Tuesday, August 26, 2008

Familial Hypercholesterolaemia and glucose

Just as an aside from hepatic lipids. This study is about heart disease within a group of people with heterozygous FH. The full text doesn't say much more than the abstract. Here are the two punch lines:


"The combination of DM [diabetes mellitus] or IGT [impaired glucose tolerance] with FH was associated with a further increase in the prevalence of CAD"

and

"total cholesterol levels were not significantly different [ie between normal, IGT or DM affected people with FH]"

The basic conclusion I get from the study is that if you take a group of statin naive FH "victims", it's not the variation of LDL cholesterol level in their bloodstream which determines CV disease, it's the degree of glucose dysregulation which seems to matter within the group.

Now what I want to know is if a heterozygous FH person maintained chronic and rigid normoglycaemic, 24/7 and so kept their blood glucose always below, say 5.0mmol/l, would they have ANY CVD above that of a non FH person under the same circumstances. Especially if they were omega 6 fatty acid restricted....

Mutations of the gene for the LDL receptor seem to be common and to come in an enormous number of flavours. If it was so very important to have two fully functional copies of the gene I would expect it to be much more highly conserved.

Peter

5 comments:

JohnN said...

"if a heterozygous FH person maintained chronic and rigid normoglycaemic, 24/7 and so kept their blood glucose always below, say 5.0mmol/l, would they have ANY CVD above that of a non FH person under the same circumstances. Especially if they were omega 6 fatty acid restricted...."

Peter: in what way should blood glucose be controlled (metformin)? and why (to reduce LDL oxidation)?
I wonder if a diet designed to really rev up fat metabolism can be helpful. What about combining it with a cocktail of mega vitamins A, D, B6 and E?

Like you I'm curious about the evolutionary benefit of heterozygous and homozygous FH.

Stan (Heretic) said...

Re: Like you I'm curious about the evolutionary benefit of heterozygous and homozygous FH.

There is one. Apparently high triglycerides offer an immune advantage against bacterial infections, for example gangrene.

There is a good article about it on the Weston A. Price foundation website ( "benefits of cholesterol" or something like that).

Drs. Cynthia and David said...

The following paper is quite interesting. It doesn't say directly that sucrose or carbs are involved, just that some environmental condition seems to have contributed to the excess mortality of FH starting about 1915, a factor that was not present earlier. Perhaps it is coincidence that mortality increased with the early 20th century's introduction of refined carbs and sucrose, but the authors saw no evidence of increased mortality in these people before the modern Western diet was adopted. The authors speculate about high fat diets predictably.

BMJ 2001 322:1019-23 "Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study."
Sijbrands EJ, Westendorp RG, Defesche JC, de Meier PH, Smelt AH, Kastelein JJ.

Full text: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11325764

Abstract:
OBJECTIVE: To estimate all cause mortality from untreated familial hypercholesterolaemia free from selection for coronary artery disease. DESIGN: Family tree mortality study. SETTING: Large pedigree in Netherlands traced back to a single pair of ancestors in the 19th century. Subjects: All members of pedigree aged over 20 years with 0.5 probability of carrying a mutation for familial hypercholesterolaemia. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: A total of 70 deaths took place among 250 people analysed for 6950 person years. Mortality was not increased in carriers of the mutation during the 19th and early 20th century; it rose after 1915, reached its maximum between 1935 and 1964 (standardised mortality ratio 1.78, 95% confidence interval 1.13 to 2.76; P=0.003), and fell thereafter. Mortality differed significantly between two branches of the pedigree (relative risk 3.26, 95% confidence interval 1.74 to 6.11; P=0.001). CONCLUSIONS: Risk of death varies significantly among patients with familial hypercholesterolaemia. This large variability over time and between branches of the pedigree points to a strong interaction with environmental factors. Future research is required to identify patients with familial hypercholesterolaemia who are at extreme risk and need early and vigorous preventive measures.

This link http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=31037&rendertype=figure&id=F2 shows the mortality ratio over the time period.

The authors note that in the 19th century, mortality for people having the mutation was actually LESS than the general population. Now if only we could correlate this information with dietary or some other environmental factors...

Cynthia

JohnN said...

Hi Cynthia,
That's the elephant in the room - the diet factor. If homozygous FH tends to occur in small clan (a genetic factor) it cannot be so deadly that children can succumb to it way before they can pass on their genes.
My thinking is if your LDL can't find a place to park (because of impaired LDL receptor or lack of it) don't try to burn sugar and keep your endothelial cells supple.

Stan (Heretic) said...

Cynthia wrote:

...excess mortality of FH starting about 1915,

I remember that Dutch study, it's a classic! That factor that begun ~1915 was WWI and then it was followed by the Great Depression of the 1930-ties and then by the WWII which hit Holland economically as hard as everybody else.

In Europe, poverty meant potatoes, potatoes and more potatoes.

Stan