Hyperuricemia is considered a multifactorial metabolic disorder in the general population. The levels of uric acid are influenced by the use of drugs, medications, renal impairment, and Alcohol also. The excess of uric acid levels gets deposited in the joints, kidneys, and a lot of tissue leading to clinical manifestations such as tophi, nephrolithiasis along the presence of urate nephropathy. Decreased excretion of uric acid contributes the maximum towards the development of Hyperuricemia. Along with the minimal contribution from other factors like increased production and increased consumption of foods rich in uric acid. The deposits in the joints, skin, and other tissues compromise the function of organs and resulting in the abnormal configuration of joint with funv=ctional limitation along with the presence of clinical signs in the form of pain and swelling.
==Pathophysiology==
In terms of pathophysiological classification, we can categorize gout into 2 main types
== Pathophysiology ==
1) '''Primary gout''': Mainly hereditary or related to enzymatic abnormalities
Gout occurs when mono-sodium urate crystals form on the articular cartilage of joints, on tendons, and in the surrounding tissues. [[Purine metabolism]] gives rise to uric acid, which is normally excreted in the urine. Uric acid is more likely to form into crystals when there is a [[hyperuricaemia]], although it is 10 times more common without clinical gout than with it<ref>{{cite journal | author=Virsaladze D, Tetradze L, Djavashvili L, Esakia N, Tananashvili D. | title=Levels of uric Acid in serum in patients with metabolic syndrome. | journal=Georgian Med News | year=2007 | volume=146 | pages=34–7 | id=PMID 17595458}}</ref>
2) '''Secondary Gout''': Secondary to other reasons like drugs, renal insufficiency, dietary or related to malignancy[[File:Gout Pathophysiology.png|456x456px|thumb|'''Pathophysiological factors for the development of Gout''' https://www.pinterest.com/pin/129971139223442993/?nic_v2=1a30H8fPo|alt=]]
Purines can be generated by the body via breakdown of cells in normal cellular turnover, or can be ingested in purine-rich foods such as seafood. the kidneys are responsible for approximately one-third of uric acid excretion, with the gut responsible for the rest. It may be possible that defects in the kidney that may be genetically determined are responsible for the predisposition of individuals for developing gout.
There are also different racial propensities to develop gout. Gout is high among the peoples of the Pacific Islands, and the Māori of New Zealand, but rare in the Australian aborigine despite the latter's higher mean concentration of serum uric acid.<!--
The pathophysiology<ref name="pmid23745463">{{cite journal |vauthors=Milas-Ahić J, Prus V, Visević R |title=[Pathophysiology of gout] |journal=Reumatizam |volume=59 |issue=2 |pages=89–92 |date=2012 |pmid=23745463 |doi= |url=}}</ref><ref name="pmid28148582">{{cite journal |vauthors=Abhishek A, Roddy E, Doherty M |title=Gout - a guide for the general and acute physicians |journal=Clin Med (Lond) |volume=17 |issue=1 |pages=54–59 |date=February 2017 |pmid=28148582 |pmc=6297580 |doi=10.7861/clinmedicine.17-1-54 |url=}}</ref>of Gout mainly relates to hyperuricemia. Greater is the degree of hyperuricemia greater is the likelihood of developing Gout<ref name="pmid23895142">{{cite journal |vauthors=Gustafsson D, Unwin R |title=The pathophysiology of hyperuricaemia and its possible relationship to cardiovascular disease, morbidity and mortality |journal=BMC Nephrol |volume=14 |issue= |pages=164 |date=July 2013 |pmid=23895142 |pmc=3750299 |doi=10.1186/1471-2369-14-164 |url=}}</ref>.
