early #AMD reversal with high-dose fish oil #med #blindness

2.12: med/amd/fisho
2.13: summary:
. AMD is a major source of blindness;
studies show that in its early stages,
it can be reversed with fish oil;
and that a key marker of healing
is there being nearly as much EPA
as the body has of AA;
fish oil supplements vary in EPA;
eg, le caps have 0.35g of EPA;
along with EPA from fish oil,
you also need to lower AA levels:
keep insulin low (avoid grains and sugars);
limit omega-6 oils and most of all
be wary of AA in fatty animal products,
especially eggs and chicken.
if you get all your fish oil from fish meat
you also get some AA along with
dioxins, PCB's and mercury].
. AMD reversal was indicated by
the ability to read more letters
on a chart with increasingly smaller letters:
8 more letters at aa/epa ratio of 2-2.7;
[from perhaps 4 le caps per day]
15 letters at aa/epa ratio of 1.1-1.6
[from perhaps 8-12 le caps].
. the study applied the oil in 2 doses.
. rancid fish oil can do more harm than good
so it's important to pick a brand
that is 3rd-party tested for low rancidity
and also has powerful antioxidants
such as rosemary or olive extract.
. when taking high-dose fish oil
you should add more antioxidants,
and also ensure you get some GLA
that is blocked by high-dose DHA
(oats are a source of GLA).

. the FDA 1997 claimed that
more than 5 le caps worth of EPA
is a hemorrhage risk; but, a recent study
found that even at the dose of
12 le caps per day (equiv DHA/EPA levels)
bleeding time was not prolonged,
although there could be complications
if also taking a medication
that prolongs bleeding time, eg aspirin;
but you can give up aspirin for heart
because going on an omega-3 Zone diet,
does everything an aspirin does for heart
with fewer side-affects
(see the many problems with aspirin).
. for those who have dry AMD
and are hesitant to give up aspirin,
The Australian Blue Mountain Eye Study
[JAMA Intern Med. 2013]
found aspirin may increase the risk of
progressing to the blinding wet AMD.
. cumulative incidence of neovascular AMD among
(regular vs non-regular aspirin users) was
(1.9, 0.8) percent at five years,
(7, 1.6) percent at 10 years, and
(9.3, 3.7) percent at 15 years;
“Regular aspirin use was significantly associated
with an increased incidence of neovascular AMD.”

. the main reason you should get tested
to see what your blood AA/EPA ratio is,
is that you could be a fast metabolizer of EPA
and actually need far more than 12 le caps
to get maximal reversal of AMD.
. Dr.Sears Lab sells such testing here:
(you draw blood from your fingertip and mail it in).

what is AMD blindness?:

Dr.Axe:
AMD (age-related macular degeneration)
733 million people are living with
low vision and blindness worldwide
due to macular degeneration.
The dry form is much more common,
accounting for about 90 percent of all cases.
When the dry form progresses,
it can become known as neovascular
age-related macular degeneration,
also called wet macular degeneration
which accounts for about 90 percent
of all cases of legal blindness due to AMD.

why the AA/EPA ratio is key to healing:

Dr.Sears 2012:
EPA is an inhibitor of the enzyme
delta-5-desaturase (D5D) that produces AA;
The more EPA you have in the diet,
the less AA you produce.
This essentially chokes off the supply of AA
necessary for the production of
pro-inflammatory eicosanoids
(prostaglandins, thromboxanes, leukotrienes, etc.).
DHA is not an inhibitor of this enzyme.
. also EPA and not DHA competes with AA
for the enzyme phospholipase A2
necessary to release AA
from the membrane phospholipids.
DHA is an inhibitor of another key enzyme,
delta-6-desaturase (D6D),
that produces GLA (gamma linolenic acid).
This is why if you use high-dose DHA,
it is essential to add back trace amounts of GLA
to maintain sufficient levels of DGLA
to continue to make anti-inflammatory eicosanoids.
DHA is still very useful:
. both EPA and DHA appear to be equally
effective in reducing triglyceride levels,
activating the gene transcription factors
PPAR alpha and PPAR-gamma,
and making anti-inflammatory resolvins.

