CONNECTIVE TISSUE Lecture 33 Page 16 of 6
CT 5/10/00 11-12
Lecture 33
Dr. Carsons
Papishule
Gout, and how to make rock candy from urate
CONTEST ANNOUNCEMENT!!! In order to make your learning more fun and fruitful, I have
endeavored to make a game out of this transcript. Throughout this transcript I have made 10 references
(stylistic or otherwise) to other transcribers/students that have repeatedly entertained us over the past two
years. Email me with a list of all of the references (in order as they appear) and the first person to get it
right gets one dollar! If you do not get the order right, the e-mail I return to you, the dollar I keep for
myself. PS. If I somehow offend you who I mock, it‟s only a joke…no hard feelings
First off, I spoke to Dr. Carson after class and he told me that he might have put questions on the test, but
he probably didn‟t. This could mean that the only questions concerning this material come from the
handout, but it might not. You can interpret it however you like, but I thought I might as well share.
I. Intro.
In contrast to the previous lecture‟s topic of osteoarthritis, Gout is a very dramatic disease which is
exceedingly painful, the original description by Sir Alfred Gara in the 1800‟s stated that the pain
was so bad that the “patient couldn‟t tolerate the weight of a bedsheet on his foot.” It occurs in
middle/younger age subset compared to OA (but the elderly get it too).
I. Basic Pathogenesis
-gout
-combination,
-metabolic hyperuricemia +
-inflammation
-Important b/c Tx.differs. a lot.
II. Some Definitions
Okay, the first definition which I‟d like to tell you all about is acute gouty arthritis. Acute gouty arthritis is
sort of an acute, self limited and sometimes (usually actually) recurrent attack of articular and periarticular
inflammation. When I say inflammation I‟m referring to the reaction that occurs with lots of white cells
and cytokines, which can even give you systemic reactions like fever!!!! (I know, it‟s crazy)…So anyway,
in between these acute attacks which are very painful there‟s usually an asymptomatic period, basically a
period in which no symptoms are arising. While this is generally true, occasionally you can have a patient
with chronic and persistent gout!!! That‟s gotta be horrible. I have an uncle with gout and he sure is
unhappy a lot of the time. Whhew!!! So that‟s the first definition. The second definition is the word
“tophus”. A tophus is not tofu!! They‟re very different. You see, a tophus is a non-inflammatory deposit
of uric acid that can accumulate in tissues. It can usually occur at the elbow or any other place in which
pressure is put on the body. Now this is important, it says in the handout we were given that these tophi are
made of uric acid crystals, but that’s not what he said in class!!!He said that sometimes, the tophus can be
both uric acid non-crystal, and uric acid crystals I don‟t know whether it really makes a difference but
figured I‟d tell you all just in case. Just lookin’ out for you guys!!!. Okay, that said, the last definition
concerns uric acid and the kidney, you see when there is too much uric acid floating around in the urine
which is made by the, you got it, the kidney, that uric acid can precipitate out and form stones, these stones
can cause a lot of damage as you all well know. They call these stones “Uric Acid Calculi”. Okay we got
all the definitions right here in roman numeral three…let‟s move on…
*he showed a picture of a middle age man with a slipper on one foot not bearing weight on the leg because
he was overwrought with pain in his toe from an acute attack of gout. He looked unhappy*
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II. How it all Happens…
The excess uric acid come from excess metabolic breakdown of nucleotide and “some other
precursors”. One third of the excess nucleotide come from the diet, things big in nucleotides are
the basis of legumes (lot of cell division going on there) and organ meet such as liver, kidney, and
brain. Dr. Carson feel that you have to be crazy to eat brain (probably not because of the inherent
infectious risks such as Prion disease, but more because it‟s disgusting).
The other two third of excess nucleotides come from endogenous sources like the
breakdown of your own cells. This was accelerated if you have a high cell turnover, i.e. are
undergoing chemo for a lymphoma for example. The normal total uric acid pool is 1000 mg/day.
This excess ok and will not be pathogenic as long as you excrete the urate appropriately.
Normally, one third excretes in the gut 200mg (bacterial degradation~ 200 mg/day) and two thirds
are excrete renally (600 mg/day). This is usually where the problem arises. As we age our GFR
go down, we develop slight renal insufficiency etc…we can‟t eliminated as well and this can
increase the uric acid concentration. If this happen in kidney you get Calcium stones NC2..
