About GT3's and our big ole fatty livers - sometimes size does matter!
Canuck said
Dec 20, 2017
Sheesh, just when this person thinks she has it figured out that owning a low LDL maybe a really good super thing? ... another "lipid" (and further atherosclerosis) related article comes along! I never wanted to be a lipid geek nerd anyway, yawn, eyes crossed, zzzzzzz
News - Ultralow LDL-C Still Predicts Early Subclinical Atherosclerosis - Steve Stiles - December 18, 2017
MADRID, SPAIN - Subclinical atherosclerosis was detectable by ultrasound or cardiac CT in about half of middle-aged adults who were without standard cardiovascular risk factors, including diabetes and high LDL cholesterol by usual definitions, in a prospective observational cohort[1].
Moreover, LDL-C, despite being in a range typically considered normal, was independently correlated with both the presence and extent of atherosclerosis - measured in coronary, limb, carotid, and infrarenal arteries - in the analysis of 1779 participants in the Progression of Early Subclinical Atherosclerosis (PESA) cohort study.
The subcohort, at baseline aged mostly in their 40s or early 50s, represented those of the entire PESA population of >4000 who were free of standard modifiable CV risk factors, including smoking along with hypertension, diabetes, and dyslipidemia according toAdult Treatment Panel (ATP) III definitions.
The relationships between LDL-C and atherosclerosis presence and extent remained significant in a further subset of 740 participants who not only met the criteria for being risk-factor free, they met more discriminating criteria for measures of blood pressure, glycemia, and total cholesterol that put them in the "optimal" ranges.
The correlation of rising LDL-C levels with greater-degree atherosclerosis suggested, for both men and women, that development of vascular disease begins at an LDL-C of about 50 mg/dL to 60 mg/dL, "similar to the level associated with disease regression," according to a report published in the December 19, 2017 issue of the Journal of the American College of Cardiologywith first author Dr Leticia Fernández-Friera (Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain).
That's also a range of LDL-C achievable with contemporary dyslipidemia agents, notably proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors on top of statins as demonstrated in the FOURIER trial, the authors observe. That trial also saw improved clinical outcomes with the combination treatment.
Odds Ratio (OR) for Atherosclerosis Presence and Extent in Population Initially Free of CV Risk Factorsa
End points
Atherosclerosis present,b OR (95% CI), P
>1 arterial system involvement, OR (95% CI), P
Age (per year)
1.11 (1.08-1.13), <0.001
1.14 (1.11-1.16), <0.001
Male
2.03 (1.66-2.47), <0.001
2.20 (1.80-2.69), <0.001
LDL-C (per 10 mg/dL)
1.14 (1.08-1.19), <0.001
1.14 (1.09-1.20), <0.001
HbA1c (per 1%)
1.77 (1.31-2.40), <0.001
1.79 (1.36-2.36), <0.001
a. CV risk-factor freedom defined as no current smoking, untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dL, total cholesterol <240 mg/dL, LDL-C <160 mg/dL, and HDL cholesterol >40 mg/dL
b. Presence of atherosclerotic plaques by ultrasound of carotid arteries, infrarenal abdominal aorta, and iliofemoral artery; CAD by calcium scores from CT imaging
The findings highlight that "physiologic" LDL-C levels - that is, those that might be present in people not exposed to diet and lifestyle patterns common to today - are probably <50 mg/dL, senior author Dr Javier Sanz (Centro Nacional de Investigaciones Cardiovasculares Carlos III) told theheart.org | Medscape Cardiology.
"It shows that relatively mild elevations of LDL-C, which we would call 'normal', are probably harmful," he said. "In advanced industrialized societies, everybody has high cholesterol. We call it normal, but in reality it's probably already creating atherosclerosis."
Odds Ratio (OR) for Atherosclerosis Presence and Extent in Population Initially with "Optimal" CV Risk Factorsa
End points
Atherosclerosis present,b OR (95% CI) P
>1 arterial system involvement, OR (95% CI), P
Age (per year)
1.11 (1.06-1.15), <0.001
1.13 (1.08-1.17), <0.001
Male
2.00 (1.45-2.77), <0.001
2.13 (1.57-2.91), <0.001
LDL-C (per 10 mg/dL)
1.16 (1.05-1.28), 0.003
1.18 (1.07-1.30), 0.001
a. CV risk-factor freedom defined as no current smoking, untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dL, total cholesterol <240 mg/dL, LDL-C <160 mg/dL, and HDL cholesterol >40 mg/dL
b. Presence of atherosclerotic plaques by ultrasound of carotid arteries, infrarenal abdominal aorta, and iliofemoral artery; CAD by calcium scores from CT imaging
The PESA risk-factor-free cohort averaged 45 in age and 50.3% were women. They were evaluated at baseline for carotid, iliofemoral, and abdominal aortic plaques by ultrasound and coronary artery calcification by CT, and for a range of serum biomarkers and lifestyle measures.
Subclinical atherosclerosis, indicated by plaques or coronary calcification, was identified in 49.7% of the group and in more than one arterial system in 30%. The relationships between LDL-C and atherosclerosis presence and extent were seen in all arterial systems, Sanz said.