Dr.Sears`list of AA/EPA measuring studies:
[list of studies that have used the AA/EPA ratio
to measure the levels of inflammation.]

reversing AMD without hemorrhage risk

from high-dose fish oil:

Dr.Sears 2016:
. hemorrhage risk from high epa comes
only from an AA/epa ratio less than 1;
a dose of 7.5g DHA + EPA [12 le caps]
resulted in aa/epa ratio of 1.2;
dose of 5g: aa/epa ratio of 1.3
dose of 2.5g: aa/epa ratio of 2.6
[Yee et al, Am J Clin Nutr 91: 1185(2010)]
details:
. testing 0.84, 2.52, 5.04, and 7.56 g
DHA + EPA daily,
that is 1,3,6, and 9 Omacor capsules
containing ethyl esters of omega-3
with each capsule providing about
0.465g EPA and 0.375g DHA.
[=0.84g of DHA + EPA]
. after 6 months on 9 caps,
platelet function closure time
was still within normal:
"None of the doses affected in vitro clotting times
at 3 or 6 mo of treatment;"
. going from 7 to 9 caps
didn't significantly increase EPA blood levels;
[however going from 7 to 9 caps
did significantly decrease AA blood levels].
AMD reversal as indicated by
letters of improvement
(ability to read more letters
on chart with increasingly smaller letters):
8 letters at aa/epa ratio of 2-2.7;
[from perhaps 4 le caps]
15 letters at aa/epa ratio of 1.1-1.6.
[from perhaps 8-12 le caps]

it may take months not weeks to see a change:

Dr.Sears:
5 grams of EPA and DHA per day
[8 le caps] for only 10 weeks
reduced the AA/EPA ratio to only 2.5
-- not the 1.3 seen in the above study.
[N Engl J Med 320:265-271 (1989)]

choice of fish oil: Life Extension (le):

Life Extension, Omega Foundations, Super Omega-3:
IFOS - 5-Star Rating
[proof it is pure and not rancid]
2 Softgels contains:
Pure+ Wild Fish Oil Concentrate 2g:
Yielding:
700 mg EPA (eicosapentaenoic acid)
500 mg DHA (docosahexaenoic acid)
Polyphen-Oil Olive extract (fruit and leaf)
[providing 19.5 mg polyphenols,
5.2 mg hydroxytyrosol/tyrosol,
4.4 mg verbascoside/oleuropein] 300 mg
Sesame seed lignan extract 10 mg

life extension (le) fish oil caps have:

0.35g epa
0.25g dha
0.35+ 0.25 = 0.6 dha+epa;
4 caps = 2.4g dha+epa --dose for resolvins;
5 caps = 3g --FDA: safe for all;
6 caps = 3.6g
8 caps = 4.8g --my current dose.
10 caps = 6g
12 caps = 7.2g --safest tested dose.

study proving bleeding not an issue:
9 study caps = 7.5g DHA + EPA:
4.185g epa,
3.375g dha.
(more details in next section).

how many le caps to use for AMD? 12:
. go by epa equivalence,
since the important parameter in healing
is the ratio of EPA to AA:
0.35g(epa/le) *x(le caps) = 4.2g(epa/9 study caps)
x = 4.2/0.35 =
12 le caps have the same epa as 9 study caps.

what is the difference in dha? le has less:

. when estimating epa blood levels,
to ensure a limit that prevents bleeding
notice that as much as 10% of dha
may be converted into epa; [Dr.Sears]
so if some of study's epa came from its dha;
we need to know if le caps have more dha
which might be a greater source of epa.
12 le caps*0.25g(dha/le cap) = 3g dha
which is 0.375g less than the
3.375g dha in 9 study caps.
. 10% of 0.375g dha is potentially 37.5mg epa;
an insignificant lesser amount of epa
from le caps.