--><ref>{{cite journal | author = Roberts-Thomson R, Roberts-Thomson P | title = Rheumatic disease and the Australian aborigine | journal = Ann Rheum Dis | volume = 58 | issue = 5 | pages = 266&ndasgh;70 | year = 1999 | id = PMID 10225809 | url=http://ard.bmjjournals.com/cgi/content/full/58/5/266}}</ref> In the United States, gout is twice as prevalent in African American males as it is in Caucasians.<!--
--><ref>{{cite web | author = Rheumatology Therapeutics Medical Center | title = What Are the Risk Factors for Gout? | url=http://www.arthritisconsult.com/gout.html#risk | accessdate = 2007-01-26}}</ref>
A seasonal link also may exist, with significantly higher incidence of acute gout attacks occurring in the spring.<ref>{{cite web | author =Schlesinger N, Gowin KM, Baker DG, Beutler AM, Hoffman BI, Schumacher HR Jr. | title = Acute gouty arthritis is seasonal. | url=http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9489831&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus | accessdate = 2007-09-27}}</ref> <ref>{{cite web | author = Gallerani M, Govoni M, Mucinelli M, Bigoni M, Trotta F, Manfredini R. | title = Seasonal variation in the onset of acute microcrystalline arthritis. | url=http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=10534553&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus| accessdate = 2007-09-27}}</ref>
Numerous reasons can lead to the development of an increase in the level of uric acids<ref name="pmid27112094">{{cite journal |vauthors=Dalbeth N, Merriman TR, Stamp LK |title=Gout |journal=Lancet |volume=388 |issue=10055 |pages=2039–2052 |date=October 2016 |pmid=27112094 |doi=10.1016/S0140-6736(16)00346-9 |url=}}</ref><ref name="pmid28233117">{{cite journal |vauthors=Schlee S, Bollheimer LC, Bertsch T, Sieber CC, Härle P |title=Crystal arthritides - gout and calcium pyrophosphate arthritis : Part 1: Epidemiology and pathophysiology |journal=Z Gerontol Geriatr |volume=51 |issue=4 |pages=453–460 |date=June 2018 |pmid=28233117 |doi=10.1007/s00391-017-1197-3 |url=}}</ref>:
Hyperuricemia is considered an aspect of [[metabolic syndrome]], although its prominence has been reduced in recent classifications. This explains the increased prevalence of gout among [[obesity|obese]] individuals.
*Enhanced or increased purine uptake.
*Decreased excretion of uric acid
*Increased production of uric acid
*Etiology in a lot of cases with rising uric acid levels is still unknown. <br />
Gout is a form of arthritis that affects mostly men between the ages of 40 and 50. The high levels of uric acid in the blood are caused by protein rich foods. Alcohol intake often causes acute attacks of gout and hereditary factors may contribute to the elevation of uric acid. Typically, persons with gout are obese, predisposed to diabetes and hypertension, and at higher risk of heart disease. Gout is more common in affluent societies due to a diet rich in proteins, fat, and alcohol.<ref>{{cite book|author = Robert S. Ivker, D.O. , et al | title = The Complete Self-Care guide to Holistic Medicine | year = 1999 | pages=186–8 | id = ISBN0-87477-986-J}}</ref> It is known that [[Lead(II) acetate|lead sugar]] was used to sweeten wine, and that chronic [[lead poisoning]] is a cause of gout,<ref>{{cite journal | author=Lin JL, Huang PT. | title=Body lead stores and urate excretion in men with chronic renal disease | journal=J Rheumatol | year=1994 | volume=21 | issue=4 | pages=705–9 | id=PMID 8035397}}</ref><ref>{{cite journal | author=Shadick NA, Kim R, Weiss S, Liang MH, Sparrow D, Hu H. | title=Effect of low level lead exposure on hyperuricemia and gout among middle aged and elderly men: the Normative Aging Study | journal=J Rheumatol | year=2000 | volume=27 | issue=7 | pages=1708–12 | id=PMID 10914856}}</ref> which condition is then known as '''saturnine gout,''' because of its association with alcohol and excess.<ref>{{cite journal | author=Ball GV. | title=Two epidemics of gout | journal=Bull Hist Med | year=1971 | volume=45 | issue=5 | pages=401–8 | id=PMID 4947583}}</ref>
Gout also can develop as co-morbidity of other diseases, including polycythaemia, [[leukaemia]], intake of [[cytotoxic]]s, [[obesity]], [[diabetes]], [[hypertension]], [[renal]] disorders, and [[hemolytic anemia]]. This form of gout is often called secondary gout. [[Diuretic]]s (particularly [[thiazide]] diuretics) have traditionally been blamed for precipitating attacks of gout, but a Dutch case-control study from 2006 appears to cast doubt on this conclusion.<ref>{{cite journal | author = Janssens H, van de Lisdonk E, Janssen M, van den Hoogen H, Verbeek A | title = Gout, not induced by diuretics? A case-control study from primary care | journal = Ann Rheum Dis | volume = 65 | issue = 8 | pages = 1080–3 | year = 2006 | id = PMID 16291814 | doi=10.1136/ard.2005.040360}}</ref>
'''Increased intake'''
(Images courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, CA)
The increased uptake is mainly related to
<div align="left">
*Increases intake of purine-rich food substances by the patient such as
Image:upper_hand_mcp_gout.jpg|Gout of Left MCP Joints: Diffuse redness and swelling over MCP joints caused by inflammation induced by gout. Right hand is normal, for comparison.
**The increased intake of all of these substances can increase the risk of accumulation of more and more purines ultimately resulting in the excess of uric acid.