After the field's long-time success of statin therapy for primary and secondary prevention, the addition of drugs like ezetimibe and the PCSK9 inhibitors that can push LDL-C to below 50 mg/dL have shaken up traditional views of how contemporary drug therapy should be used for prevention of atherosclerotic cardiovascular disease (ASCVD), according to an editorial accompanying the report[2].
"In this context, the current analysis by Fernández-Friera et al is highly relevant and now raises the question of what the optimal cholesterol level may be in the primordial and primary prevention of ASCVD," write Dr Vijay Nambi (Baylor College of Medicine, Houston, TX) and Dr Deepak L Bhatt (Brigham and Women's Hospital, Boston, MA).
They speculate that "arterial imaging at an early age," perhaps supplemented by biomarker and genetic screening, "would help further refine and personalize risk assessment prior to the establishment of atherosclerosis and/or ASCVD." But there are no appropriate trials supporting that approach, they add.
Meanwhile, they write, "physicians should consider avoiding the term 'normal' and instead inform their patients of their current cholesterol, blood pressure, or blood glucose values and discuss what preventive efforts may be needed given their level of risk."
PESA was funded in part by Banco de Santander (Madrid). The authors had no relevant financial relationships. Nambi reports holding a provisional patent with Baylor College of Medicine and Roche entitled "Use of biomarkers in prediction of heart failure," serving as an event adjudicator for Siemens Diagnostics, and serving as a site principal investigator for Merck. Bhatt discloses serving on the advisory board of Medscape Cardiology and Regado Biosciences; receiving honoraria from WebMD; receiving research funding from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi, and the Medicines Company; serving as site coinvestigator for Biotronik, Boston Scientific, and St Jude Medical (now Abbott); "and has performed unfunded research for FlowCo, Merck, PLx Pharma, and Takeda."
Canuck said
Dec 20, 2017
"Differing Lipid Labs Tests"
... I didn't know exactly where to stick this post, so, just put it here (in this "fatty" section), as it has to do with following a person's cholesterols (for which you DO NOT need to be a GT3!), but it is all loosely related, as lipids and/or fatty livers (steatosis) are just a wise things to have followed. I did not paste the whole of the abstract (below/bottom), just excerpted more of it's salient points that interested me ...
I kinda had by "accident" two lipid panels drawn at my last hep doc visit - I provided the blood for both these tests at the exact same fasting time and draw): One lipid panel that went to and was processed by a Canadian Lab just like any lipid panel might be done for any regular pt anywhere in BC, and another (a second) lipid panel (for Gilead purposes) went off to whomever THEY use for a lab - no idea where - it may even be sent to a U.S. lab, as I do believe "some" my trial labs ARE indeed sent to a U.S. lab, just not sure WHICH of all the bloods are sent there.
Regardless, the two identical lipid panels (same draw) were sent off to two completely dif labs, the "Canadian lab and requisition" operates NOT using the Friedewald method, but I note the U.S. or "Gilead follow-up trial" lipid panel DOES use the Friedewald method - it was interesting (to me) to see minor variations between the two labs results, being that the samples were from the exact same draw. Not much dif, but dif! The Friedewald LDL being lower. Maybe my "double" test supports the theories of the article below!
My (prior) lipid panel (via "Gilead's follow-up trial" lab, using the Friedewald method) had me flagged with an abnormal "low" LDL, (first time for me ever). Nothing to compare to for that one. But this current (last) "double" test ... while both labs LDL results were within each labs normal ref ranges, both were just low normal's ... the Friedewald method DID have me lower than the non-Friedewald method.
Since I was cured of my HCV, I believe my steatosis has basically just "disappeared", lastest summation by my hep doc mentioned ONLY "course liver texture", which does not sound too bad at all, and, (since I started my "follow-up trial", all of 2017), I have had 3 lipid panels done (and as well as having that one extra "duplicated" sample done, the one that went to the Canadian lab) - all of my 2017 results have only been flagged "abnormal" for mild high total chol. and for mild high HDL's, but show virtually nice triglycerides, and non-risky ratios, and generally low normal LDL's (except for that one flagged as an abnormal "low" LDL, and that low was via the U.S. Friedewald method). I am not worried (in fact I am very happy with my lipids all in all!), I'm just interested in the difs (given this article) even though it appears that overall the difs may be small. I do note as well, the Gilead trial lab, in general, uses more "forgiving", more wide-spread generous ranges than the Canadian lab - the Canadian lab ranges being more stringent/restrictive. Just what I need!, labs using dif ranges (just to make it as hard as they can for me to comprehend/compare). But it's a "never-know-mind" thing anyway - I get the gist of the articles theory, and the gist and bottom line of my lipids, my lipids are doing pretty darn good!
Underestimation of Low DensityLipoprotein-Cholesterol With the Friedewald Equation Versus a Direct Homogenous Low Density Lipoprotein-Cholesterol Assay
Ishwarlal Jialal, MD; Michael Inn, BS; David Siegel, MD; Sridevi Devaraj, PhD
Lab Med. 2017;48(3):220-224.