Dr.Sears 2018`the AMD reversal studies:

. 2 studies show significant improvements
using between 5 and 7.5 grams
of EPA and DHA per day [10 to 15 le caps
but with less DHA].

study#1 (3.4 g EPA = 10 le caps):

[PharmaNutrition 2014:
Georgiou T, Neokleous A, Nikolaou D, and Sears B.
“Pilot study for treating
dry age-related macular degeneration (AMD)
with high-dose omega-3 fatty acids.”
ethyl esters with EPA and double the DHA:
3.4g EPA + 1.6g DHA
divided into 2 doses for 6 months.
Visual acuity was determined by the improvement of
lines of vision that could read by a patient
using an electronic ETDRS chart
[Early Treatment Diabetic Retinopathy Study].
One line of vision consists of five letters
that can be clearly read by the subject.
Each line of vision has a geometric progression
with increasing difficulty to read.
All subjects were taking vitamin supplements
according to AREDS2 recommendations
and were asked to stop this treatment
prior to beginning the omega 3 fatty acids supplementation.
The mean age was 67 years
with a range from 50 years to 85 years.
The visual acuity of patients ranged
from 20/25 (80% of normal vision)
to 20/200 (10% of normal vision)
according to the ETDRS electronic chart.
significant improvement:
By the six-month time point,
the average increase in vision was
2 lines of vision or 10 letters.
All eyes had improvement of visual acuity.
Approximately, 1/3 of eyes improved by
1 line of vision (5 letters),
the other third by 2 lines of vision
and the last third by 3 lines of vision.
]

study#2(up to 15 le caps depending upon AA/EPA ratio):

[J Stem Cells 2015:
Georgiou T, Prokopiou E.
The New Era of Omega-3 Fatty Acids Supplementation:
Therapeutic Effects on Dry Age-Related Macular Degeneration.
. effects of high omega-3 fatty acids
as anti-inflammatory agents.
. in two sub-groups of dry AMD patients with
1) mild to moderate visual impairment and
2) with severe visual impairment (blindness).
The key feature of this investigation is the
frequent monitoring of the levels of
specific fatty acids in patient's blood
in order to adjust the treatment dose
within the ideal therapeutic window.
The latest data which is presented in this chapter
suggests that the eyes which had
the greatest gain in vision
(≥ 15 letters gain at 6 months)
were from patients with mild to moderate
visual impairment,
who were taking between 5-7.5 g/day EPA and DHA
and had a ratio of arachidonic acid to EPA
of less than 2 AA/EPA.
][. this study refers to the prior study
that included a special fish oil
that has more than the usual epa;
so, when they said 5g epa+dha,
they implied 3.4 g EPA;
thus, for the dose of 7.5 (1.5*5)
they likely used 1.5(3.4g) = 5.1g EPA:
that is 15 le caps worth of epa,
but the le caps have far more dha than they used,
and that may be as they intended
-- be sure to get some GLA from oats!]

no benefit from only 2 le caps:

Dr.Sears(cont):
Studies with a much lower dose of EPA and DHA
demonstrated no benefits
suggesting a potential dose-response relationship
[JAMA Intern Med 2014:
“Effect of long-chain n-3 fatty acids
and lutein + zeaxanthin supplements
on cardiovascular outcomes:
results of the Age-Related Eye Disease Study 2
(AREDS2) randomized clinical trial.”
. the 0.350g DHA + 0.650g EPA [2 le caps]
were in addition to the AREDS formulation:
ascorbic acid (500 mg),
vitamin E (dl-alpha tocopherol acetate, 400 IU),
[toxic form of vit'e]
beta carotene (15 mg),
and zinc (80-mg zinc oxide) [toxic form]
with copper (2-mg cupric oxide),
[a form of copper that turns the vit'c
into cancer-causing dehydro-vit'C]
]

Dr.Sears(cont):
neo-Paleolithic man may have had
2.26– 17 g fish oil /day
[Br J Nutr 2010:
Kuipers RS, Luxwolda MF, Dijck-Brouwer DA, Eaton SB, Crawford MA, Cordain L, and Muskiet FA.
“Estimated macronutrient and fatty acid intakes from
an East African Paleolithic diet.”
We found (range of medians in % of energy)
intakes of moderate-to-high fat (30–39)
The fatty acid composition was
SFA (11·4–12·0),
MUFA (5·6–18·5) and
PUFA (8·6–15·2).
The latter was high in α-linolenic acid
(ALA) (3·7–4·7 % of energy),
low in LA (2·3–3·6 % of energy),
and high in long-chain PUFA (LCP):
[PolyUnsaturated Fatty Acids]
LCP n-3 (2·26–17·0 g/d),
LCP n-6 (2·54–8·84 g/d),
ALA/LA ratio (1·12–1·64 g/g)
and LCP n-3/LCP n-6 ratio (0·84–1·92 g/g).
We conclude that compared with Western diets,
Paleolithic diets contained
consistently higher protein and LCP,
and lower LA.
more.

