Gout (Podagra)

Dr. Weyrich's Naturopathic Functional Medicine Notebook

Overview

Gout is a painful inflammatory disease characterized by abnormal deposition of uric acid crystals, especially in tissues with limited blood flow, such as the synovial joint of the big toe. Acute attacks that are untreated may last from a couple days up to several weeks. Attacks often start at night. If untreated, attacks may recur with increasing frequency and longer duration.

Deposits (tophi) may also appear on bones, tendons, and under the skin, especially on the extensor surface of joints and the antihelix of the ear. On rare occasions, deposits may occur in the cornea of the eye.

Uric acid kidney stones and nephrotoxicity are other potentially serious sequellae of gout.

Effective treatment protocols consisting of diet and lifestyle changes along with herbal or pharmaceutical interventions are available. However, if left untreated, irreversible kidney damage, chronic arthritis, and recurring exacerbations are likely.

95% of patients suffering from gout are men over the age of 30. Gout is often called the rich man's disease because it is exacerbated by over consumption of rich foods and alcohol [Pizzorno2006, pg 1703].

Signs and Symptoms

Acute onset of symptoms may be triggered by overindulgence in rich foods and alcohol, minor trauma, or various forms of stress. Usually a single joint is affected, and the symptoms may resemble an acute infection: tumor, rubor, calor, dolor (swelling, redness, warmth, pain).

Fever/chills, tachycardia, and elevated WBC may be observed.

Etiology

Purines are a necessary cellular component, and are contained in DNA and RNA. Uric acid is a metabolic waste product of the normal degradation of purines.

The two main factors leading to gout are overproduction of uric acid and the under-elimination of uric acid, either or both of which can lead to precipitation of uric acid crystals. Since uric acid is more soluble in basic solutions, pH below 6.0 (acidic) tends to promote precipitation of uric acid crystals. Since uric acid is more soluble in warmer solutions, the precipitation tends to occur in cooler parts of the body, such as the helix and pinna of the ear and the feet, where blood circulation is reduced [Merck1999, pg 460].

More than one factor may contribute to the development of gout, including:

• Overproduction of uric acid:
  • Excess purines in diet.
    • Normal diet contains about 450 mg of uric acid precursors; a reduced purine diet can cut this to about 300 mg.
    • Foods high in purines: anchovies, sardines, organ meats (sweetbreads, kidney, liver), meat extracts. Other foods sometimes considered high in purines include yeast, meat, shellfish, herring, mackerel. Moderately high sources of protein are sometimes also considered, including dried legumes, spinach, asparagus, fish, poultry, and mushrooms [Pizzorno2006, pg 1706].
  • Excess alcohol consumption (alcohol induces nucleotide breakdown in the liver).
  • Increased purine production due accelerated cell turnover (purines are a degradation product of DNA and RNA).
    • Trauma, surgery, cancer chemotherapy, or radiation treatment.
    • Myeloproliferative diseases.
    • Lymphoproliferative disorders (lymphoma, leukemia).
    • Carcinoma or sarcoma (disseminated).
    • Hemolytic anemias.
    • Hyperproliferative skin disorders (psoriasis).
    • Cytotoxic drugs (cyclosporine).
  • Inborn errors of metabolism (genetic)
    • Family history. Polynesian.
    • Under-activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase.
    • Overactivity of the enzyme phosphoribosylpyrophosphate synthetase.
    • Lesch-Nyhan Syndrome.
    • Glycogen storage disease.
• Under-elimination of uric acid:
  • Excess alcohol consumption (alcohol is metabolized to lactic acid, which blocks renal excretion of uric acid).
  • Reduced renal clearance:
    • Reduced GFR due to kidney disease.
    • Diuretics (thiazide).
    • Low dose aspirin and salicylates.
    • Probenecid (low dose)
    • Ethambutol
    • Pyrazinamide
    • Lead poisoning (leaded crystal, moonshine).
• Low body pH:
  • Excess alcohol consumption (alcohol is metabolized to lactic acid).
  • Diabetic, fasting, or starvation ketoacidosis.
  • Lactic acidosis (toxemia of pregnancy, chronic beryllium disease).
• Dehydration
• Other Medications [Domino2008, pg 518]:
  • Aminophylline
  • Caffeine
  • Corticosteroids
  • Diazepam
  • Diphenhydramine
  • Diuretics (20% of secondary gout)
  • L-Dopa, dopamine, L-methadopa
  • Epinephirine
  • Methaqualone
  • Nicotinic Acid
  • Salicylates
  • Sulfinpyrazone (low dose)
  • Vitamin B12
  • Vitamin C
• Associated Risk Factors [Domino2008, pg 518]:
  • Obesity (50%)
  • Hypertension (50%)
  • Vascular disease
  • Hypothyroidism
  • Hyperparathyroidism, hypoparathyroidism
  • Hyperlipidemia types II, IV, V
  • Paget's disease (osteitis deformans)
  • Calcium pyrophosphate deposition disease
  • Sarcoidosis
  • Hemoglobinopathies
  • Pernicious anemia
  • Type I glygogen storage disease
  • Down Syndrome
  • Gut sterilization by antibiotics
  • Hemoproliferative disorders
  • Carpal Tunnel Syndrome
  • Diabetes insipidus [Pizzorno2006, pg 1705]
  • Barter syndrome [Pizzorno2006, pg 1705]
  • Glucose-6-phosphatase deficiency [Pizzorno2006, pg 1705]

