Thursday, December 31, 2015

Gout

Uric Acid and Gout

Gout is a disease that involves the accumulation monosodium urate crystals in synovial fluid or soft tissues due to high uric acid levels.  These monosodium urate crystals are ingested by immune cells, which trigger an inflammatory response* that leads to pain [1].  Uric acid levels are associated with gout (see graph below) [2] and reducing uric acid levels to ≤ 6mg/dl lowers the risk and symptoms of gout [3]


Uric acid levels become elevated when the demand of uric acid excretion exceeds the capacity of the kidney to excrete uric acid [4].  A high dietary purine intake (discussed below) is a main factor that increases excretion demand, while impaired kidney function is the main factor that would decrease excretion capacity.  Kidney function tends to decline with age, with some of this decline in function probably just being normal aging, but there are also many factors that impair kidney function that largely apply to older people.  These include pre-diabetes and type 2 diabetes [5] (insulin also reduces uric acid clearance [6]), cardiovascular disease [7], hypertension [8], diuretics [9] and low dose aspirin [10]

* The role of inflammation makes sense given the cyclical pattern of symptom severity in accordance with the circadian rhythm.  Gout tends to be worse in the evening/night and the least painful in the morning, which corresponds to the circadian rhythm regarding inflammatory cytokines (higher cortisol in the AM and higher IL-6, melatonin, growth hormone and leptin in the evening).  Treatments that reduce inflammation would be expected to improve symptoms but probably won’t address the underlying cause

Diet and Lifestyle Risk Factors

Reviews of observational studies [2] [11] [12] found that several things are associated with gout including:

·         Diet (see this table)
o   Alcohol
o   Sugar sweetened beverages and fruit juice (but no mention of evidence regarding fruit)
o   Purine rich foods such as meat and fish, but not total protein intake
o   Dairy foods and coffee are inversely associated with gout
·         Other chronic diseases such as:
o   Cardiovascular diseases
o   Metabolic syndrome and type 2 diabetes
o   Obesity
o   Kidney disease
·         Some classes of drugs:
o   Diuretics
o   Aspirin
o   Beta-blockers
o   ACE inhibitors

Most of these aren’t particularly surprising considering what I mentioned above

* Vitamin C intake of >1500 mg was associated with a lower incidence of gout (RR = 0.55) in the HPFS [2].  A meta-analysis of RCTs found that vitamin C supplementation (median dose = 500 mg) reduces uric acid in people with normal uric acid levels and without gout [13].  However, a clinical trial on people with gout found that vitamin C supplementation (500 mg) had no effect on uric acid levels [14] (this trial had 40 participants (good enough) and I didn’t notice any similar trials to confirm this result)

Purines

Purines are organic compounds that contain that contain those two nitrogen and carbon based rings.  Adenine and guanine are nucleotides which are part of DNA and RNA (uracil for guanine).  They are converted to hypoxanthine by purine nucleoside phosphorylase, and then xanthine oxidase converts hypoxanthine to xanthine and xanthine to uric acid.  As a result a high purine diet could increase uric acid and lead to gout, especially once kidney function has become impaired.  Foods rich in purines include: meat, fish, organ meats, legumes, some vegetables, coffee and chocolate.  Foods low in purines include grains and dairy [15].  Allopurinol, a drug used in the treatment of gout, reduces uric acid by inhibiting xanthine oxidase


A PubMed search of ‘purine diet gout’ for clinical trials only turned up two papers.  The first study found that a purine free diet doesn’t significantly reduce uric acid and purine levels in people with gout (the purine free diet was isocaloric, lower in fat (20% vs. 25%) and “purine-rich foods were rigorously eliminated, such as meat, fish, salads, eggs, sausages, legumes, chocolate, alcohol, tea, coffee and Coca Cola; noodles, bread, cheese, dairy products, fruit and vegetables were allowed“) [16].  The second study found that advice that an education program that recommended “(i) reducing red meat intake, and avoiding offal, shellfish and yeast extract; and (ii) including low fat dairy products, vegetables and cherries and the potential benefit of coffee and vitamin C” improved participants’ knowledge, but didn’t lower uric acid levels (whether they followed the advice is unknown) [17].  I’ll do some broader searches and write a blog post if I find anything interesting