Abstract and Introduction
Abstract
Background: Low-density lipoprotein cholesterol (LDL-C) concentrations are the primary therapeutic target in patients with atherosclerotic cardiovascular disease (ASCVD). However, at low LDL-C concentrations, there is a significant underestimation using the Friedewald equation compared with ultracentrifugation.
Methods: In this pilot study, we compared LDL-C concentrations obtained using the Friedewald equation (LDL-F) vs those concentrations from a direct LDL-C (LDL-D) assay in 152 consecutive specimens from patients with triglyceride levels between 200-399 mg/dL and LDL-F <100 mg/dL. Also, we compared LDL-F and LDL-D results to the novel formula (LDL-N).
Results: The LDL-F value was significantly lower than that of LDL-D when LDL concentrations were 70-99 mg/dL (P <.001, 14% negative bias), and this decrease was accentuated in specimens with LDL <70 mg/dL, (P <.001, 27% negative bias). When compared with the LDL-N value, LDL-F and LDL-D values showed a 17% and 2% negative bias for specimens with LDL-C values of 70-99 mg/dL and 36% and 1% negative bias, respectively, at LDL-C <70 mg/dL (P <.001 for comparisons of LDL-F and LDL-N values).
Conclusions: To provide accurate LDL-C levels in patients at high risk for ASCVD, if beta quantification by ultracentrifugation is unavailable and if LDL-C is <100 mg/dL and triglycerides are 200-399 mg/dL, laboratories should revert to direct LDL-C measurements or use the novel formula. Although LDL-N is more cost-effective, LDL-D can be run on most platforms, does not require a specimen from a fasting individual, is standardized, and has the advantage of being validated in large trials such as the Heart Protection Study.
Introduction
Recent guidelines have recommended a 50% reduction in LDL-cholesterol (LDL-C) concentrations, or an LDL-C goal of less than 70 mg per dL, in patients at highest risk for atherosclerotic cardiovascular disease (ASCVD).[1]It has been documented that the Friedewald equation underestimates LDL-C at low levels compared with ultracentrifugation methods.[2,3] However, these studies did not compare the Friedewald calculation with the more readily available homogenous assays that measure LDL-C directly ...
... Discussion
In this preliminary report, we confirm, using a direct-LDL-C assay, that to attain the targets for patients at greatest risk for ASCVD (those with multiple risk factors or with current ASCVD), using the Friedewald equation calculate LDL-C is misleading and underestimates LDL-C, as reported previously using ultracentrifugation.[2,3] This finding has the potential to lull healthcare professionals into a false sense of security that specimens from their patients are at the desired goal values. The issue remains true whether one uses targets of LDL-C of less than 100 mg per dL or less than 70 mg per dL, or percentage LDL-C reduction of greater than 50% or 30% to 50%. This problem is particularly relevant in patients with plasma triglyceride values in the range of 200 mg per dL to 399 mg per dL, when laboratories use the calculated LDL-F rather than the LDL-D assay to measure LDL-C levels.
Although using beta-quantification to report LDL-C would be most accurate,[2,3] this method is cumbersome, labor-intensive, and requires a dedicated ultracentrifuge;[6] as a result, it is not available in most clinical laboratories, to our knowledge. Also, the LDL-C is obtained by subtracting the HDL-C from the infranatant total cholesterol value after ultracentrifugation rather than being directly assayed. Although both groups showed a significant underestimation of LDL-C by the Friedewald equation compared with ultracentrifugation, we did not undertake that comparison. Instead, we focused on the LDL-D assay as our reference standard. This action could be perceived as a weakness of our pilot study.
Many have sought to improve on the Friedewald equation, as reported by Martin et al.[2] However, that research group uses a novel formula involving a calculation based on non-HDL and TG values and is not easily applicable to clinical laboratories, given the adjustable factor that needs to be derived from the 180-strata table and thus is not easy to automate. Further, it is affected by high triglyceride levels and, hence, fasting; it has not been validated in a large clinical trial. Also, unlike LDL-D, it has not entered the mainstream of laboratory medicine and is not part of CAP surveys.
One of us has previously shown that the direct LDL-C assay is reliable in the entire range of triglycerides up to values of 1000 mg per dL.[6] In that study, 32% of the 156 specimens had triglyceride levels of less than 400 mg per dL and less than 1000 mg per dL. LDL-C levels determined by beta quantification showed excellent concordance for LDL-C values less than 130 mg per dL, which is an accepted target at that point in the assessment of ASCVD risk. In addition, we have confirmed the validity of the direct LDL-C assay compared with beta-quantification in specimens from patients with diabetes, another group at high risk for ASCVD.[7] A critical review on this topic also supported the validity of the direct LDL-C assay compared with beta-quantification.[8] Hence, we suggest using the direct LDL-C assay for reporting LDL-C in patients with triglyceride levels between 200 mg per dL and 399 mg per dL and LDL-C levels less than 100 mg per dL. These findings appear to be particularly important for patients with LDL-C values of less than 70 mg per dL, which would result in more reliable measurements to guide patient care. In fact, the direct LDL-C assay has been used in statin trials such as the Heart Protection Study, the largest statin trial in the literature, involving 20,536 patients, in which lowering of the LDL-C by means of statin therapy was shown to reduce cardiovascular events and mortality.[9]
In our pilot study, the misclassification rates of LDL-F for our 2 subgroups (ie, LDL-C <70 mg/dL and LDL-C 70 mg/dL-99 mg/dL were 49% and 34%, respectively. Hence, these rates appear to be a serious problem in the patients at highest risk for ASCVD and need to be confirmed by other groups using larger sample sizes because it could have major implications for reporting LDL-C concentrations in the clinical laboratory.
