# Talk:Familial hypercholesterolemia

(in addition to LDL phoresis - there are other acceptable mechanisms to mitigate the LDL load on the human... plasma exchange is one missing)  "Heterozygous FH is normally treated with statins, bile acid sequestrants, or other lipid lowering agents that lower cholesterol levels. New cases are generally offered genetic counseling. Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis or plasma exchange (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.[1]"
Vegaproc (talk) 19:52, 6 July 2017 (UTC)

In reading other articles about this genetic disease on the web, i have noticed population studies that mention that FH is most common in certain racial/genetic groups, namely Finns & Icelanders, Ashkenazi Jews, Lebanese Christians, and some Afrikaans populations in South Africa. Might it be a good idea to mention such things here? I think so, but am not qualified to do so. Just sign me, "Another Ashkenazi Jew with an LDL of 200, chronic Achilles tendonitis, and a family history of Angina, CAD, and Myocardial Infarction." 64.142.90.32 (talk) 16:45, 15 December 2007 (UTC)

A good source would be needed, but I agree that this needs to be brought up. JFW | T@lk 10:43, 3 February 2008 (UTC)
PMID 9853432 - molecular epidemiology. Can't see the paper from home (1998, need to order it from the library). JFW | T@lk 21:44, 3 February 2008 (UTC)

PMID 17569881 discusses the use of statins in children with FH. JFW | T@lk 10:43, 3 February 2008 (UTC)

PMID 18262040 - some more genes doing LDL, not quite the same as the LDL receptor though. JFW | T@lk 23:35, 12 February 2008 (UTC)

Surely a 1986 publication is not going to be an example of work that led to them winning the Nobel Prize. Which is the most representative paper from their 1970s work? JFW | T@lk 20:12, 28 February 2008 (UTC)

Useful JRSM article by Durrington: PMC 1079462 JFW | T@lk 13:36, 19 March 2008 (UTC)

WHO 1998 http://whqlibdoc.who.int/hq/1998/WHO_hgn_fh_CONS_98.7.pdf JFW | T@lk 23:52, 2 April 2008 (UTC)

This mutation is already in the page for LDL-R.82.10.78.130 (talk) 09:55, 6 May 2008 (UTC)

The problem is, even the LDLR page doesn't provide a source. JFW | T@lk 10:49, 13 May 2008 (UTC)
Possible source: http://atvb.ahajournals.org/cgi/content/full/19/2/408 JFW | T@lk 09:47, 13 May 2008 (UTC)

Two more things to do before going to GAC:

Reviewing PMID 18402545 - if it contains actual trial data on interventions (with good endpoint data) will include this in the article.
Reviewing the WHO document for anything important we are not presently discussing.
Other comments invited. JFW | T@lk 14:21, 13 May 2008 (UTC)

Hi, saw the request for a peer review on WT:MED. Very well done!  Good job explaining terms for laypeople.  A few comments:

"leads to atherosclerosis, the underlying cause of cardiovascular disease." Should this be "of some cardiovascular diseases", "the underlying cause of cardiovascular disease resulting from this condition" or something?  There's many causes of cardiovascular disease.
JFW: atherosclerosis is the underlying cause of all cardiovascular disease. JFW | T@lk 10:13, 14 May 2008 (UTC)
I would create a single, separate paragraph under "Signs and symptoms" for the discussion of cardiac-related symptoms. Also, that way you don't have the one sentence paragraph about risks. "Coronary artery disease is more common than other forms of cardiovascular disease in FH" sounds kind of tacked on at the end of that paragraph. If you don't give the heart stuff its own paragraph, maybe integrate this sentence into the discussion of cardiovascular disease, e.g. by saying, "...cardiovascular disease, of which coronary artery disease is the most common form."  That way you keep the coronary artery topic together within that paragraph.
 Done I have kept the content in the same paragraph without resorting to a subsection, but I have placed more emphasis on Durrington's observation that CAD is more common than other cardiovascular diseases. JFW | T@lk 16:03, 14 May 2008 (UTC)
This sentence is hard to understand: "Lipid infiltration and consequent thickening can cause aortic stenosis if the aortic root (supravalvular) or aortic valve is involved."  You may want to define "Lipid infiltration" and put the anatomy terms in layman's terms.
 Done by Steven. JFW | T@lk 16:03, 14 May 2008 (UTC)
I think MOS recommends en dashes (–) rather than hyphens (-) for number ranges.  In percent ranges, only the last number has a % sign (e.g. 50–80%, not 50%-80%).
 Done Thanks for clarifying that. JFW | T@lk 16:03, 14 May 2008 (UTC)
Define xanthomata under "differential diagnosis".
JFW: Is the plural of xanthoma. Will need to clarify. JFW | T@lk 10:13, 14 May 2008 (UTC)
 Done Changed it to an English plural. JFW | T@lk 16:03, 14 May 2008 (UTC)
Link the first use of unusual measurements, such as kb and Mb.
 Done I think. JFW | T@lk 16:03, 14 May 2008 (UTC)
"It comprises 18 exons and spans 45kb, and the gene product contains 839 amino acids in mature form." What is a mature form of a nucleic acid?
 Done Mature form of the protein. Will need clarification. JFW | T@lk 10:13, 14 May 2008 (UTC)
Non breaking spaces between numbers and units.
"In LDL receptor mutations, this is the mechanism behind the receptor malfunctioning; in ApoB mutations, this is due to reduced binding of LDL particles to the receptor."  It's not clear what the second this is referring to.
"The degree of atherosclerosis roughly depends of the amount of LDL receptors" Is amount the right word?  What about 'the number of receptors'?
 Done JFW: That is probably wrong. Will need revision. JFW | T@lk 10:13, 14 May 2008 (UTC)
"In more serious forms, the homozygous form, the receptor is not expressed at all." Should this be "In more serious forms, such as the homozygous form..."?  Or "In the more serious form, the homozygous form"?
 Done clarified - some homozygotes still express some poorly functional receptors, while others have no LDL receptor at all. JFW | T@lk 03:40, 15 May 2008 (UTC)
"this provides a liver with "normal" LDL receptors" —Just curious, why is "normal" in quotation marks?
 Done JFW: Fixed. JFW | T@lk 03:40, 15 May 2008 (UTC)
"Gene therapy could be a possible future alternative"— Too many qualifiers IMO.  'Is possible' is just as safe.
 Done JFW: Fixed. JFW | T@lk 03:40, 15 May 2008 (UTC)
"...it is sometimes necessary to treat adolescents or sometimes even teenagers"—Too many sometimes's.  Sometimes is so vague it's not that useful anyway.
 Done JFW: seems to have been fixed. JFW | T@lk 03:40, 15 May 2008 (UTC)
Citation needed for "In most populations studied, heterozygous FH occurs in about 1:500 people, but not all develop symptoms" and all sentences with statistics.  If it's the same ref as the next sentence, consider a semicolon to combine the shortish sentences.
 Done This is all from Rader, but Durrington says much the same. JFW | T@lk 03:40, 15 May 2008 (UTC)
"...because of a genetic phenomenon known as the founder effect"—It's good that 'founder effect' is wikilinked, but might be even better to give a little parenthetical explanation of what it is so the reader doesn't have to leave your article.
 Done JFW: sorted. JFW | T@lk 03:40, 15 May 2008 (UTC)
Very short sections are discouraged.  Maybe rather than having the two sentence section "Screening", you could integrate those sections into diagnosis.  Maybe you could call it "screening and diagnosis".
JFW: No, WP:MEDMOS suggests a separate section for screening. In this case, one form of screening is linked to diagnosis (case finding) but the other form of screening is proposed at population level and has no bearing on the investigation of current patients. JFW | T@lk 10:13, 14 May 2008 (UTC)
Similarly, maybe you could add a couple sentences to the "History" section.
JFW: Will try to. JFW | T@lk 10:13, 14 May 2008 (UTC)
Looks like some of the references are primary sources, I'd stay away from them per WP:PSTS.
JFW: Some primary sources are very recent, and have not yet been incorporated into secondary reviews. The fact that they have appeared in core journals like BMJ, The Lancet and NEJM makes them relatively suitable as a source. The other references are historical sources that need to be maintained for interest's sake. JFW | T@lk 10:13, 14 May 2008 (UTC)
These are all just suggestions, if you know of a reason not to implement them that's fine.  Overall very well done, nice treatment of a complex topic. Excellent work on references, well-written.  Easy for the lay reader to understand on the whole, though anything you can do to make it more so would be great.  Personally, I think it's GA-worthy now.  delldot talk 05:02, 14 May 2008 (UTC)