Diagnosis

Definitive diagnosis of gout is made by detection of urate crystals in the aspirated synovial fluid of the affected joints. Tentative diagnosis may be made on the basis of history and physical examination [Merck1999, pg 461].

Serum urate may be elevated (70%) but is neither specific nor sensitive [Merck1999, pg 461].

X-ray may show punched-out lesions in subchondral bone and/or tophi, but these lesions are neither diagnostic nor specific [Merck1999, pg 461].

Differential Diagnosis

• Septic arthritis (bacteria in synovial fluid culture). Emergency!
• Pseudogout (calcium pyrophosphate dihydrate crystal deposition disease).
• Type IIa hyperproteinemia.
• Amyloidosis.
• Multicentric reticulohystiocytosis.
• Hyperparathyroidism.
• Spondyloarthropathy.
• Rheumatic and rheumatoid diseases.

Treatment

• Rule out septic arthritis (needle aspiration of synovial fluid).
• Monitor CBC, renal, LFT, and urinalysis at 1 week, 6 weeks, and every 3 months during drug therapy. On unrestricted diet, urinary excretion should be at least 800 mg/day; on purine-restricted diet, urinary excretion should be at least 600 mg/day (if less, then patient is a hypoexcretor) [Domino2008, pg 519].
• Monitor serum urate.
• Consider X-ray of affected joints (punched out regions with preservation of joint space) [Domino2008, pg 518].
• Palliate acute symptoms:
  • Avoid treatment with urate-lowering drugs during the acute phase, as they may exacerbate symptoms [Merck1999, pg 462].
  • Eliminate dietary triggers (alcohol, high purine foods).
  • Ensure adequate hydration to reduce precipitation of uric acid and to promote excretion via the kidneys.
  • Consider splinting of the inflamed joint to minimize exacerbating motion.
  • Natural therapeutics to reduce inflammation:
    • Eicosapentanoic Acid [Pizzorno2006, pg 1707-8].
    • Vitamin E [Pizzorno2006, pg 1707-8].
    • Selenium [Pizzorno2006, pg 1707-8].
    • Folic Acid [Pizzorno2006, pg 1707-8].
    • Bromelain [Pizzorno2006, pg 1707-8].
    • Quercetin [Pizzorno2006, pg 1707-8].
    • Consider Alanine, Aspartic Acid, Glutamic Acid, and Glycine [Pizzorno2006, pg 1707-8].
    • Cherries, Blueberries, and similar red-purple fruits [Pizzorno2006, pg 1707-8].
  • NSAIDs are the drug of choice to reduce acute symptoms. Full dose until attack is controlled, then reduce to half dose [Domino2008, pg 519]. Note possibility of gastric disturbance, and hyperkalemia due to decreasing prostaglandin E2-dependent renal blood flow, especially in elderly and dehydrated patients [Merck1999, pg 462].
  • Alternatively, colchicine 1 mg po q 12 hour until a response is obtained or until diarrhea or vomiting occurs, up to a maximum of 7 mg in 48 hours. Note that electrolyte imbalances induced by diarrhea may be life threatening in brittle patients [Merck1999, pg 462]. Colchicine therapy must be initiated within 24 hours of acute onset to be effective [Domino2008, pg 519] Colchicine is derived from the plant Colchicum autummale (Autumn crocus, Meadow saffron). It acts as an anti-inflammatory, by inhibiting neutrophil migration. Potential side effects include bone marrow suppression, hair loss, liver damage, depression, siezures, and respiratory depression [Pizzorno2006, pg 1706].
  • Alternatively, colchicine 1 mg in 20 mL 0.9% NaCl solution may be administered IV in a slow push (2-5 minutes), with no more than 2 mg administered in 24 hours. Note that severe bone marrow suppression and death may occur in patients receiving prophylactic oral colchicine when also given IV doses [Merck1999, pg 462].
  • Alternatively, after aspiration of the affected joint, 10 to 50 mg prednisolone tebutate can be instilled into the joint space [Merck1999, pg 462].
  • Alternatively, a single dose of ACTH 40-80 IU may be injected IM to stimulate endogenous corticosteroid production [Merck1999, pg 462] [Domino2008], pg 519.
  • Alternatively, a short course of oral prednisone 20 to 30 mg/day may be used [Merck1999, pg 462].
  • Other anti-inflammatories to consider include indomethacin, phenylbutazone, naproxen, and fenoprofen [Pizzorno2006, pg 1706].
  • If additional pain relief is required, consider a narcotic such as Vicodin 1-2 tabs po q 4-6 hours prn for pain, not to exceed 8 tabs/24 hours (do not take additional acetaminophen-containing products).
• Prevent recurrent attacks:
  • Colchicine 0.6 mg 1/day to tid (depending on tolerance and severity of gouty condition) can prevent most recurrences. An extra 1 to 2 mg of colchicine taken at the first hint of a flare-up may abort the flare-up. Note that chronic colchicine ingestion has been associated with neuropathy or myopathy. Also note that colchicine does not halt the disease progress, but only provides symptomatic relief [Merck1999, pg 462].
• Prevent precipitation of uric acid crystals:
  • Maintain adequate hydration (at least 3 L/day, more in hot/dry climates).
  • Avoid alcohol, which metabolizes to lactic acid.
  • Avoid diets that produce ketoacidosis.
  • Manage diabetes to avoid ketoacidosis.
  • Alkalize urine to reduce precipitation of uric acid in the kidneys and urinary tract. This is a balancing act - if the urine is made too alkaline then calcium oxalate crystals will precipitate instead [Merck1999, pg 463].
    • Sodium bicarbonate 5 g tid.
    • Alternatively, trisodium citrate 5 g tid.
    • Alternatively, acetazolamide 500 mg hs.
• Lower uric acid levels in body:
  • Maintaining low serum levels of uric acid ( < 0.45 mg/dL) can slowly (months to years) resolve deposits of uric acid crystals, thus preventing progression of the disease.
  • Reduce consumption of foods high in purines: anchovies, sardines, organ meats (sweetbreads, kidney, liver), meat extracts. Other foods sometimes considered high in purines include yeast, meat, shellfish, herring, mackerel. Moderately high sources of protein are sometimes also considered, including dried legumes, spinach, asparagus, fish, poultry, and mushrooms [Pizzorno2006, pg 1706].
  • Increase excretion of uric acid:
    • Avoid alcohol, which inhibits excretion of uric acid.
    • Probenecid 500 mg tab. Indicated if urinalysis indicates patient is a hypoexcretor [Domino2008, pg 519]. Start with 1/2 tab bid, increasing by 500 mg/day each month to 4 tab bid or until symptoms are controlled. Avoid NSAIDS, which antagonize probenecid (use acetaminophen). Initiation of probenecid treatment may give a temporary exacerbation of symptoms. Wait until acute symptoms have subsided, and maintain NSAID and/or colchicine dosage until probenecid treatment has been established. Contraindicated with uric acid overproduction, uric acid stones, renal impairment. Caution with tophi [Merck1999, pg 462] [Domino2008, pg 519].
    • Alternatively, sulfinpyrazone 100 mg tab. Start with 1/2 tab bid, slowly increasing to 4 tab bid. Avoid NSAIDS, which antagonize sulfinpyrazone (use acetaminophen). Sulfinpyrazone is more effective than probenecid, but is also more toxic. Initiation of sulfinpyrazone treatment may give a temporary exacerbation of symptoms. Wait until acute symptoms have subsided, and maintain NSAID and/or colchicine dosage until sulfinpyrazone treatment has been established [Merck1999, pg 463].
    • Fenofibrate 160 mg/day augments urate clearance [Domino2008, pg 519].
  • Destroy uric acid:
    • Rasburicase (Elitek) is a urate-oxidase enzyme that metabolizes uric acid, and is indicated when substantial purine overload is expected, as in cancer chemotherapy. See black-box warnings regarding anaphylaxis reactions and contraindications in patients with glucose-6 phosphate dehydrogenase deficiency or methemoglobinemia. Administration is by IV drip (not bolus) [Domino2008, pg 519].
• Prevent conversion of purines into uric acid:
  • If serum levels of uric acid exceed 0.9 mg/dL, allopurinol (Zyloprim) 100 mg/day in divided doses, increased by 100 mg/d each week to a maximum of 600 mg/day can be used to prevent the conversion of purines into uric acid [Domino2008, pg 519]. Initiation of allopurinol treatment may give a temporary exacerbation of symptoms. Wait until acute symptoms have subsided, and maintain NSAID and/or colchicine dosage until allopurinol treatment has been established. Potential side effects of allopurinol include mild GI distress, potentially dangerous skin rashes, hepatitis, vasculitis, and leukopenia. Contraindicated with bone marrow suppression, liver disease, and concomitant cytotoxic drugs. [Merck1999, pg 463] [Domino2008, pg 519].
• A new drug, febuxostat (Uloric - Takeda) is in the final approval stage by the FDA, and is promoted as being safer than allopurinol in patients with impaired kidney function. Dosing is 80-120 mg/day [Domino2008, pg 519].
• Excise large superficial tophi (consider biopsy using anhydrous specimen container).
• Other dietary interventions:
  • Reduce fat intake to decrease uric acid retention [Domino2008, pg 519] [Pizzorno2006, pg 1706-7].
  • Reduce refined carbohydrate intake to reduce uric acid production [Pizzorno2006, pg 1706-7].
  • Limit protein intake to 0.8 g/Kg body weight, since excess protein enhances production of uric acid. Note however that amino acids help enhance excretion of uric acid [Pizzorno2006, pg 1706].
  • Increase complex carbohydrate intake [Pizzorno2006, pg 1706].
• Treat comorbidities and predisposing factors.
  • Obesity: Weight reduction in obese individuals significantly decreases serum uric acid levels. A low-glycemic diet designed to improve insulin sensitivity is alkalinizing, which also benefits gout [Pizzorno2006, pg 1707].
  • Hypertension
  • Dyslipidemia
  • Diabetes