We believe that the novel formula proposed by Martin et al[2] clearly has merit; its advantage over the LDL-F was confirmed in our report. However, this advantage needs to be validated in large statin trials. Until then, for this group of patient specimens with LDL-C values less than 100 mg per dL and triglyceride levels between 200 mg per dL and 399 mg per dL, we favor the direct LDL assay. A drawback of the direct LDL-C assay is that there are concerns regarding its accuracy in patients with liver disease, kidney disease, and familial dyslipidemias. However, we believe these are minor issues compared with the underestimation of LDL-C using the Friedewald equation, which also results in inaccuracies in these illness groups.[4] Also, certain recently FDA-approved proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can lower the LDL-C level beyond the maximum tolerated statin dose by approximately 60%, to levels approaching 30 mg per dL.[10]The availability of these novel agents underscores the need to provide reliable LDL-C reporting by using the direct LDL-C homogenous assays if beta-quantification is unavailable because the Friedewald equation is inaccurate in patients with such low LDL-C concentrations. Thus, in the spirit of providing optimum laboratory support for ASCVD, we need to consider the novel LDL-C assay formula and the direct LDL assays as part of our repertoire of tests when reporting low LDL-C levels. From our data we favor the direct-LDL-C assays as laboratory professionals, based on the reasons provided herein ...
Tig said
Apr 22, 2017
Thanks for the post and link. That was a very interesting article and resource. One of these days I have to get my bookmarks organized so I can actually recall all of this valuable information. It's good to have current data on treatments, as well as reasoning and prognosis.
I believe we are going to see increased research and positive results because of these types of studies. Doctors and researchers need to follow more patients after HCV treatment to better realize the effect treatment and medication have on levels of steatosis and fibrosis. It would be nice to have a larger pool of data from non study sources. That would serve to shine a brighter light on the maladies and extra hepatic manifestations caused by HCV following successful treatment (SVR).
Canuck said
Apr 22, 2017
About GT3's and our big ole fatty livers - sometimes size does matter!
Now, I'm not necessarily talking about having an enlarged, inflamed liver, or a big ole fatty liver, these are never wanted things, just like having the HCV that may have caused same, is an unwanted thing, but rather I speak of big viral loads.
We have, over the last years, seen the experts revise and change what "number" is to be considered a "high" or "low" viral load, quite a few times. Changing benchmarks for changing times. With the advent of the new DAA's, less importance has been attached to high VL's, as far as the stellar SVR success rates we are seeing nowadays. It seems high loads are being considered more now only in relation to length of treatment decisions.
Apparently where VL size DOES still matter, is in the lucky GT3's, who have a particular predilection for fat screw-ups and fatty livers. Us GT3's, neverminding what fibrosis or cirrhosis levels we may be sporting, may as well be gifted with big ole hard fatty livers, to the point of perhaps skewing our fibroscan Fscores upward.
I have been reading much about GT3's and our fat "problem", but did not realize how much it was tied to our high VL's!! Not until I read these snippets below, did I realize nor fully appreciate the way GT3's can build their fatty livers, the direct co-relation between rises in the GT3's VL's and the gains in our fatty livers. Interesting (to me)!
So, for GT3's - size STILL does matter, as far as high VL's and our big ole fatty livers.
My circumstance, of formerly (I love saying that ... formerly! hee hee) being a GT3 with a fatty liver visualized pre-treatment, and then, post-treatment, receiving evidence that my Fscore has decreased markedly and that my liver apparently is now not "appearing" fatty on imaging (fingers crossed this is true, but I think it must be), this then lends support to the other comment in the article, that with HCV cured it may be possible to see significant or complete resolution of our fat problem too!
We should all be "followed" well (before, during and after cure), but the fatty liver thing, is one more good reason to follow GT3's well.
(Excerpts collected from HCV blog and articles in Hep C Trust) - commentary, and a study they have referred to, about fatty livers in GT 3's)
There are two discrete forms of steatosis that may be found in patients infected with hepatitis C virus (HCV). Metabolic steatosis can coexist with HCV, regardless of genotype in patients with risk factors such as obesity, hyperlipidemia, and insulin resistance. The second form of hepatic steatosis in HCV patients is a result of the direct cytopathic effect of genotype 3 viral infections. There have been proposed mechanisms for this process but it remains elusive. Both categories of steatosis tend to hasten the progression of liver fibrosis and therefore prompt recognition and management should be initiated in patients with HCV and steatosis.