Thanks for your review, Delldot. I will leave comments above (marked JFW) and try to implement most of your recommendations over the course of today. I am still reading the sources above, and may still do further expansion. Also many thanks to Stevenfruitsmaak (talk · contribs) for identifying some important recent papers and incorporating them. JFW | T@lk 10:13, 14 May 2008 (UTC)
Great, thanks for the fixes and explanations, I'm fine with everything.  You might want to add a couple sentences to the screening section too if there's more available.  delldot talk 20:35, 14 May 2008 (UTC)

Figured I'd review this since I'd already read it and all.  It's very good and I was looking forward to passing it no problem, but ran into one minor, easily fixable hitch.  Here's the breakdown of my assessment.  

Well written?: No major problems, very readable, especially for an article on a topic so complex and technical.
Factually accurate?: Well referenced. Use of the few primary sources has been explained above, no major facts missing citations.
Broad in coverage?: Appears to cover every major aspect of the condition, doesn't go into unnecessary detail.
Neutral point of view?: No NPOV problems.
Article stability? No stability problems.
Images?: Image:HMG-CoA reductase pathway.png looks like it needs a tweak of the copyright tag. Looks like just a matter of switching a template.  I'm not sure how big a deal this is, but I'm gonna hold this till it's fixed to be safe.  Sorry, I should have checked this when doing the review.  But it shouldn't be hard to fix.
Excellent work! Sorry to hold this on such a minor thing.  Gimme a heads up when you're ready for me to re-review.  delldot talk 05:46, 15 May 2008 (UTC)

 Done Image rights updated. Sorry, was simply unaware that there was a problem. JFW | T@lk 09:09, 15 May 2008 (UTC)
Great work, sorry to have held it up on such a minor thing.  I've passed it now.  Congratulations!  delldot talk 14:21, 15 May 2008 (UTC)

Guess I missed a few on my first read through.

Introduce the ApoB term on first use, or let on that it will be discussed later.
 Done - it is already in the intro but I added ApoB there for clarity. JFW | T@lk 09:34, 15 May 2008 (UTC)
Why is it sometimes LDL-receptors and sometimes LDL receptors?
 Done - the dash is wrong and has been removed JFW | T@lk 09:34, 15 May 2008 (UTC)
"Other surgical techniques include partial ileal bypass surgery and portocaval shunt surgery." Might want to explain what these types of surgery are, since the links are red. delldot talk 05:46, 15 May 2008 (UTC)
 Done - have too little knowledge of these procedures to write stubs, but will try at some point. JFW | T@lk 09:34, 15 May 2008 (UTC)

NICE are working on a guideline, out in August: http://www.nice.org.uk/guidance/index.jsp?action=byID&o=11627 JFW | T@lk 09:06, 15 June 2008 (UTC)

Still wondering if there is much we can cite from this guideline. I'm not convinced if we should add the Simon Broome criteria, because they are country-specific. Opinions invited.
doi:10.1016/S0021-9150(02)00330-1 is another recent review. Can't access it without shelling out $ 31.50. JFW | T@lk 08:15, 7 September 2008 (UTC)

More data supporting the massive benefit enjoyed from statins in this disease population: doi:10.1136/bmj.a2423 JFW | T@lk 23:12, 28 January 2009 (UTC)

PMID 20614444 - Cochrane review suggests children benefit from statins but long-term effects unknown. JFW | T@lk 11:13, 22 August 2010 (UTC)

These terms should be combined into the text. Maybe a section on classification? --Doc James (talk · contribs · email) 02:52, 17 November 2010 (UTC)

I finally managed to find Muller's first description, which is highly elegant in its setup. Wiley, the journal's publisher, has followed the fairly recent trend to make their historical content available online, and this paper even got a DOI. All linked now. JFW | T@lk 11:44, 17 November 2010 (UTC)

WhoNamedIt has the term "Harbitz-Müller syndrome" for FH, but I suspect this is more a term for xanthomatosis and I have never seen it used for FH. I hope everyone agrees to leave this out of the article for the moment. JFW | T@lk 11:46, 17 November 2010 (UTC)

I've noticed the fact that this article still has a lot of primary references. Oddly, there's been no recent major review of FH in the literature.