Wednesday, December 30, 2015

Diabetes Epidemic & You: Part 2

Insulin Patterns During the Oral Glucose Tolerance Test

Dr. Kraft discerned 5 patterns of insulin levels from those 14,384 oral glucose tolerance tests.  Pattern 1 is considered to be a normal insulin response (euinsulinemia), patterns 2, 3 and 4 are considered to be high insulin responses (hyperinsulinemia) and pattern 5 is considered to be a low insulin response (hypoinsulinemia).  These patterns are presented in the graph below


Another measure of the patterns that Dr. Kraft used was the sum of the insulin levels at 2 and 3 hours, which shows a substantial difference between each pattern


Pattern 1
Pattern 2
Pattern 3
Pattern 4
Pattern 5
2h +3h Insulin
43
126
213
320
25

The following table lists the percentage of people in each glucose tolerance and insulin pattern category


NGT (%)
IGT (%)
T2D (%)
TOTAL (%)
Pattern 1
14.7
0.6
0.2
15.5
Pattern 2
29.4
5.2
1.2
35.7
Pattern 3
16.0
11.2
9.3
36.5
Pattern 4
4.0
1.9
2.3
8.2
Pattern 5
2.7
0.4
1.1
4.2
TOTAL
66.7
19.3
14.0


And this table lists the percentage of individuals with normal, impaired and diabetic glucose tolerance for each pattern of insulin levels during the oral glucose tolerance test


NGT (%)
IGT (%)
T2D (%)
Pattern 1
95.0
3.7
1.3
Pattern 2
82.2
14.6
3.2
Pattern 3
43.9
30.7
25.4
Pattern 4
48.8
23.5
27.7
Pattern 5
64.3
9.2
26.5

Interestingly a large number of people with normal glucose tolerance have some degree of hyperinsulinemia, and so the percentage of people with both normal glucose tolerance and insulin levels is staggering small at just 14.7% (or 17.4% if people with NGT and pattern 5 are also included)

Perhaps this is argument that Dr. Kraft inappropriately considered pattern 2 as hyperinsulinemia, whereas it may simply be the upper end of normal.  But this argument – that pattern 2 should also be considered normal – largely depends on an assumption that most of the population is healthy and not on the path to developing disease.  In defence of Dr. Kraft’s classifications, it’s worth pointing out that pattern 1 is almost exclusively the domain of normal glucose tolerance.  Whereas pattern 2 and especially pattern 3 show some overlap with impaired and diabetic glucose tolerance.  The people with normal glucose tolerance and hyperinsulinemia may represent those people who will go onto develop impaired glucose tolerance or type 2 diabetes in the future or are the lucky ones who have a robust pancreas.  However, insulin resistance per se (even without higher glucose levels) isn’t particularly desirable (more on that later)

Lastly while glucose tolerance isn’t a perfect indicator of someone’s insulin levels, I want to also mention that there isn’t often much relationship between fasting glucose and insulin pattern.  The following table lists the fasting glucose levels (average ± SD) by glucose tolerance and insulin pattern.  In summary fasting glucose appears to be an almost completely useless indicator of insulin pattern if the person is not diabetic, but is a good indicator that someone with very severe diabetes has low insulin levels (busted pancreas) 


Pattern 1
Pattern 2
Pattern 3
Pattern 4
Pattern 5
T2D
118 ± 71
126 ± 45
125 ± 45
140 ± 54
240 ± 100
IGT
96 ± 14
97 ± 14
97 ± 14
102 ± 13
102 ± 16
NGT
86 ± 11
85 ± 11
85 ± 11
89 ± 12
84 ± 11