Japanese noted for good AA/EPA ratio:

Dr.Sears:
The ideal AA/EPA ratio is 1.5 - 3
as found in the Japanese population.
dhaomega3:
. large sectors of the Japanese population
have consumed daily intakes of approximately
700-1200 mg of DHA/EPA daily for decades.
[1-2 le caps]
sciencedaily:
Japanese people eat about 3 ounces of fish daily;
the intake of omega-3 fatty acids from fish
averages 1.3 grams per day in Japan.
[J Am Coll Cardiol 2008]
[. that's not a lot of fish oil;
what are they doing to keep their AA so low?]

history of the AA/EPA ratio:

Professor Lesley Braun 2013
The suggestion that fish oil consumption
could affect bleeding time
was first made when it was reported that
Greenland Eskimos who consumed a diet
rich in fish and marine mammal oils
had marked increases in bleeding time
and decreased platelet aggregation.
The plasma and platelets of these Eskimos
contained high concentrations of EPA and DHA,
and very low concentrations of
arachidonic acid (AA),
a fatty acid normally derived from linoleic acid
or ingested directly through dietary sources
such as meat, eggs and dairy products.
[Lancet 1979:
Dyerberg J, Bang HO.
Haemostatic function and platelet polyunsaturated fatty acids in Eskimos.
]
In contrast, a study of Alaskan Eskimos found that
although they had a high dietary fish intake,
[they didn't have problems like Greenland had.]
[Am J Clin Nutr 1994:
Parkinson AJ, Cruz AL, Heyward WL, et al.
Elevated concentrations of plasma omega-3 polyunsaturated fatty acids among Alaskan Eskimos.
]
A closer look at the results indicates that
the Greenland Eskimos at the time (1975)
had very low levels of AA,
lower than the Alaskan Eskimos (1985)
and a suggestion has been made that
bleeding risk may relate to the ratio:
not just a high EPA intake
but also a low AA level.

how very high doses cause bleeding
[Dr.Anthony J. Busti].

krill oil vs the studied ethyl esters:

krill oil fails the AA test:
Lipids. 2011:
Metabolic effects of krill oil are essentially similar
to those of fish oil but at lower dose of EPA and DHA,
in healthy volunteers.
six capsules of krill oil (N = 36; 3.0 g/day,
EPA + DHA = 543 mg) or three capsules of
fish oil (N = 40; 1.8 g/day,
EPA + DHA = 864 mg) daily for 7 weeks.
No statistically significant differences
in changes in any of the serum lipids
or the markers of oxidative stress and inflammation
between the study groups were observed.
Krill oil and fish oil represent
comparable dietary sources of n-3 PUFAs,
even if the EPA + DHA dose in the krill oil was
62.8% of that in the fish oil.
more:
krill oil by Aker BioMarine ASA.
Each capsule contained 500 mg oil
that provided 90.5 mg EPA and DHA.
The comparator omega-3 fish oil product
by Peter Möller AS, Oslo, Norway.
600 mg fish oil
that provided 288 mg EPA and DHA,
dose:
Fish oil 3 capsules (1.8 g oil)
450mg epa; 414mg dha; =864mg both;
Krill oil 6 capsules (3.0 g oil)
348mg epa; 195mg dha; =543mg both;

The fatty acid profile(area %):

(Fish oil, Krill oil):
--less than 1% fractions deleted.