III. Mechanisms of Hyperuricemia
Idiopathic-you just have too much (or you have some enzyme deficiency leading to
hyperuricemia).
Myeloproliferative Disorder- too much DNA around…*Note-when I worked on an ambulance
before coming to medical school I once took a guy with a myeloproliferative disorder who was
taking cytotoxic therapy and he had a very bad case of gout*
Cytotoxic Therapy-see above
Alcohol-stimulates the PRPP Synthetase in the liver (see the coming diagram), also someone told
me beer has a lot of nucleotides in it too.
Obesity- if you have a lot of body mass, you‟ll break down more cells, and you‟ll have a higher
uric acid level.
VI. The Diagram:
So, listen, I just spent
about an hour getting this
stupid freakin‟ picture on
this transcript, so if it
doesn‟t come out
right…deal.
This picture to your left
illustrates the pathway
leading to uric acid
production. Important
points that you need to
understand are the
following: HGPRT is the
salvage pathway enzyme.
It takes the hypoxanthine
and recycles it back to
inosinic acid so it can be
remade into a new NT.
A complete deficiency of
HGPRT will make you
severely retarded and
violent and you‟ll bite
your fingers off. The
fact that you also have
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gout will probably go unnoticed since the straightjacket you‟re wearing will cover your big toe.
Nevertheless, even a partial deficiency will give you hyperuricemia even though you‟re not violent and
retarded. Any deficiency in the salvage pathway will lead to hyperuricemia. Excess PRPP activity will
also lead to hyperuricemia (aforementioned alcohol use).
VII. Key Enzymes Defects that will lead to hyperuricemia:
Attention: For this section the tape was totally and completely inaudible-I had to get by solely with my own
notes, so I‟m sorry…
PRPP overactivity -x-linked disorder
HGPRT Deficiency- x-linked (Lesch-Nyan)
Glucose 6 Phosphate Deficiency- autosomal dominant-glycogen breakdown increases hepatic
ATP levels, more adenosine present as a substrate for breakdown.
VIII. Other mechanisms of Hyperuricemia
-decreased GFR=decreased filtered load
-diuretic induced hypovolemia- leads to decreased GFR.
-renal tubular dysfunction caused by: low dose ASA,alcohol, other drugs all compete with urate
excretion. Also lead poisoning leads to what‟s called Saturnine Gout. Moonshine drinkers that
developed lead poisoning from drink moonshine made from old car radiator stills. These people
get gout in their 20s and 30‟s.
IX. Overall Causes in real life:
90% of hyperuricemia is due to underexcretion.
10% is due to overproduction, of which 1% is due to specific enzyme defects. So much for all that
enzyme nonsense (sorry Sandy…)
X. hyperuricemia:
Serum uric acid is supersaturated at levels above 7-8 mg%. Normal levels are hard to define
because they correlate with age/sex/ and body weight. Always look at the person compared to the
lab profile…a level of 8mg% in an eighty lb. Old lady versus a 230 lb. Israeli athlete would have
different significance. Females generally have a lower uric acid level than males until menopause
at which point it equalizes. The female risk of hyperuricemia is equal to men after menopause. (an
estrogen thing I guess…:)
Also, the risk of Gout increases with increasing uric acid levels. This may seem obvious, but it
actually is. At a level greater than 9 mg% you have 90 times the relative risk of a normal person
of suffering from Gout. Another obvious fact is that the longer you have hyperuricemia, the
greater your risk is of suffering from Gout.
Cool picture of a gouty Tophus shown in someone‟s ear. It was yellowy/white with little blood vessels
running across the stretched out skin over the tophi (tofu? Same difference…)*
XI. How does the Gout occur?
My version: Well, there‟s this guy named Eric. He‟s from Uruguay, so most of his friends call
him Uric. Uric was really into this girl and he was all over her, all the time. Her name was Blood.