Image:upper_wrist_gout.jpg|Gout of the Right Wrist: Note swelling and redness over right wrist area. Left wrist is normal.
</gallery>
</div>
*Beer is also particularly rich in guanosine which is a purine nucleotide.
<div align="left">
[[File:Gout pathogenesis.png|alt=Numerous factors and conditions responsible for the development of gout|thumb|469x469px|'''Pathophysiology of Gout'''
Image:upper_wrist_gout1.jpg|Gout of the Left Wrist: Note swelling and redness over left wrist area.
Image:upper_wrist_gout2.jpg|A normal wrist for comparison.
</gallery>
</div>
<div align="left">
'''Increased production'''
<gallery heights="175" widths="175">
Image:upper_tophaceous_gout2.jpg|Tophaceous Gout
Image:upper_gout_toph.jpg|Tophaceous Gout
</gallery>
</div>
The increased production is mainly
<div align="left">
*Increase in turn over of cells like in various hematological conditions such as Hemolytic anemia, leukemia, and lymphoma.
<gallery heights="175" widths="175">
*Conditions associated with an increased rate of cell proliferation and cell death.
Image:upper_toph_gout.jpg|Tophaceous Gout
**Cytotoxic therapy
Image:extremities_gout.jpg|Gout of the Left Great Toe: Diffuse swelling and redness centered at the left MTP joint.
**Radiation
</gallery>
**Psoriasis<ref name="pmid30317664">{{cite journal |vauthors=Hu SC, Lin CL, Tu HP |title=Association between psoriasis, psoriatic arthritis and gout: a nationwide population-based study |journal=J Eur Acad Dermatol Venereol |volume=33 |issue=3 |pages=560–567 |date=March 2019 |pmid=30317664 |doi=10.1111/jdv.15290 |url=}}</ref>
</div>
*Obesity - As the urate production is directly proportional to the body surface area
*Hereditary conditions[[File: Purine catabolism pathway.jpg|thumb|'''Enzymatic Pathway''' resulting in hyperuricemia- De novo synthesis pathway and HGPRT pathway http://themedicalbiochemistrypage.org/nucleotides-biosynthesis-catabolism/]]
Image:extremities_greattoe_gout.jpg|Gout of the Right Great Toe: Diffuse swelling and redness centered at the right MTP joint, but extending over much of the foot.
Image:upper_tophaceous_gout.jpg|Tophaceous Gout
</gallery>
</div>
'''Decreased/Reduced renal excretion'''
<div align="left">
This is the most common cause of hyperuricemia. Various factors responsible for its reduced elimination are:
<gallery heights="175" widths="175">
Image:extremities_gout_normal.jpg|Gout of the Knee: Image demonstrates redness and swelling caused by acute gouty arthritis.
Image:extremities_gout_inflamed.jpg|Picture demonstrates normal knee for comparison. skin changes seen in both legs are related to burns that patient suffered previously.
</gallery>
</div>
*Hereditary
*Compromised renal function ( Reduced GFR)
*On Diuretics<ref name="pmid27498351">{{cite journal |vauthors=Ben Salem C, Slim R, Fathallah N, Hmouda H |title=Drug-induced hyperuricaemia and gout |journal=Rheumatology (Oxford) |volume=56 |issue=5 |pages=679–688 |date=May 2017 |pmid=27498351 |doi=10.1093/rheumatology/kew293 |url=}}</ref>
*Alcohol intake<ref name="pmid26082349">{{cite journal |vauthors=Towiwat P, Li ZG |title=The association of vitamin C, alcohol, coffee, tea, milk and yogurt with uric acid and gout |journal=Int J Rheum Dis |volume=18 |issue=5 |pages=495–501 |date=June 2015 |pmid=26082349 |doi=10.1111/1756-185X.12622 |url=}}</ref>
**The lactic acid blocks the excretion of urate from the renal tubules. Alcohol induces the purine metabolism in the liver and increases the formation of lactic acid and
**Alcohol also directly stimulates the synthesis of urate by the liver
<div align="left">
*Drugs like cyclosporine that are toxic to the renal tubules leads to the decreased elimination of uric acid and ultimately resulting in the urate retention.
<gallery heights="175" widths="175">
Image:ChronicGout.jpg|Gout with tophi on elbow and knee.