On average steatosis is about two and half times more common in people with HCV than in the general population, so it is clear that the presence of the virus in the body can actually trigger steatosis. Biopsy samples in people with HCV who have steatosis tend to show that fat accumulates around the portal areas, rather than in the middle of the lobules of the liver, as is usually the case Non Alcoholic Fatty Liver Disease (NAFLD) which point to the virus being the trigger rather than other factors.
For people with genotype 3 though, the link between steatosis and the virus has now been definitively established. Up to 60-80% of people with genotype 3 have moderate to severe steatosis. It seems that that there is a complex interaction between the core protein of the genotype 3 strand of the virus and liver cells that leads to steatosis. It also seems that the severity of steatosis in these patients is directly related to their viral load. The higher the viral load the greater the amount of steatosis.
Surprisingly people with genotype 3, who achieve sustained virologic response (SVR) through treatment, have a marked decrease in and sometimes a complete resolution of steatosis. If they then relapse steatosis then reappears.
Sheesh, just when this person thinks she has it figured out that owning a low LDL maybe a really good super thing? ... another "lipid" (and further atherosclerosis) related article comes along! I never wanted to be a lipid geek nerd anyway, yawn, eyes crossed, zzzzzzz
MADRID, SPAIN - Subclinical atherosclerosis was detectable by ultrasound or cardiac CT in about half of middle-aged adults who were without standard cardiovascular risk factors, including diabetes and high LDL cholesterol by usual definitions, in a prospective observational cohort[1].
Moreover, LDL-C, despite being in a range typically considered normal, was independently correlated with both the presence and extent of atherosclerosis - measured in coronary, limb, carotid, and infrarenal arteries - in the analysis of 1779 participants in the Progression of Early Subclinical Atherosclerosis (PESA) cohort study.
The subcohort, at baseline aged mostly in their 40s or early 50s, represented those of the entire PESA population of >4000 who were free of standard modifiable CV risk factors, including smoking along with hypertension, diabetes, and dyslipidemia according to Adult Treatment Panel (ATP) III definitions.
The relationships between LDL-C and atherosclerosis presence and extent remained significant in a further subset of 740 participants who not only met the criteria for being risk-factor free, they met more discriminating criteria for measures of blood pressure, glycemia, and total cholesterol that put them in the "optimal" ranges.
The correlation of rising LDL-C levels with greater-degree atherosclerosis suggested, for both men and women, that development of vascular disease begins at an LDL-C of about 50 mg/dL to 60 mg/dL, "similar to the level associated with disease regression," according to a report published in the December 19, 2017 issue of the Journal of the American College of Cardiologywith first author Dr Leticia Fernández-Friera (Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain).
That's also a range of LDL-C achievable with contemporary dyslipidemia agents, notably proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors on top of statins as demonstrated in the FOURIER trial, the authors observe. That trial also saw improved clinical outcomes with the combination treatment.
Odds Ratio (OR) for Atherosclerosis Presence and Extent in Population Initially Free of CV Risk Factorsa
The findings highlight that "physiologic" LDL-C levels - that is, those that might be present in people not exposed to diet and lifestyle patterns common to today - are probably <50 mg/dL, senior author Dr Javier Sanz (Centro Nacional de Investigaciones Cardiovasculares Carlos III) told theheart.org | Medscape Cardiology.
"It shows that relatively mild elevations of LDL-C, which we would call 'normal', are probably harmful," he said. "In advanced industrialized societies, everybody has high cholesterol. We call it normal, but in reality it's probably already creating atherosclerosis."
Odds Ratio (OR) for Atherosclerosis Presence and Extent in Population Initially with "Optimal" CV Risk Factorsa
The PESA risk-factor-free cohort averaged 45 in age and 50.3% were women. They were evaluated at baseline for carotid, iliofemoral, and abdominal aortic plaques by ultrasound and coronary artery calcification by CT, and for a range of serum biomarkers and lifestyle measures.
Subclinical atherosclerosis, indicated by plaques or coronary calcification, was identified in 49.7% of the group and in more than one arterial system in 30%. The relationships between LDL-C and atherosclerosis presence and extent were seen in all arterial systems, Sanz said.
After the field's long-time success of statin therapy for primary and secondary prevention, the addition of drugs like ezetimibe and the PCSK9 inhibitors that can push LDL-C to below 50 mg/dL have shaken up traditional views of how contemporary drug therapy should be used for prevention of atherosclerotic cardiovascular disease (ASCVD), according to an editorial accompanying the report[2].
"In this context, the current analysis by Fernández-Friera et al is highly relevant and now raises the question of what the optimal cholesterol level may be in the primordial and primary prevention of ASCVD," write Dr Vijay Nambi (Baylor College of Medicine, Houston, TX) and Dr Deepak L Bhatt (Brigham and Women's Hospital, Boston, MA).
They speculate that "arterial imaging at an early age," perhaps supplemented by biomarker and genetic screening, "would help further refine and personalize risk assessment prior to the establishment of atherosclerosis and/or ASCVD." But there are no appropriate trials supporting that approach, they add.
