Crystalline Arthritis (Gout) Flashcards
What defines hyperuricemia?
• how long does hyperuricemia have to persist before the onset of gout?
• Where does gout typically occur when it onsets? Resolution?
Serum urate greater than 7.0 mg/dL is defined as hyperuricemia. Levels of urate must persist above these levels for a 20-30 years before we start to see the first incidence of gout which typically occurs in the 1st MTP (podagra). Resolution of gout typically occurs in 5-7 days.
Where else should you look for the manifestations of gout in a patient with hyperuricemia?
tophi may be present over the extensor surface of upper or lower extremity joints. Monosodiumurate may also deposit in the kidney causing renal failure. (not infrequent in people with chronic gout)
T or F: Gout is a monoarticular disease and if you see more than one joint involved this rules out gout.
False, in late stages of gout the disease may strongly resemble RA.
What are the 2 major causes of:
• Primary hyperuricemia?
• Secondary hyperuricemia?
Primary hyperuricemia is caused by underexcretion of Uric acid in the kidney 90% of the time with overproduction being a problem 10% of the time.
Secondary is also usually a problem with renal clearance and is less commmonly (less than 1%) a problem with overproduction
What 4 metbolites kick off the Purine Degradation pathway?
• what enzymes act on these?
• what products are produced?
What metabolites and enzymes are involved in the second phase of catabolizing Purines?
What enzyme is responsible for converting Adenosine to Inosine?
• What does a deficiency in this cause? why?
• How is this disorder inherited?
Adenosine deaminase (ADA) converts adensosine to inosine and is vital to the survival of Lymphocytes that are extremely metabolically active. Without this enzyme deoxyadenosine builds up in the cell is toxic killing off lymphocytes and causing SCID. Inheritance of this SCID phenotype is autosomal recessive.
What is the common metabolite of the purine degradation pathway?
• what enzyme works on this metabolite? What final product is produced?
Xanthine is converted to Uric Acid => this is the final step in humans. This is performed by XANTHINE OXIDASE
What two enzymes are important in recovery of purines from the purine degradation pathway?
• what is the inheritance of Lesch-Nyhan syndrome?
APRT and HGPRT
• Lesch-Nyhan is an X-linked recessive disorder resulting in a lack of HGPRT that is characterized by gout, mental dysfunction, self-mutilation.
How is Uric Acid Filtered in the Kidney?
ALL of the uric acid that passes through the glomeruli (100% filtration) is pushed into the tubular fluid (pre-urine) and virtually ALL of that uric acid is initially reabsorbed. About half of the reabsorbed urate is secreted BACK into the preurine (via Organic Acid Transporter - OAT). Reabsoprtion of uric acid then happens a 2nd time via a Brush Boarder Transporter. 8-12% of the uric acid filtered by the glomeruli initially is actually peed out.
What transporters are involved in urate resorption?
- URAT1
- OAT4
- OAT10
What uric acid transporters are involved in uric acid secretion?
- OAT1
- OAT3
- ABCG1
- MRP4
- NPT1,4
85-90% of hyperuricemias are caused by underexcretion of uric acid. What accounts for the other 10-15%?
- Defects in regulation of purine nucleotide synthesis (Lesch-Nyhan)
- Disordered ATP metabolism
- Increased Rates of Cell Turnover (cancer, chemo)
In underexcretors who make up the majority of your Gout patients what is abnormal about their rate of urniary uric acid excretion?
• What do these people have a higher serum urate concentration than your average joe?
The RATE of excretion in these patients is fine but excretion is not keeping up with steady state demands due to decreased EFFICIENCY of urate excretion. Therefore, a higher serum concentration is required to build the gradient high enough to achieve the same rates of excretion.
Why are men more prone to gout than women?
• physiologic explaination?
Men have a 1200 mg urate pool (2x of what women have). Estrogen is thought to increase the rate of renal urate excretion in premenopausal women.
How is urate absorbed and excreted in the intestines?
• Urate is Passively absorbed in the intestines and intestinal bacteria are responsible for digesting about 1/3 of all uric acid taken in allows us to excrete it in feces. `
What two general methods are there of urate deposition in tissue are there and what implications does this have on the duration needed for treatment to be effective?
Uric Acid may deposit:
- Occultly
- As Tophi
Occult uric acid storage may serve as a reservior that resists any major changes in serum urate concentrations after you initiate treatment
***Explain the inflammatory response in gout***
LEFT:
Uric acid crystals tend to deposit in synovial joints due to cooler temperatures and acidic environments. Crystals themselves may:
a. Activate complement causing C5a release and MAC formation
b. get engulfed by Synovial Macrophages or Mast Cells which release IL-1ß and Histamine (respectively) as well as other mediators
IL-1ß and C5a act as neutrophil chemoattractants
RIGHT:
a. Complement and Ig Coated Crystals may promote IL-1ß, IL-8, TNF, and protease release from neutrophils
b. Naked Crystals may lyse neutrophils and lead to the release of ROS, proteases, LTB4, etc.
**The end result is severe and rapidly progressing inflammation synthesis of LTB4 is important in chemotaxis which recruits and upregulates factors that allow neutrophil entry in to inflammed site.**
Where are some places that you should look for Tophi in?
- Digits
- Ears
- Bursae (oclecranon)
- Achilles Tendons
Is gout a process that is destructive to the joint?
Yes, think about all the damage that occurs as a result of neutrophil content release
What are some key features of this radiograph showing gouty arthritis?
- Solf Tissue distortion
- Erosions with Sclerotic Margins and Overhanging edges
- Minimal Joint space narrowing is minimal despite large erosions
**These changes are typical of bony tophi**
Are genetic defects leading to the onset of Primary Gout typically Polygenic or Monogenic?
• what monogenic gene products are typically altered in Primary Gout?
• which is a more common reason for primary gout: Underexcretion or Overproduction?
Primary Gout is typically a disease of underexcretion of uric acid as a result of polygenic factors. Overproduction is also polygenic and account for about 10% of primary gout cases. A small fraction of Primary gout is caused by monogenic problems such as a recessive inheritance of mutations leading to increased production/activity of PRPP synthetase or and x-linked inhereitance of PARTIAL losses of HGPRT production/function.
What is it called with you have surplus PRPP driving purine synthesis. Is this a Primary or Secondary condition causing hyperuricemia?
Kelley-Seegmiller syndrome - this is a primary cause becuase overproduction of this enzyme doesn’t lead to other debillitating defects like those seen in FULL loss of HGPRT where the gout is not the PRIMARY focus of the clinical picture
What are 3 specific enzyme defects associated with secondary gout?
• are these monogenic or polygenic?
• Inheritance?
What are the indications for prescribing a Xanthine Oxidase inhibitor in patients?
• what agents should you try first? name them.
Try Uricosurics first. These are Probenecid, Benzbromarone, and Sulfinpyrazine