Sequelae

Untreated chronic elevations in uric acid lead to repeated exacerbations of gout and uric acid nodules (tophi), and predispose for kidney stones.

Damage to the kidney (nephritis) caused by the excess uric acid leads to a vicious downward spiral of decreased excretion of uric acid, increased levels of retained uric acid, and increased kidney damage.

With proper adherence to preventative measures most patients can live normal lives.

Hypotheses

The diet recommended by [Pizzorno2006, pg 1706] appears to be particularly beneficial for persons with severely compromised renal function. A less aggressive approach that allows more protein in the diet may be appropriate for persons with normal renal function.

ICD-9 Codes

ICD9-Code	Description	Comments
274.0	Gout, joint
274.10	Gout, nephropathy
274.11	Uric acid kidney stone
274.81	Gout, tophi of ear
984.9	Lead toxicity	Potential cause of gout.

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References

Unless specifically noted above, references used in the construction of this web page include the following:

[FDM] Lecture notes from Functional Medicine University.

[SCNM] Lecture notes from Southwest College of Naturopathic Medicine.

[UT] Lecture notes from the University of Tennessee graduate programs in Chemistry and Biochemistry.

[Merck1999] Merck Manual, 17th Edition (Centennial). Whitehouse Station NJ: Merck Research Laboratories (1999).

[Domino2008] Frank J Domino. The 5-Minute Clinical Consult 2008, Sxteenth Edition. Philadelphia: Lippincott Williams & Wilkins (2008).

[Pizzorno2006] Joseph E Pizzorno, Michael T Murray. Textbook of Natural Medicine, Third Edition. St. Louis: Churchill Livingstone (2006).

[WWW.ARTHRITIS.ORG] http://www.arthritis.org/conditions/diseasecenter/gout.asp

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