Meanwhile, they write, "physicians should consider avoiding the term 'normal' and instead inform their patients of their current cholesterol, blood pressure, or blood glucose values and discuss what preventive efforts may be needed given their level of risk."
PESA was funded in part by Banco de Santander (Madrid). The authors had no relevant financial relationships. Nambi reports holding a provisional patent with Baylor College of Medicine and Roche entitled "Use of biomarkers in prediction of heart failure," serving as an event adjudicator for Siemens Diagnostics, and serving as a site principal investigator for Merck. Bhatt discloses serving on the advisory board of Medscape Cardiology and Regado Biosciences; receiving honoraria from WebMD; receiving research funding from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi, and the Medicines Company; serving as site coinvestigator for Biotronik, Boston Scientific, and St Jude Medical (now Abbott); "and has performed unfunded research for FlowCo, Merck, PLx Pharma, and Takeda."
"Differing Lipid Labs Tests"
... I didn't know exactly where to stick this post, so, just put it here (in this "fatty" section), as it has to do with following a person's cholesterols (for which you DO NOT need to be a GT3!), but it is all loosely related, as lipids and/or fatty livers (steatosis) are just a wise things to have followed. I did not paste the whole of the abstract (below/bottom), just excerpted more of it's salient points that interested me ...
I kinda had by "accident" two lipid panels drawn at my last hep doc visit - I provided the blood for both these tests at the exact same fasting time and draw): One lipid panel that went to and was processed by a Canadian Lab just like any lipid panel might be done for any regular pt anywhere in BC, and another (a second) lipid panel (for Gilead purposes) went off to whomever THEY use for a lab - no idea where - it may even be sent to a U.S. lab, as I do believe "some" my trial labs ARE indeed sent to a U.S. lab, just not sure WHICH of all the bloods are sent there.
Regardless, the two identical lipid panels (same draw) were sent off to two completely dif labs, the "Canadian lab and requisition" operates NOT using the Friedewald method, but I note the U.S. or "Gilead follow-up trial" lipid panel DOES use the Friedewald method - it was interesting (to me) to see minor variations between the two labs results, being that the samples were from the exact same draw. Not much dif, but dif! The Friedewald LDL being lower. Maybe my "double" test supports the theories of the article below!
My (prior) lipid panel (via "Gilead's follow-up trial" lab, using the Friedewald method) had me flagged with an abnormal "low" LDL, (first time for me ever). Nothing to compare to for that one. But this current (last) "double" test ... while both labs LDL results were within each labs normal ref ranges, both were just low normal's ... the Friedewald method DID have me lower than the non-Friedewald method.
Since I was cured of my HCV, I believe my steatosis has basically just "disappeared", lastest summation by my hep doc mentioned ONLY "course liver texture", which does not sound too bad at all, and, (since I started my "follow-up trial", all of 2017), I have had 3 lipid panels done (and as well as having that one extra "duplicated" sample done, the one that went to the Canadian lab) - all of my 2017 results have only been flagged "abnormal" for mild high total chol. and for mild high HDL's, but show virtually nice triglycerides, and non-risky ratios, and generally low normal LDL's (except for that one flagged as an abnormal "low" LDL, and that low was via the U.S. Friedewald method). I am not worried (in fact I am very happy with my lipids all in all!), I'm just interested in the difs (given this article) even though it appears that overall the difs may be small. I do note as well, the Gilead trial lab, in general, uses more "forgiving", more wide-spread generous ranges than the Canadian lab - the Canadian lab ranges being more stringent/restrictive. Just what I need!, labs using dif ranges (just to make it as hard as they can for me to comprehend/compare). But it's a "never-know-mind" thing anyway - I get the gist of the articles theory, and the gist and bottom line of my lipids, my lipids are doing pretty darn good!
Medscape - Laboratory Medicine
Underestimation of Low Density Lipoprotein-Cholesterol With the Friedewald Equation Versus a Direct Homogenous Low Density Lipoprotein-Cholesterol Assay
Ishwarlal Jialal, MD; Michael Inn, BS; David Siegel, MD; Sridevi Devaraj, PhD
Lab Med. 2017;48(3):220-224.
Abstract and Introduction
Abstract
Background: Low-density lipoprotein cholesterol (LDL-C) concentrations are the primary therapeutic target in patients with atherosclerotic cardiovascular disease (ASCVD). However, at low LDL-C concentrations, there is a significant underestimation using the Friedewald equation compared with ultracentrifugation.
Methods: In this pilot study, we compared LDL-C concentrations obtained using the Friedewald equation (LDL-F) vs those concentrations from a direct LDL-C (LDL-D) assay in 152 consecutive specimens from patients with triglyceride levels between 200-399 mg/dL and LDL-F <100 mg/dL. Also, we compared LDL-F and LDL-D results to the novel formula (LDL-N).