Image:Gout (no birefringence).jpg|Gout (Needles, no birefringence, monosodium urate) <ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
[[Image:Gout case 1.jpg|left|thumb|400px|This is a gross photograph of an index finger from a patient with gout. The finger has been sectioned longitudinally to demonstrate the distal interphalangeal joint. Note the white chalky material within and adjacent to the joint (arrows). ]]
<br clear="left"/>
[[Image:Gout case 2.jpg|left|thumb|400px|This is a gross photograph of the elbow of this patient. The subcutaneous nodules (arrows) on this arm are tophi caused by gout. ]]
===Gross and Microscopic Pathology===
<br clear="left"/>
{| align="center"
|- valign="top"
|[[Image:Gout 0001.jpg|thumb|Kidney: Uric Acid Deposition: Gross, an excellent example of gouty nephropathy with deposits and excavation in pyramids]]
|[[Image:Gout 0002.jpg|thumb|Kidney: Papillary Necrosis: Gross, yellow foci in pyramids, a gout kidney]]
|[[Image: Gout (no birefringence).jpg|thumb|Gout (Needles, no birefringence, monosodium urate)]]
|[[Image: Gout 0003.jpg|thumb|Skin: Tophus: Micro med mag H&E uric acid deposits with giant cells. Easily recognizable as gout or uric acid tophus]]
|
|}
[[Image:Gout case 3.jpg|left|thumb|400px|This is a low-power photomicrograph of the tophus removed from the elbow of this patient. Note the fibrous connective tissue (1) and the large foci containing the urate crystals (2) surrounded by the intense chronic inflammatory reaction. ]]
[[Image:Gout case 4.jpg|left|thumb|400px|This higher-power photomicrograph of the tophus demonstrates the collections of urate crystals (1) and the inflammatory cells at the edge of these foci (2). ]]
<br clear="left"/>
[[Image:Gout case 5.jpg|left|thumb|400px|This is a higher-power photomicrograph of the edge of the tophus. Most of the urate crystals dissolve away during processing. The inflammatory cells at the edge of these foci are clearly visible (arrow). ]]
<br clear="left"/>
[[Image:Gout case 6.jpg|left|thumb|400px|This is a high-power photomicrograph of the edge of the tophus. The character of the intense chronic inflammatory cell reaction is evident and note the presence of giant cells within this inflammatory cell reaction (arrows). ]]
<br clear="left"/>
[[Image:Gout case 7.jpg|left|thumb|400px|This is a photomicrograph of a tophus that was fixed in alcohol prior to histologic processing. The alcohol fixation preserves the water soluble urate crystals within the tissue. Note the urate crystals visible in this photomicrograph (arrows). Also note the chronic inflammatory reaction in the background. ]]
<br clear="left"/>
[[Image:Gout case 8.jpg|left|thumb|400px|This is a gross photograph of a tophus on the great toe of another patient with gout (arrow). The healed surgical incision and the size of this tophus indicate that this was a long-standing problem for this patient. ]]
Image:Gout 0001.jpg|Kidney: Uric Acid Deposition: Gross, an excellent example of gouty nephropathy with deposits and excavation in pyramids
Image:Gout 0002.jpg|Kidney: Papillary Necrosis: Gross, yellow foci in pyramids, a gout kidney
Image:Gout 0003.jpg|Skin: Tophus: Micro med mag H&E uric acid deposits with giant cells. Easily recognizable as gout or uric acid tophus
</gallery>
</div>
<div align="left">
<gallery heights="175" widths="175">
Image:Gout 0004.jpg|Bone, synovium: Gout: Gross natural color opened joint with extensive white deposits of uric acid
Image:Gout 0005.jpg|Bone, synovium: Gout: Gross natural color close-up of extensive uric acid deposits
Image:Gout 0006.jpg|Bone, synovium: Gout: Gross natural color section through sternum and clavicle showing very well uric acid deposits in the periarticular tissue
</gallery>
</div>
<div align="left">
<gallery heights="175" widths="175">
Image:Gout 0007.jpg|Bone: Gout: Gross close-up of elbow with enlargement of proximal radius due to gout
Image:Gout 0008.jpg|Hand: Gout: Gross view of both hand with enlarged joints
Image:Gout 0009.jpg|Kidney: Gout: Gross natural color close-up view of uric acid deposit in medullary pyramid
</gallery>
</div>
<div align="left">
<gallery heights="175" widths="175">
Image:Gout 0010.jpg|Hand: Gout: Gross natural color
Image:Gout 0011.jpg|Urinary Tract: Staghorn calculi in renal pelvis, Gout
Image:Gout 0032.jpg|Kidney: Uric Acid Deposition: Gross good example uric acid streaks in medulla (very ischemic kidney)
Image:Gout 0033.jpg|Kidney: Uric Acid Nephropathy: Gross, natural color, an excellent view of hydronephrosis with inflamed pelvis and multiple calculi with deposits in medullary pyramids