PMID 19589528 seems to be a consensus document on LDL apheresis
PMID 20091526 is a Cochrane review of dietary treatment in FH
PMID 17569881 statins in children (systematic review)
--JFW | T@lk 12:04, 17 November 2010 (UTC)

This discussion continues the drumbeat that FH must always lead to atherosclerosis and that idea is absolutely wrong. Individuals exist (I am one) with extreme lifetime total and LDL cholesterol that are completely free of calcified plaque by EBCT. My family history back four generations in the presumed FH sector is entirely long-lived. A complete discussion of FH needs to at least discuss plaque buildup models in light of the fact that non-trivial numbers of individuals with extreme levels (at age 69 my LDL alone is over 500 mg/dl). Even after 50 years of speculation, the mechanism for plaque development is unacceptably sketchy and very likely does not involve LDL levels anymore than tobacco-stained fingers cause lung cancer.
RockyBob (talk) 18:45, 22 June 2015 (UTC)

@RockyBob: Do you have any sources on which such an observation could be based? By this I mean sources that meet the standards outlined in WP:MEDRS. JFW | T@lk 19:59, 23 June 2015 (UTC)
https://www.cureus.com/articles/11752-a-72-year-old-patient-with-longstanding-untreated-familial-hypercholesterolemia-but-no-coronary-artery-calcification-a-case-report RockyBob (talk) 21:28, 21 July 2022 (UTC)

The one in 500 occurrence of FH is widely accepted, yet this relatively frequent occurrence produces an unaddressed problem. If a genetic condition is as detrimental as is attributed to FH, evolutionary logic dictates that the FH allele or alleles would rapidly disappear from the gene pool. How can a life-shortening disorder that affects so many in their 30's and 40's (obviously reducing reproductive success compared to those living longer) flourish so that today it occurs in 14 million individuals? The usual response that average age was lower in the past is inadequate because for an average age to be even 30 means that many individuals were living well into the ages where this condition is supposed to have been detrimental. All that is necessary to eliminate an allele is a few percent less reproductive success. This would have been the case for many tens of thousands of years, yet the allele today is, by genetic disease standards, among the most, if not the most prevalent "disease".
````  — Preceding unsigned comment added by RockyBob (talk • contribs) 19:08, 22 June 2015 (UTC) 

@RockyBob: An interesting question. It bears remembering that the premature atherosclerosis often seen in people with FH does often not affect them clinically until after childbearing. Do you have any sources (see WP:MEDRS) to work with? JFW | T@lk 19:59, 23 June 2015 (UTC)
When something "does often not affect them clinically until after childbearing" the assumption that evolutionary consequences are not in play is incorrect. First of all, "often" is not the same thing as "never", and for evolutionary processes to be in play only means that a particular allele is slightly less successful than competing alleles. Five percent less reproductive success is devastating to an allele's existence in only a short evolutionary time. Therefore, even if "often" is correct, the allele ought to disappear if it affects even a small number of reproductive successes.
Secondly, first generation reproductive success is far too limiting in evaluating evolutionary success. If a gene plays a role in decreasing post-reproductive lifetimes it may be significantly unsuccessful simply because, in societal animals like man, post-reproductive members (think grandparents and elder family leaders) increase survivability of younger generations. To the specifics of FH, if it shortens any lifetimes appreciably, the reproductive success of the lineage would go down a) directly because some reproductive age individuals would die during reproductive years, and b) less directly because the pool of grandparents and family leaders would be reduced. 
Again, somehow this "devastating" set of alleles seems not to have been eliminated by either path and in fact has spread worldwide to millions of people and had greater success than any of the other truly devastating genetic anomalies. 
RockyBob (talk) 21:47, 19 August 2015 (UTC)

From Circulation doi:10.1161/CIR.0000000000000297 JFW | T@lk 12:12, 2 December 2015 (UTC)

There's also an integrated guideline that I missed: doi:10.1016/j.jacl.2014.01.002 JFW | T@lk 12:12, 2 December 2015 (UTC)

JAMA doi:10.1001/jama.2017.8543 JFW | T@lk 14:40, 26 July 2017 (UTC)

Schematic representation of the LDL receptor protein (image) cannot be the full LDL-R, at best a part of it, and without further explanations quite useless.  — Preceding unsigned comment added by 82squaremetres (talk • contribs) 19:01, 10 August 2017 (UTC) 

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Has updated the guideline: https://www.nice.org.uk/guidance/cg71 JFW | T@lk 15:02, 29 November 2017 (UTC)