Results: The LDL-F value was significantly lower than that of LDL-D when LDL concentrations were 70-99 mg/dL (P <.001, 14% negative bias), and this decrease was accentuated in specimens with LDL <70 mg/dL, (P <.001, 27% negative bias). When compared with the LDL-N value, LDL-F and LDL-D values showed a 17% and 2% negative bias for specimens with LDL-C values of 70-99 mg/dL and 36% and 1% negative bias, respectively, at LDL-C <70 mg/dL (P <.001 for comparisons of LDL-F and LDL-N values).
Conclusions: To provide accurate LDL-C levels in patients at high risk for ASCVD, if beta quantification by ultracentrifugation is unavailable and if LDL-C is <100 mg/dL and triglycerides are 200-399 mg/dL, laboratories should revert to direct LDL-C measurements or use the novel formula. Although LDL-N is more cost-effective, LDL-D can be run on most platforms, does not require a specimen from a fasting individual, is standardized, and has the advantage of being validated in large trials such as the Heart Protection Study.
Introduction
Recent guidelines have recommended a 50% reduction in LDL-cholesterol (LDL-C) concentrations, or an LDL-C goal of less than 70 mg per dL, in patients at highest risk for atherosclerotic cardiovascular disease (ASCVD).[1]It has been documented that the Friedewald equation underestimates LDL-C at low levels compared with ultracentrifugation methods.[2,3] However, these studies did not compare the Friedewald calculation with the more readily available homogenous assays that measure LDL-C directly ...
... Discussion
In this preliminary report, we confirm, using a direct-LDL-C assay, that to attain the targets for patients at greatest risk for ASCVD (those with multiple risk factors or with current ASCVD), using the Friedewald equation calculate LDL-C is misleading and underestimates LDL-C, as reported previously using ultracentrifugation.[2,3] This finding has the potential to lull healthcare professionals into a false sense of security that specimens from their patients are at the desired goal values. The issue remains true whether one uses targets of LDL-C of less than 100 mg per dL or less than 70 mg per dL, or percentage LDL-C reduction of greater than 50% or 30% to 50%. This problem is particularly relevant in patients with plasma triglyceride values in the range of 200 mg per dL to 399 mg per dL, when laboratories use the calculated LDL-F rather than the LDL-D assay to measure LDL-C levels.
Although using beta-quantification to report LDL-C would be most accurate,[2,3] this method is cumbersome, labor-intensive, and requires a dedicated ultracentrifuge;[6] as a result, it is not available in most clinical laboratories, to our knowledge. Also, the LDL-C is obtained by subtracting the HDL-C from the infranatant total cholesterol value after ultracentrifugation rather than being directly assayed. Although both groups showed a significant underestimation of LDL-C by the Friedewald equation compared with ultracentrifugation, we did not undertake that comparison. Instead, we focused on the LDL-D assay as our reference standard. This action could be perceived as a weakness of our pilot study.
Many have sought to improve on the Friedewald equation, as reported by Martin et al.[2] However, that research group uses a novel formula involving a calculation based on non-HDL and TG values and is not easily applicable to clinical laboratories, given the adjustable factor that needs to be derived from the 180-strata table and thus is not easy to automate. Further, it is affected by high triglyceride levels and, hence, fasting; it has not been validated in a large clinical trial. Also, unlike LDL-D, it has not entered the mainstream of laboratory medicine and is not part of CAP surveys.
One of us has previously shown that the direct LDL-C assay is reliable in the entire range of triglycerides up to values of 1000 mg per dL.[6] In that study, 32% of the 156 specimens had triglyceride levels of less than 400 mg per dL and less than 1000 mg per dL. LDL-C levels determined by beta quantification showed excellent concordance for LDL-C values less than 130 mg per dL, which is an accepted target at that point in the assessment of ASCVD risk. In addition, we have confirmed the validity of the direct LDL-C assay compared with beta-quantification in specimens from patients with diabetes, another group at high risk for ASCVD.[7] A critical review on this topic also supported the validity of the direct LDL-C assay compared with beta-quantification.[8] Hence, we suggest using the direct LDL-C assay for reporting LDL-C in patients with triglyceride levels between 200 mg per dL and 399 mg per dL and LDL-C levels less than 100 mg per dL. These findings appear to be particularly important for patients with LDL-C values of less than 70 mg per dL, which would result in more reliable measurements to guide patient care. In fact, the direct LDL-C assay has been used in statin trials such as the Heart Protection Study, the largest statin trial in the literature, involving 20,536 patients, in which lowering of the LDL-C by means of statin therapy was shown to reduce cardiovascular events and mortality.[9]
In our pilot study, the misclassification rates of LDL-F for our 2 subgroups (ie, LDL-C <70 mg/dL and LDL-C 70 mg/dL-99 mg/dL were 49% and 34%, respectively. Hence, these rates appear to be a serious problem in the patients at highest risk for ASCVD and need to be confirmed by other groups using larger sample sizes because it could have major implications for reporting LDL-C concentrations in the clinical laboratory.
