9-24 Gout Pathophysiology PDF

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Gout Objectives  Define gout  Describe gout risk factors  Define the clinical features of gout  Describe the manifestations of attacks of gout at different stages of development  Describe appropriate treatment for the different stages of gout and their mechanism of action Overview  What is gout?  Etiology and risk factors  Uric acid  What is Podagra?  Clinical presentation of gout  Drugs used for treatment for the different stages of gout and their mechanism of action Case 

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A 68-years-old man presents to the ED with acute swelling and pain in his right knee. He recalls no trauma. It started suddenly about 2:30 AM and is getting worse. He can no longer bear weight on his right knee because of the excruciating pain. He tried ibuprofen, but the pain remains +10/10. He works as an accountant, denies smoking or drug use. He’s monogamous with his wife of 25 years. He had 4 beers last night while watching the football game. He says he drinks about 2-3 drinks per week but drank a bit more than usual last night. PMHx: Six months ago, he had acute pain in his great toe that resolved after 3 days without treatment. He has a history of hypertension (controlled by amlodipine, hydrochlorothiazide) and diabetes (controlled by metformin). He’s also taking low dose aspirin. Vitals: T 100.1, BP 142/74, HR 95, RR 15, BMI 32. PE: The right knee is swollen and warm. It is tender to palpation with passive range of motion. All other joints are normal. TX: The patient was prescribed a medication to reduce the pain. His joint was aspirated, and then was started on another medication to prevent future attacks. o Second attack of gout. First attack usually happens in big toe (first metatarsal joint), but could happen elsewhere.

Gout Introduction  Has been recognized for centuries as disease of the kings (Pharos, Henry VIII, Benjamin Franklin) o Associated with people who eat more meat- purines in meat  A metabolic disease characterized by recurrent attack of acute inflammatory arthritis caused by chronically elevated levels of uric acid in the blood (hyperuricemia)  Gout= monosodium urate (MSU) crystals deposit within the joints. The uric acid crystallizes and deposits in joints, tendons, and surrounding tissues o Cause severe inflammation and pain o Consider gout = hyperuricemia, but an acute attack will not always result from high levels of uric acid  Hyperuricemia: overproduction/underexcretion/both. However, Hyperuricemia ≠ Gout  In pseudogout, calcium pyrophosphate crystals are deposited (CPPD)  Crystals produce disease by triggering the cascade that results in cytokine-mediated cartilage destruction. Prevalence (NOT IN REVISED SLIDES)  Gout continues to occur more commonly in developed countries  In the US, the prevalence is increasing (21.4% of adults in 2008 compared to 18.2% in 1998) 1

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The increased prevalence of gout and hyperuricemia may be partly explained by the aging of the population, the obesity epidemic (twice the rate of gout), dietary and lifestyle and the increased consumption of alcohol and sugary drinks More gout cases are seen in older adults aged 80 years and older. Prevalence levels jumped from 5.9% to 12.6%. This is mostly related to medications (for hypertension, cancer) or not drinking enough water  dehydration

Etiology  Gout is a disorder resulting from high concentration of uric acid in the blood due to underexcretion (10%) or overproduction (90%) or both  However, not all patients with a high blood uric acid level get gout and having a low blood uric acid level does not rule out gout as a diagnosis. That’s why serum levels of uric acid cannot be used to diagnose gout.  Multifactorial: genetic and others o Genetic mutations: in urate transporters URAT1 and GLUT9  In younger individuals  In a genetically susceptible individual, certain circumstances may trigger the condition

Oxidation by xanthine excretes through kidneys. More uric acid will deposit MSU crystals and result in acute flare or systematic hyperuricemia. Risk Factors  High levels of urate in the blood (hyperuricemia)  Males > 55 years and younger if hereditary factors involved. More gout cases are seen in older adult patients. M:F ratio 3:1 in > 65 years old  Postmenopausal female (estrogen promotes UA excretion)  Renal insufficiency  reduced excretion of uric acid and deposition of the MSU crystals  High BMI (obesity) higher incidence of gout, but unknown why.  Alcohol intake (especially binging)- most pt’s caused by excess ETOH (interferes with secretion of uric acid), or eating lots of meat  Fructose and sugary drinks  metabolism leads to release of purines  Diet high in purine content, such as meat & seafood  more purines  more uric acid  Pharmaceuticals: o Diuretics (given to hypertensive patients to reduce the blood volume  elevated MSU concentrations) o Cyclosporine (given in transplant patients to prevent rejection is toxic to kidneys reduced excretion) o Aspirin: low doses raise uric acid levels, while high doses lower uric acid levels (mildly) 2