</gallery>
</div>
<div align="left">
<gallery heights="175" widths="175">
Image:Gout 0034.jpg|Kidney: Uric Acid Deposition: Gross natural color close-up and excellent view of opaque material in medullary pyramid of adult kidney
Image:Gout 0035.jpg|Kidney: Uric Acid Infarcts: Gross natural color opened kidney showing marked ischemia with dark red medullary pyramids which contrast sharply with the uric acid deposits
Image:Gout 0036.jpg|Kidney: Uric Acid Infarcts: Gross natural color typical lesion well shown
</gallery>
</div>
<div align="left">
<gallery heights="175" widths="175">
Image:Gout 0037.jpg|Kidney: Uric Acid In Medulla: Gross natural color cut surface of kidney uric acid easily seen
Image:Gout 0038.jpg|Kidney: Uric Acid Infarcts: Gross natural color close-up outstanding photo of the uric acid streaks in medullary pyramids
Image:Gout 0039.jpg|Skin: Tophus: Micro med mag H&E easily recognized uric acid deposit lesion from elbow
Hyperuricemia is considered a multifactorial metabolic disorder in the general population. The levels of uric acid are influenced by the use of drugs, medications, renal impairment, and Alcohol also. The excess of uric acid levels gets deposited in the joints, kidneys, and a lot of tissue leading to clinical manifestations such as tophi, nephrolithiasis along the presence of urate nephropathy. Decreased excretion of uric acid contributes the maximum towards the development of Hyperuricemia. Along with the minimal contribution from other factors like increased production and increased consumption of foods rich in uric acid. The deposits in the joints, skin, and other tissues compromise the function of organs and resulting in the abnormal configuration of joint with funv=ctional limitation along with the presence of clinical signs in the form of pain and swelling.
Pathophysiology
In terms of pathophysiological classification, we can categorize gout into 2 main types
1) Primary gout: Mainly hereditary or related to enzymatic abnormalities
2) Secondary Gout: Secondary to other reasons like drugs, renal insufficiency, dietary or related to malignancy
The pathophysiology[1][2]of Gout mainly relates to hyperuricemia. Greater is the degree of hyperuricemia greater is the likelihood of developing Gout[3].
Numerous reasons can lead to the development of an increase in the level of uric acids[4][5]:
Enhanced or increased purine uptake.
Decreased excretion of uric acid
Increased production of uric acid
Etiology in a lot of cases with rising uric acid levels is still unknown.
Increased intake
The increased uptake is mainly related to
Increases intake of purine-rich food substances by the patient such as
The increased intake of all of these substances can increase the risk of accumulation of more and more purines ultimately resulting in the excess of uric acid.
Beer is also particularly rich in guanosine which is a purine nucleotide.
The lactic acid blocks the excretion of urate from the renal tubules. Alcohol induces the purine metabolism in the liver and increases the formation of lactic acid and
Alcohol also directly stimulates the synthesis of urate by the liver
Drugs like cyclosporine that are toxic to the renal tubules leads to the decreased elimination of uric acid and ultimately resulting in the urate retention.
Gross and Microscopic Pathology
Kidney: Uric Acid Deposition: Gross, an excellent example of gouty nephropathy with deposits and excavation in pyramids
Kidney: Papillary Necrosis: Gross, yellow foci in pyramids, a gout kidney
Gout (Needles, no birefringence, monosodium urate)
Skin: Tophus: Micro med mag H&E uric acid deposits with giant cells. Easily recognizable as gout or uric acid tophus
↑Schlee S, Bollheimer LC, Bertsch T, Sieber CC, Härle P (June 2018). "Crystal arthritides - gout and calcium pyrophosphate arthritis : Part 1: Epidemiology and pathophysiology". Z Gerontol Geriatr. 51 (4): 453–460. doi:10.1007/s00391-017-1197-3. PMID28233117.
↑Hu SC, Lin CL, Tu HP (March 2019). "Association between psoriasis, psoriatic arthritis and gout: a nationwide population-based study". J Eur Acad Dermatol Venereol. 33 (3): 560–567. doi:10.1111/jdv.15290. PMID30317664.
↑Ben Salem C, Slim R, Fathallah N, Hmouda H (May 2017). "Drug-induced hyperuricaemia and gout". Rheumatology (Oxford). 56 (5): 679–688. doi:10.1093/rheumatology/kew293. PMID27498351.
↑Towiwat P, Li ZG (June 2015). "The association of vitamin C, alcohol, coffee, tea, milk and yogurt with uric acid and gout". Int J Rheum Dis. 18 (5): 495–501. doi:10.1111/1756-185X.12622. PMID26082349.
.jpg)