Blood was just filled, I mean saturated with Uric, he never left her alone. So anyway, one day
they‟re at a party and Blood felt like taking a hit of acid. So she drops acid and lo and behold Uric
comes by and again, he‟s all over her. As the LSD takes effect she starts hallucinating and
wherever she turns she sees him, all over the place and his image starts to look like it‟s
crystallizing all over her. She goes crazy and runs outside and when she gets out it is colder out
and the uric crystals are now planted all over body. The friendly neighborhood police officer sees
her going crazy surrounded by Uric crystals and tries to help her (they‟re all on acid by now, as am
I). The police officer‟s name was Officer Phagocyte. He didn‟t get a chance to eat dinner on his
shift yet „cause he was so busy, so he took one look at blood and all that Uric crystal saturating her
and he began eating it right off of her skin. While she was happy to have the excess Uric off of
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her, she was a little embarrassed and her face got very red and swollen and hot. Needless to say,
they all went back into the party and flushed themselves down the toilet a few times.
Dr. Carson‟s version: basically the uric acid is supersaturated in the blood, it then becomes
supersaturated in the tissues, as a result when the excess uric acid sees an area of lower
temperature it can precipitate out and form crystals. The crystals become targets for phagocytic
cells which try to ingest them. Once they ingest the crystals they go crazy spitting out
inflammatory cytokines and the like and you get a big and painful inflammatory reaction in the
area. The reason the big toe seems to get hit first is because of the low temperature in the area.
*Picture of synovial fluid with a urate crystal sitting inside of a phagocyte‟s stomach*
XII. You too can make Gout Crystals!!!
You can actually make uric acid crystals if a)you are involved in research on the subject or b) you are bored
and lame. It‟s very easy. Take uric acid and put it in boiling water. Put the combo in a flask and drop in a
glass rod that‟s been scratched (or a string if you‟re going to make rock candy). Put it in the fridge and
wait, the next day you should have crystals forming.
*Picture of a gouty arthritic toe occurring at the first MTP joint. This first toe attack is called podagra. It
can be accompanied by fever*
XIV. Clinical Course Outline-without intervention.
1) Asymptomatic hyperuricemia for many years.
2) First attack of podagra of 1st MTP joint.
3) Intercritical gout-asymptomatic.
4) Gouty Polyarthritis-progresses to other joints, can mimic RA.
5) Chronic Tophaceous gout can leas to destructive bone lesions in which the tophi cause local
bone degradation.
*picture of grossly eroded phalanx on a gouty laden hand*
*another picture of a nasty bumpy hand, real big lumps all over, looks a lot like RA, can have
autoamputating fingers because of the bone degradation*
XV. Making the diagnosis
-you really don‟t need to make a diagnosis of gout because it doesn‟t really matter anyway. So I
left this part out. It‟s not testable anyway…
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Just kidding…
XV. Making The Diagnosis -Use polarizing microscopy with bifringence. Crystals look yellow
when parallel to a red compensator. They should look blue when perpendicular to a red
compensator.
If you‟re evaluating a Tophus you can aspirate some of the white chalky stuff with a needle and
spread it on a slide and do this polarizing microscopy. Just so you know, if the crystals are more
rectangular than needle-like and are blue when parallel to the red compensator then you have
calcium-pyrophosphate crystals…AKA pseudo-gout (more later).
XVI Management of Gout
There are two different things you manage, the acute attack of Gout and the chronic
metabolic problem.
Acute Gout- NSAIDS, Colchicine-causes GI problems, corticosteroids (IV or intra-articular).
Hyperuricemia- you treat it depending on the presentation, not everybody gets managed because
it means life-long medication and might not be totally necessary.
Definitely treat: Uric acid stones, gouty nephropathy, tophi that are eroding into bone.
Probably treat- frequent attacks of Gout despite Colchicine prophylaxis.
Possibly treat-marked Hyperuricemia.
You would treat this with Allopurinol- the potent inhibitor of Xanthine Oxidase which would
eliminate production of uric acid. It takes 2-4 weeks to work and over a course of years can
actually dissolve tophi.
XVIII Pseudo-Gout
See the previous section on “diagnosis” for its appearance.
-you can see it on x-rays as a stippled linear deposition of calcium in a cartilage space.
It is associated with: 1)hyperparathyroidism-too much Calcium
2)hemochromatosis-Fe inhibits enzyme pyrophosphatase.
3)hypomagnesemia-see #2
4)Wilson‟s disease
5)Ochonosis-alkaptanuria see previous lecture.
6)hypophosphatasia.
7)hypothyroidism
8)Gout-both of „em can happen together.
9) Osteoarthritis.
It‟s treated with NSAIDS, Steroids, and Colchicine.
Peace.
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