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AVOID in TX gout d/t this variable effect Anything in general that affects the kidney will affect uric acid excretion

Uric acid  Ionized forms of uric acid are found as the monosodium urate at pH 7.4. Normal serum urates levels identified in individuals without gout symptoms are: 3.5 and 7.2 mg/dL in adult males and postmenopausal women, and between 2.6 and 6.0 mg/dL in premenopausal women.  Uric acid permits the necessary removal of nitrogen waste from the body  Uric acid may play a role in immunity as an adjuvant  Endogenously, uric acid is produced when the cells break down (by virus, trauma or chemo) leading to producing a “danger signal” to the immune system for the body to get rid of the dead cells  Uric acid is a weak acid that may exert antioxidant effects  Only humans lack uricase, the enzyme responsible for the degradation of uric acid in other mammals. This, in combination with a high reabsorption rate of filtered urate, predisposes humans to hyperuricemia and gout.  Normal Uric acid levels are 2.4-6.0 mg/dL (female) and 3.4-7.0 mg/dL (male). - When uric acid levels are high, it crystallizes as the levels would exceed its solubility levels, so it accumulates where circulation is slow, like in joints.  Removes nitrogen waste, ammonia, through its detoxification into the relatively- nontoxic urea or uric acid  UA crystals potently induce Th17 responses both in vitro and in vivo. These effects were dependent on the inflammasome-related cytokines IL-1α/β and IL-18,An adjuvant is a substance that enhances the body’s immune response to an antigen Pathogenesis  Hyperuricemia results in supersaturation of extracellular fluids and deposition of MSU crystals in the joints  Gout is manifested by recurrent attacks of acute inflammatory arthritis, the development of uric acid stones and renal disease  Acute gout, also called podagra (first attack in the one joint) when it affects the first metatarsophalangeal joint. o Happens in first big toe joint: d/t colder temperature of feet. Crystals tend to deposit at lower temperatures.  Gout is diagnosed mainly by aspiration of the joint fluid (arthrocentesis) shows negatively birefringent needle-shaped crystals  Uric acid blood levels can be high or low during a gout attack. That’s why it is not used for diagnosis of gout Causes of Hyperuricemia (NOT IN UPDATED SLIDES)  Impaired excretion of uric acid = 10% o Chronic renal disease o Drug therapy, e.g. thiazide diuretics, low-dose aspirin, cyclosporine o Hypertension o Lead toxicity o Primary hyperparathyroidism or hypothyroidism o Increased lactic acid production from alcohol, exercise, starvation o Glucose-6-phosphate dehydrogenase deficiency and sickle cell anemia  RBCs destruction  altered renal function  reduced excretion o Alcohol  Increased production of uric acid = 90% o Increased purine synthesis de novo due to:  Hypoxanthine-guanine-phophoribosyl transferase (HGPRT) reduction (an X-linked inborn error causing Lesch-Nyhan syndrome  Phosphoribosyl-pyrophosphate synthase over activity  Glucose-6-phosphatase deficiency/ Glycogen storage disease type 1 (Von Gierke disease) o Increased turnover of purines due to: 3

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 Myeloproliferative disorders, e.g. polycythemia vera  Lymphoproliferative disorders, e.g. leukemia  Others, e.g. carcinoma Increased consumption of diets rich in purines (meat, shellfish, organ meat)

Lesch-Nyhan Syndrome (NOT IN UPDATED SLIDES)  Begins in 1st year of life, X-linked  Absence of the HGPRT  buildup of hypoxanthine and guanine  increased de novo purine synthesis   Excess UA in urine  orange crystals in the diaper of affected children  kidney failure and gout  Reduced levels of dopamine  Intellectual disability, emotion and behavior changes  compulsive nail biting and self-mutilation +  Hypotonia and delay in reaching childhood milestones  ballismus, chorea, and head banging  TX: allopurinol (or febuxostat), benzodiazepines to reduce anxiety

Joint Structure

Joint capsule on outside. Inside includes synovial membrane (smooth). Outside of synovum is lots of capillaries, which will bring from blood into joint. What we eat reaches the joint via this blood, hence, uric acid deposits. Also mechanism for why septic arthritis can occur. Gout Stages  Asymptomatic hyperuricemia  Acute Flares of crystallization (first attack goes away in a few days, painful, but goes away without medication)  Intervals between flares (intercritical periods)  Advanced Gout & Complications