saturates: 16.0, 30.7
14:0 3.2, 7.4
Palmitic 16:0 7.8, 21.8
18:0 2.6, 1.3

mono's: 18.0, 25.9
16:1n-7   3.9, 5.4
18:1n-9,-7,-5   6.1, 18.3
20:1n-9,-7   2.0, 1.2
22:1n-11,-9,-7   2.5, 0.8

poly omega-6: 2.9, 2.5
AA 20:4n-6  1.5, 0.5

poly omega-3: 59.0, 34.1
EPA 20:5n-3 27.0, 19.0
DPA 22:5n-3 4.8, 0.5
DHA 22:6n-3 24.0, 10.9

Other 7.2, 6.4

how did krill raise AA?:

The level of arachidonic acid (C20:4n-6)
increased from baseline in the krill group,
whereas a decrease was observed in the fish oil group
but a decrease was found in the control group too.
The changes in arachidonic acid between the fish oil
and the krill oil groups,
and the control group differed significantly (p = 0.001).

example of a good krill product:

NutriGold/ Krill Oil Gold™
[ifos tested for purity and rancidity]
eg, a batch expiring 2019 [accessed 2018.2]:
Krill Oil Gold™ (Lot#:8873G, 8804G)
contains 225 mg of EPA+DHA per serving
in addition to 420 mg of phospholipids
and 835 mcg of the antioxidant astaxanthin.
0.516 ppb of PCBs is less than 45 ppb;
0.971 ppt of Dioxins & Furans
-- just barely less than 1 ppt;
0.154 ppt of Dioxin-Like PCBs less than 1.5 ppt.
0.012 ppm of Mercury (Hg) is less than 0.1 ppm.

www.nutrigold.com/Krill-Oil
Clinically-proven NKO
IKOS 5-star certified
Highly bioavailable omega-3s
Natural astaxanthin source
Hexane-free processing
2 caps of NKO krill oil has 1g of oil
containing:
420mg phospholipids;
0.14g EPA; 0.085g DHA; 40mg other omega-3
--
compare that to le caps
where for each gram of oil you have to take
you get much more active ingredient;
nutrigold krill has only:
40% of le's epa (0.14/0.35)
34% of le's dha (0.085/0.25)

Dr.Sears prefers ethyl esters:
Krill oil is extracted from small shrimp
first by hexane (i.e. gasoline)
and then precipitated by the addition of
acetone (i.e. nail polish remover).
[this might not be true of all krill oil:
Nutrigold denies it]
The resulting product is a combination of
free fatty acids, monoglycerides,
and maybe 20% phospholipids.
These products can’t be refined
to remove contaminants such as PCBs.
[if it is true they can't be refined,
then perhaps krill is not contaminated,
because some does pass 3rd-party testing.]

Dr.Sear sells what has been studied most:
ethyl esters
and the kind used in his AMD study:
with EPA double that of DHA.

Dr. Sears’ OmegaRx 2 Fish Oil – 10oz Liquid:
With 500mg of EPA and 250mg of DHA per gram;
or 60 servings of 4.5g oil
with 2.25g epa and 1.125g dha;
rosemary extract, sunflower oil;
natural tocopherols, lime oil.

Dr. Sears’ OmegaRx 2 Fish Oil:
4g fishoil; 2g epa; 1g dha
mixed vit e, rosemary extract.

resistance to high-dose fish oil:

Dr.Ehrlich:
EPA in fish oil supplements
may increase bleeding time;
That does not seem to be true of DHA by itself.
[except when it converts to epa]

FDA evaluation of high-dose fish oil:

. the FDA says up to 3g of DHA+EPA
[5 le caps] per day
is generally considered safe.
. the FDA may not be taking into account
the importance of oil quality,
ensuring that fish oil is not rancid,
and that it's combined with antioxidants.
. they mention studies of bleeding
that lack data on clinical significance,
or the importance of relative AA levels.