We believe that the novel formula proposed by Martin et al[2] clearly has merit; its advantage over the LDL-F was confirmed in our report. However, this advantage needs to be validated in large statin trials. Until then, for this group of patient specimens with LDL-C values less than 100 mg per dL and triglyceride levels between 200 mg per dL and 399 mg per dL, we favor the direct LDL assay. A drawback of the direct LDL-C assay is that there are concerns regarding its accuracy in patients with liver disease, kidney disease, and familial dyslipidemias. However, we believe these are minor issues compared with the underestimation of LDL-C using the Friedewald equation, which also results in inaccuracies in these illness groups.[4] Also, certain recently FDA-approved proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can lower the LDL-C level beyond the maximum tolerated statin dose by approximately 60%, to levels approaching 30 mg per dL.[10]The availability of these novel agents underscores the need to provide reliable LDL-C reporting by using the direct LDL-C homogenous assays if beta-quantification is unavailable because the Friedewald equation is inaccurate in patients with such low LDL-C concentrations. Thus, in the spirit of providing optimum laboratory support for ASCVD, we need to consider the novel LDL-C assay formula and the direct LDL assays as part of our repertoire of tests when reporting low LDL-C levels. From our data we favor the direct-LDL-C assays as laboratory professionals, based on the reasons provided herein ...
Thanks for the post and link. That was a very interesting article and resource. One of these days I have to get my bookmarks organized so I can actually recall all of this valuable information. It's good to have current data on treatments, as well as reasoning and prognosis.
I believe we are going to see increased research and positive results because of these types of studies. Doctors and researchers need to follow more patients after HCV treatment to better realize the effect treatment and medication have on levels of steatosis and fibrosis. It would be nice to have a larger pool of data from non study sources. That would serve to shine a brighter light on the maladies and extra hepatic manifestations caused by HCV following successful treatment (SVR).
About GT3's and our big ole fatty livers - sometimes size does matter!
Now, I'm not necessarily talking about having an enlarged, inflamed liver, or a big ole fatty liver, these are never wanted things, just like having the HCV that may have caused same, is an unwanted thing, but rather I speak of big viral loads.
We have, over the last years, seen the experts revise and change what "number" is to be considered a "high" or "low" viral load, quite a few times. Changing benchmarks for changing times. With the advent of the new DAA's, less importance has been attached to high VL's, as far as the stellar SVR success rates we are seeing nowadays. It seems high loads are being considered more now only in relation to length of treatment decisions.
Apparently where VL size DOES still matter, is in the lucky GT3's, who have a particular predilection for fat screw-ups and fatty livers. Us GT3's, neverminding what fibrosis or cirrhosis levels we may be sporting, may as well be gifted with big ole hard fatty livers, to the point of perhaps skewing our fibroscan Fscores upward.
I have been reading much about GT3's and our fat "problem", but did not realize how much it was tied to our high VL's!! Not until I read these snippets below, did I realize nor fully appreciate the way GT3's can build their fatty livers, the direct co-relation between rises in the GT3's VL's and the gains in our fatty livers. Interesting (to me)!
So, for GT3's - size STILL does matter, as far as high VL's and our big ole fatty livers.
My circumstance, of formerly (I love saying that ... formerly! hee hee) being a GT3 with a fatty liver visualized pre-treatment, and then, post-treatment, receiving evidence that my Fscore has decreased markedly and that my liver apparently is now not "appearing" fatty on imaging (fingers crossed this is true, but I think it must be), this then lends support to the other comment in the article, that with HCV cured it may be possible to see significant or complete resolution of our fat problem too!
We should all be "followed" well (before, during and after cure), but the fatty liver thing, is one more good reason to follow GT3's well.
(Excerpts collected from HCV blog and articles in Hep C Trust) - commentary, and a study they have referred to, about fatty livers in GT 3's)
There are two discrete forms of steatosis that may be found in patients infected with hepatitis C virus (HCV). Metabolic steatosis can coexist with HCV, regardless of genotype in patients with risk factors such as obesity, hyperlipidemia, and insulin resistance. The second form of hepatic steatosis in HCV patients is a result of the direct cytopathic effect of genotype 3 viral infections. There have been proposed mechanisms for this process but it remains elusive. Both categories of steatosis tend to hasten the progression of liver fibrosis and therefore prompt recognition and management should be initiated in patients with HCV and steatosis.
On average steatosis is about two and half times more common in people with HCV than in the general population, so it is clear that the presence of the virus in the body can actually trigger steatosis. Biopsy samples in people with HCV who have steatosis tend to show that fat accumulates around the portal areas, rather than in the middle of the lobules of the liver, as is usually the case Non Alcoholic Fatty Liver Disease (NAFLD) which point to the virus being the trigger rather than other factors.
For people with genotype 3 though, the link between steatosis and the virus has now been definitively established. Up to 60-80% of people with genotype 3 have moderate to severe steatosis. It seems that that there is a complex interaction between the core protein of the genotype 3 strand of the virus and liver cells that leads to steatosis. It also seems that the severity of steatosis in these patients is directly related to their viral load. The higher the viral load the greater the amount of steatosis.
Surprisingly people with genotype 3, who achieve sustained virologic response (SVR) through treatment, have a marked decrease in and sometimes a complete resolution of steatosis. If they then relapse steatosis then reappears.
Review the study, here.
http://www.medsci.org/v03p0053.htm