Tuesday, December 29, 2015

Diabetes Epidemic & You: Part 1

I recently read ‘Diabetes Epidemic & You’ by Dr. Joseph Kraft, a pathologist whose clinic conducted 14,384 oral glucose tolerance tests with insulin assays.  This book is primarily about the results from those oral glucose tolerance tests and the diabetes epidemic in general.  I found the book quite interesting and would be ideal for clinicians or people who are just interested in the topic

* I’ve kept the units for glucose in mg/dl.  To convert to mmol/l simply divide by 18

The Importance of the Oral Glucose Tolerance Test

One of the early points in the book is that fasting blood glucose is not always a reliable diagnostic measure of impaired glucose tolerance (IGT; 2 hour glucose = 140-199 mg/dl) or type 2 diabetes (T2D; 2 hour glucose ≥ 200 mg/dl).  The first table looks at the percentage of people who have a fasting glucose below certain points within each category of glucose tolerance.  This table highlights that 60% with impaired glucose tolerance and 20% with type 2 diabetes have normal fasting glucose.  These particular people would often have their problem of impaired glucose tolerance or type 2 diabetes go unnoticed as most doctors initially rely solely on fasting glucose

Fasting Blood Glucose (mg/dl)
NGT (%)
(N=9598)
IGT (%)
(N=2775)
T2D (%)
(N=2011)
< 110
99
84
40
< 100
93
60
20
< 90
71
32
13
< 80
32
12
4
< 70
9
9
2
< 60
2
2
< 1

The following table is based on data from the previous and lists the percentage of people by categories of both fasting glucose (FBG) and glucose tolerance.  Just keep in mind that this is unlikely to be a representative sample given the skew in the sample towards women (73.4%) and 21-60 year olds

FBG (mg/dl)
NGT (%)
IGT (%)
T2D (%)
TOTAL (%)
> 110
0.7
3.1
8.4
12.1
100-110
4.0
4.6
2.8
11.4
90-100
14.7
5.4
1.0
21.1
80-90
26.0
3.9
1.3
31.1
70-80
15.3
0.6
0.3
16.2
< 70
6.0
1.7
0.3
8.0
TOTAL
66.7
19.3
14.0


And finally, using the same results, this table lists the percentage of people who have normal, impaired and diabetic glucose tolerance for each category of fasting glucose.  For example, if your fasting glucose is between 90-100 mg/dl you have a 25.6% of having impaired glucose tolerance

FBG (mg/dl)
NGT (%)
IGT (%)
T2D (%)
> 110
5.5
25.4
69.1
100-110
35.0
40.5
24.5
90-100
69.7
25.6
4.6
80-90
83.6
12.4
4.0
70-80
94.7
3.6
1.7
< 70
74.9
21.6
3.5

Fasting Insulin

Dr. Kraft makes a similar point for fasting insulin – that it’s not a great indicator of glucose tolerance.  At least fasting glucose was quite effective at identifying individuals with T2D, fasting insulin appears to be quite a bit worse.  The first table is the percentage of people with fasting insulin at various for each category of glucose tolerance

Insulin (mU/ml)
NGT (%)
IGT (%)
T2D (%)
0-10
53
43
33
11-15
23
19
19
16-20
11
14
14
20-30
8
14
18
> 30
5
10
16

The second table is based on data from the previous and lists the percentage of people by categories of both fasting insulin and glucose tolerance (again, may not be representative)

Insulin (mU/ml)
NGT (%)
IGT (%)
T2D (%)
TOTAL (%)
0-10
35.4
8.3
4.6
48.3
11-15
15.3
3.7
2.7
21.7
16-20
7.3
2.7
2.0
12.0
20-30
5.3
2.7
2.5
10.6
> 30
3.3
1.9
2.2
7.5
TOTAL
66.7
19.3
14.0


And the final table lists the percentage of people who have normal, impaired and diabetic glucose tolerance for each category of fasting insulin 

Insulin (mU/ml)
NGT (%)
IGT (%)
T2D (%)
0-10
73.3
17.2
9.6
11-15
70.8
16.9
12.3
16-20
61.2
22.5
16.3
20-30
50.6
25.6
23.8
> 30
44.5
25.7
29.8