recurrent gout attacks was found to be minimal, which may be explained
by insufficient amounts or bioavailability of purine in these plants and by other healthy
constituents (fiber or healthy fat) that may reduce insulin resistance and, therefore, risk for
gout.
•Alcohol: increase of risk by dose-dependent manner. >30-50g of alcohol/d
(3-4 beers, glasses of wine or shots) increases gout risk by 2-2.5x.
Beer has high purine content, predominantly guanosine which is
converted to guanine and then directly to xanthine (while adenine converts to IMP via ADA).
i) ↑production: ethanol increases hepatic degradation of ATP to AMP
ii) ↓ excretion: competitive inhibition of secretion by the proximal tubule by
a) lactic acid (alcohol → lactic acidosis)
b) fasting-induced ketones
•Fructose-rich foods: fructose is the only common dietary sugar that directly
and significantly raises UA as it is rapidly phosphorylated by fructokinase (in the liver) and
this rapidly consumes ATP (producing AMP → IMP → […] → UA). Other sugars do not trigger
the same ATP-depletion and purine breakdown pathway. Also, fructose intake is associated
with increased insulin levels and insulin resistance.
Glucose & other sugars don’t do so because glucose metabolism
is tightly regulated by phosphofructokinase (doesn’t cause sudden ATP depletion) (it’s
muscle isoform is deficient in Tarui) and other sugars like galactose or sucrose (which
contains fructose, but also glucose) are metabolized more slowly or indirectly and don’t
trigger the same response unless the fructose content is high.
Diseases (with increased cell turnover): myeloproliferative (leukemia, lymphomas,
tumor lysis syndromes, polycythemia vera, sickle cell disease), psoriasis, hemolytic states,
lead toxicity (renal failure, cognitive impairment, neuropathy, anemia, pica eating),
preeclampsia, Down syndrome, genetic diseases with hyperuricemia.
Hypothyroidism: ↓ GFR
Medications:
Mnemonic: TA CAPELA
Thiazides (+ other diuretics)
ACEis/ARBs (except for losartan*)
CNIs (nephrotoxicity, hypertension, block UA excretion. TAC better)
Alcohol
Pyrazinamide
Ethambutol
Levodopa
Aspirin (low dose)
Also: β-blockers, nicotinic acid, theophylline (asthma), didanosine (reverse
transcriptase/HIV), lead intoxication (saturnine gout).
losartan: its uricosuric effects is maximal at 50mg/d, but even then, the
effect is transitory and mild, around 10%.
Alcohol UA raising pathophysiology
When alcohol is metabolized, it uses a lot of NAD⁺ and turns it into NADH.
1. Gluconeogenesis needs NAD⁺ to convert lactate → pyruvate, but since there’s
lack of it, lactate accumulates → lactic acidosis (competitive inhibition of UA excretion).
2. Ethanol detoxification uses ATP derivatives (so it consumes ATP → more AMP).
, 3. High NADH blocks the TCA cycle and oxidative phosphorylation → mitochondria
cannot efficiently regenerate ATP. Oxidative phosphorylation in mitochondria needs NADH
to donate electrons to the electron transport chain (ETC). As electrons move through the
ETC, protons are pumped across the inner mitochondrial membrane, creating a H⁺ gradient.
ATP synthase uses this gradient to generate ATP from ADP + Pi. NADH is reoxidized to NAD⁺
in this process. However, when there's too much of NADH, it can’t be reoxidized efficiently
as the ETC becomes saturated. This limits oxidative phosphorylation and reduces ATP and
NAD⁺ regeneration.
The TCA cycle needs NAD⁺, which it reduces to NADH. High NADH levels
slow the TCA cycle by negative feedback, further reducing production of substrates (NADH)
for ATP generation, so ATP generation is slowed down. As ATP is consumed, AMP levels rise.
So ATP is consumed more rapidly than it’s produced, leading to accumulating AMP.
Then, the adenylate kinase reaction helps regenerate ATP by converting
2ADP ⟷ ATP + AMP. This is a buffer system: when ATP is being consumed, ADP rises. To
prevent ADP from accumulating (which would stall many reactions), adenylate kinase
converts it to ATP. This gives the cell a little extra ATP, but at the cost of making AMP. So
AMP builds up when ATP regeneration is impaired. This enzyme can be defective in
myoadenylate kinase metabolic myopathy.
Genetic syndromes with hyperuricemia
•(in)complete HPRT deficiency: there’s no purine salvage so all hypoxanthine and
guanosine are metabolized to xanthine.
-Lesch-Nyhan syndrome: X-linked, recessive, complete deficiency of HPRT.
These boys develop gout and nephrolithiasis by the age of 10 if not treated very early. They
also develop severe neurologic manifestations in infancy or early childhood consisting of
variable mental retardation, dystonia and compulsive self-mutilating behavior.
-Kelley-Seegmiller syndrome: X-linked, recessive, partial deficiency of HPRT.
A milder phenotype that usually manifests as gout and nephrolithiasis in male teenagers
without neurologic abnormalities.
•PRPP synthetase overactivity: X-linked mutation in the PRPP synthetase gene that
makes it insensitive to downregulation by purine nucleotides, so it overproduces PRPP (PPP
pathway) which is used for de novo purine synthesis. One of the two phenotypes is the
infantile-onset form in which gout and uric acid nephrolithiasis are combined with
neurodevelopmental impairment, including sensorineural hearing loss. The milder
phenotype can be seen in older children, who have gout, nephrolithiasis and either mild or
no neurologic impairment. This form of PRPP synthetase overactivity is caused by
overexpression of a normal (non-mutated) PRPP synthetase gene.
•Glycogen storage disease types I, III, V, VII, IX: autosomal recessive. Early-onset
gout.
-Von Gierke disease (type IA) or glucose-6-phosphatase deficiency (= can't
convert G6P → glucose), childhood hyperuricemia can lead to acute and chronic gout in the
adolescent years, short stature, hepatomegaly, hypertriglyceridemia and fasting, non-ketotic
hypoglycemia. The reason for hyperuricemia in these children is an accelerated degradation
of ATP in the liver as excess G6P is shunted to PPP (which leads to ↑ purine synthesis).
Once glycogen is broken down to G6P, the cell has a choice either to directly convert
it to Glu (via glucose-6-phosphatase) [happens in liver & kidney, not in muscle]and release it
into the blood or initiate glycolysis. Muscles don’t have glucose-6-phosphatase, so it can only
send G6P into glycolysis. Without glucose-6-phosphatase, G6P is trapped inside hepatocytes
and cannot be released as free Glu into the blood, but it can still enter glycolysis. That means
hepatocytes can generate ATP for themselves via glycolysis, but the problem in Von Gierke