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Acute gouty arthritis (Pedagra)  can be first, 2nd, etc. ACUTE ATTACK!  The initial symptoms of a gouty attack are sudden and violent, taking place nearly always at night or early morning hours  The patient feels a sudden onset of pain often affecting the big toe 1st MTP joint, which becomes rapidly red and swollen; the veins of the leg can become dilated, and the leg can become purple and sometimes accompanied by bruising  90% 1st attacks are monoarticular  50% are podagra  If left untreated it resolves in 3-10 days  Acute synovitis in the ankle and first MTP joints  Acute Gouty Arthritis: Diagnosis (Dx) o Clinical picture, history, PE o Observation of monosodium urate crystals in synovial fluid leukocytes (via arthrocentesis) o Monosodium urate crystals are  needle-shaped  negatively birefringent o Serum urate levels: Not reliable, maybe normal with flares, not specific; maybe high with other joint lesions 

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Negative Birefringence o When the axis is oriented so that it is parallel to the long axis of the crystal, the color of the crystal will appear yellow, if perpendicular it will appear blue o Negatively birefringent needle-shaped crystals o A negatively birefringent needle-shaped crystal is in all probability an MSU crystal. o Crystals that are capable of polarizing light are referred to as being birefringent. So, both the MSU and CPPD crystals are birefringent. o This means that they have the ability to split a single beam of light into 2 beams rotating 90° from each other. o A crystal that rotates the beam clockwise is said to have positive birefringence; a crystal that rotates the beam counterclockwise has negative birefringence. o She mentioned that the bright means negative just to make you remember that the bright needleshaped crystals of gout are negatively birefringent, and to differentiate them from the less bright (and actually more difficult to identify) positively birefringent CPPD crystals

crystals of the gout are NEEDLE SHAPED, negatively birefringent/appear blue Elevated uric acid levels only occur in people who have gout. A. True B. False What do I do to a patient who has high levels of uric acid with no symptoms?  lifestyle modification Intervals between flares (intercritical periods)  Asymptomatic- still dangerous bc still high levels of uric acid  If untreated, may advance  Intervals may shorten  Crystals are being deposited in joints  Body urate stores increase  Silent deposition of tophi: deposits of urate crystals in the skin. Chalky in texture. o Tophi are monourate crystals deposited in joins, skin, etc.  Silent damage of the joint  Repetitive precipitation of urate crystals  visible deposits in the synovium

Advanced gout  Chronic Arthritis  Synovium becomes hyperplastic and fibrotic and thickened by inflammatory cells  destruction of the underlying cartilage bone erosions  A pannus of granulation tissue grows over the articular surface and invades and replaces the cartilage.  In severe cases, fibrous or bony ankylosis ensues (disappearance of the joint space)  loss of joint function  X-ray changes: showing bony erosions  More tophi develop  Polyarticular acute flares with upper extremities more involved  Acute flares continue 6

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Gouty nephritis Turn into osteoclasts (bone-eroding cells), become bony erosions underneath as the disease progresses. Fibrosis (inflammation/loss of function), fusion of two bones together (anklisosis)

Chronic inflammation in gout  Stimulated by the repetitive precipitation of MSU crystals  inflammatory response  Chronic inflammation is characterized by: o Infiltration by mononuclear cells including macrophages, lymphocytes, and plasma cells.  Macrophage are typically divided into two broad subtypes M1 (classical) and M2 (alternate).  SPECIAL MACROPHAGES!  M1 = Cancer, continue process of inflammation  M2 = stop the process of inflammation  If these are not successful, they will continue to be inflammatory and body will not be able to control inflammation.  M1 is proinflammatory  primary function: eradicating/removing the offending agent  M2 is anti-inflammatory  primary function: resolution of inflammation through tissue repair.  The activation of M1 and M2 macrophages produces the varied morphological tissue patterns seen in chronic inflammation.  Tissue destruction  Attempts at healing/tissue repair

cause inflammation by stimulation of TH17 (keep inflammation going) Gout likes OA... most patients will have OA and develop gout after. Goes undiagnosed, especially in women because we think gout always happens in men, but also happens in women. (Gout DX by arthrocentesis, if seeing negatively birefringent crystals) Common sites of tophi deposition

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Can occur in other joints, bursa & tendons