FDA 1997:
Menhaden oil is oil from menhaden fish;
EPA and DHA are the major source of
omega-3 fatty acids from fish oil
and together comprise approximately 20 percent
by weight of menhaden oil.
. (the June 1997 final rule), affirming menhaden oil
as GRAS [generally recognized as safe]
for use as a direct human food ingredient
with limitations on the maximum use levels
of menhaden oil in specific food categories.
FDA concluded that these limitations
are necessary to ensure that
daily intakes of EPA and DHA from fish oil
do not exceed 3.0 grams
per person per day (g/p/d).
As discussed in the following paragraphs,
the maximum limit of 3.0 g/p/d on the
total daily intake of EPA and DHA
is a safeguard against the possible
effects of these fatty acids on
increased bleeding time
(the time taken for bleeding from a
standardized skin wound to cease),
glycemic control in
non-insulin-dependent diabetics,
and increased levels of LDL cholesterol.
As part of FDA's evaluation of GRASP 6G0316,
FDA examined the scientific literature
for evidence that consumption of fish oils
may contribute to excessive bleeding.
In the June 1997 final rule,
FDA concluded based on this examination
of the scientific literature,
including more than 50 reports on fish oils
with data on bleeding time,
that when consumption of fish oils is limited to
3.0 g/p/d or less of EPA and DHA,
there is no significant risk for increased bleeding time
beyond the normal range (62 FR 30751 at 30752 to 30753).
FDA also concluded that amounts of fish oils
providing more than 3.0 g/p/d of EPA and DHA
have generally been found to produce
increases in bleeding time that are statistically significant,
but that there are insufficient data
to evaluate the clinical significance
of this finding. Therefore,
because of the lack of data on clinical significance
and because of the potential risk of excessive bleeding
in some individuals with intakes at higher levels,
FDA concluded that the safety of menhaden oil
was generally recognized only at levels that
limit intake of EPA and DHA to 3.0 g/p/d.
FDA also concluded in the June 1997 final rule
that 3.0 g/p/d of EPA and DHA is a safe level
with respect to glycemic control (62 FR 30751 at 30753).
This conclusion was based on FDA's review of
a series of studies on non-insulin-dependent diabetics.
Studies on type-II diabetics that reported
increased glucose used higher amounts
(4.5 to 8 g/p/d) of omega-3 fatty acids.
One study found no change in fasting
blood glucose levels among type-II
(insulin resistant) diabetics
treated with 3.0 g/p/d EPA plus DHA for 2 weeks.
Two other studies that used 3.0 g/p/d EPA plus DHA
for 6 weeks and 2.7 g/p/d EPA plus DHA for 8 weeks
found only transient increases in blood glucose
halfway through their respective supplementation periods.
Another study that used 3.0 g/p/d EPA plus DHA for 3 weeks
found comparable increases in fasting blood glucose
when either fish oil or safflower oil was fed,
so the increase cannot be attributed
specifically to omega-3 fatty acids.
A study that compared the effects of fish oil and olive oil
fed 3.0 g/p/d of EPA plus DHA
did not find a difference in fasting glucose
or glycosylated hemoglobin
after fish oil supplementation compared to baseline;
they did find a significant difference compared to
the olive oil treatment,
which produced changes in the opposite direction
from fish oil. Based on its evaluation of the available information,
FDA concluded in the June 1997 final rule
that consumption of EPA and DHA in fish oils at 3.0 g/p/d
by diabetics has no clinically significant effect on glycemic control,
although higher amounts of EPA and DHA (4.5 g/p/d and above)
remain of concern.

what about whole fish? FDA:
2-3 4oz servings per week
of fish low in contaminants;
(eg, sardine, salmon)
or 1 serving per week of
(eg, tuna, halibut, snapper).
get variety, start children on fish by age 2.

unofficial FDA memo:
. one agency suggested
those who consume more than
two 3-ounce servings of fish per week
should choose a variety of types of seafood
to reduce the risk for exposure to contaminants
from a single source.
[a good case for purified supplements]
. USDA used modeling to examine predicted changes in
U.S. nutrient intake due to approximately
doubling current fish consumption
to a total intake of 8 ounces of fish per week
(Advisory Committee Report, Appendix G-3).
The model classified fish into two groups,
having more or less than 500 mg
EPA plus DHA per three ounces.
Current consumption is
about 80 percent low n-3 fish.
Changing fish consumption to eight ounces
of high n-3 fish per day per day
would provide 512 mg EPA plus DHA.
This can be compared with the Committee’s
estimate that in five U.S. studies,
the lowest risk of clinical coronary events was associated with
EPA plus DHA intake of approximately
496 mg/day (or about 3.5 g/week),
with a range of 246 to 919 mg/day.