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Tophi are dermal and subcutaneous deposits of MSU crystals. Generally occur after 10 years or more of recurrent polyarticular gout. Tophi are larger than the MSU joint crystals. Their consistency is usually hard, chalky and destructive to underlying joint and bone. The overlying skin may be normal or colored pink or violet. Most typically the skin is thin, and the whitish color of the urate deposit is seen. Subcutaneous tophi are mostly seen in the vicinity of joints, which can be simultaneously affected by gout. Pathognomonic of gout (high confidence in the disease) Exophthalmos in hypothyroidism  bulging eyes is pathognomonic for TSH. Punched out erosions “rat bite” erosions

bony erosions, bone underneath. Joints are destroyed. Gouty nephropathy  The precipitation of uric acid in the renal medulla with formation of characteristic tophi  These will evoke an inflammatory response leading to fibrosis, a loss of nephrons, and ultimately to chronic irreversible renal failure o Need transplant Diagnosis  Hx & PE  Synovial fluid analysis (arthrocentesis)  negatively birefringent needle-shaped crystals under the polarized microscope Treatment of Gout  The recommendations of the American College of Rheumatology (ACR) guidelines for gout management focus on: o terminate the pain of the acute attack, o prevent recurrent attacks of gouty arthritis, o prevent complications associated with chronic deposition of urate crystals in tissues.  These can be accomplished through a combination of pharmacologic and nonpharmacologic methods, including focused patient education efforts. Patient Education  Maintaining a healthy body weight, exercise  Avoiding excessive intake of purine-rich foods  Restricting intake of alcohol  Avoiding foods rich in fructose and sucrose  Drinking plenty of water to dilute and assist urate excretion  Avoiding prolonged exposure to low temperature

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IN BETWEEN ATTACKS

Under-secretors Probenecid Over-producers  Allopurinol

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Uric acid either reabsorbed/secreted in renal tubules. How do NSAIDs and corticosteroids work?

Colchicine: used to relieve acute attacks (KNOW TUBULIN MOA!!!!!!)  Given to patients who cannot tolerate NSAIDs o First line: NSAIDs o Some think that it can be used for ppx, but it should not be!  Binds to tubulin in cells  inhibits tubulin (microtubules near nucleus, like train tracks. Drug binds microtubules- protein is tubulin) polymerization  inhibits microtubule formation (important for cell division, so prevents neutrophil production)   Inhibits the function of neutrophils (migration and phagocytosis)  Inhibits inflammasome and IL-1 production  Inhibits the release of histamine  Inhibits leukotriene-mediated chemotaxis  Side effects: diarrhea (can be severe) & neuromyopathic effects. Only used orally. Urate lowering therapy: Allopurinol  Allopurinol is the preferred and standard-of-care therapy for gout during the period between acute episodes. It reduces total uric acid body burden by inhibiting xanthine oxidase (enzyme that makes uric acid at end of pathway). o The prodrug is converted by xanthine oxidase  alloxanthine, which inhibits XO  reduce purine metabolism  reduce uric acid o Dose needs to be adjusted to maintain UA at levels < 4 mg/dL  Side effects: rash, always check renal functions with these drugs

stops the production of uric acid! 

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Allopurinol use in cancer o In rapidly dividing cancer cells (leukemia or lymphoma) or tumors with rapid response to chemotherapy, e.g. CLL or SCLC

Sudden lysis of tumor cells  release large amounts of purines and other metabolites (K+, phosphorus)  can result in acute kidney injury and increased UA levels o To protect the patients’ kidneys from tumor lysis syndrome is the administration of allopurinol with chemotherapy. Blocking uric acid synthesis reduces the load on the kidneys and can prevent kidney stones and renal failure. o Sudden lysis of tumor cells  hyperuricemia, hyperPhos, hyperK. Allopurinol drug interaction o If allopurinol is taken with azathioprine (immunosuppressive drug given in some autoimmune disorders), it interferes with the metabolism of its toxic metabolite, 6-mercaptopurine  can cause aplastic anemia  Usually inhibited by xanthine oxidase, so inhibiting this and using azathioprine is dangerous! o 6-mercaptopurine, is normally inactivated by xanthine oxidase which we inhibited by allopurinol). o

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Probenecid  Probenecid increases UA excretion in urine by inhibiting its reabsorption. Can precipitate kidney stones.  Drug interaction: o Probenecid interferes with the renal secretion of penicillin, other beta-lactam antibiotics, and methotrexate  decreasing their renal clearance + increasing their half-life  elevating their plasma concentrations. So, dose adjustment is necessary

Probenecid

Losartan/HCTZ combo has synergistic effect for treatment of gout, per HTN lecture. But new study shows ARBs are associated with lung cancer. ASA is not among the list of drugs for treating gout's acute episodes because A. Aspirin (in low doses) decrease uric acid excretion (low doses increase uric acid levels) B. Aspirin stimulates xanthine oxidase production C. Aspirin induces leukocyte proliferation In an acute gout attack you treat the patient with allopurinol A. True B. False Prevent this!

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SAMPLE EXAM QUESTIONS A 32-year-old man recently underwent a liver transplant and was prescribed cyclosporine to reduce the ...