You can predict who will respond to immunotherapy:
A clinical activity score of 3 or more is predictive of a patient’s response to immunosuppressive therapy. Each component of the activity score is worth one point.
Components of the Clinical Activity Score
Spontaneous retrobular pain
Pain with eye movement
Redness of the eyelids
Redness of the conjunctiva
Swelling of the eyelids
Swelling of the caruncle
Conjunctival edema (chemosis)
The other option is radioiodine, but 15% of people have their ophthalmopathy get worse.
A randomised trial comparing orbital radiotherapy with oral glucocorticoids showed a similar rate of remission with approximately 50% of eye disease improving. While there is no universally agreed treatment schedule for sight-threatening dysthyroid optic neuropathy a common approach is intravenous glucocorticoids with prompt surgical orbital decompression if there is no clinical improvement.
Risk factors for Grave’s opthalmopathy following radioiodine include cigarette smoking, severe hyperthyroidism, high levels of thyrotropin receptor antibodies and uncontrolled hypothyroidism.
Grave’s Ophthalmopathy is usually bilateral but can be unilateral or asymmetrical. It may precede or follow hyperthyroidism but most often develops during the period of thyrotoxicosis. Several other conditions that can cause similar bilateral or unilateral appearance include: Cushing’s syndrome, obesity, orbital pseuotumour, idiopathic myositis and cellulitis, primary or metastatic orbital tumours, vascular conditions such as aneurysms and granulomatous diseases.
Calcium levels fall in pregnancy from dilution and this leads to increased vitamin D production, which means that more calcium is absorbed from the gut. Hypercalciuria therefore results.
The increased calcium levels lead to suppression of PTH.
For unclear reasons, PTHrP levels also increase, and this further suppresses PTH. The PTHrp comes from breast. It is also made in the placenta, decidua, amnion, fetal parathyroid glands and umbilical cord but fetal PTHrP has been shown not to cross the placenta.
calcium 1.2g, either as supplements or as food. For every 240ml of yoghurt or milk, 240g of cottage cheese, or 30g of hard cheese, you get 300mg of elemental calcium.
A summary of calcium in foods is that any green, leafy vegetable will be rich in calcium.
It is pointless having an adequate dietary intake of calcium, and an inadequate intake of magnesium, because calcium is only well absorbed when the body is replete with magnesium first. These foods are magnesium-rich:
-beans such as lentils, kidney, and limas
-most tofu
-almonds
-sesame seeds
-spinach
- seaweed.
Calcium supplements are not all the same. The two main ones on the market are calcium citrate and calcium carbonate. In general, citrate is better than carbonate because it is cheaper to manufacture the carbonate in a compact form, and this form does not dissolve well. Chewable carbonate will be OK though. They are best taken with a meal so that there is stomach acid present.
If you have reduced stomach acid, then the one to take is citrate because the carbonate will be very poorly absorbed (unless taken with citrus fruits).
The problems with calcium supplements are;
1. An increase in dietary calcium does not lead to increased risk of urinary stones because the oxalates in the food form a calcium-oxalate complex in the intestine, and so you do not get the increase oxalate levels in the blood that are responsible for forming calcium oxalate stones in the urine. However, calcium supplements come without oxalate, so they do increase the risk of kidney stones.
2. It inhibits absorption of thyroid medication - therefore needs to be spaced away from the calcium.
3. It inhibits iron absorption (citrate less so) - therefore needs to be spaced away from the calcium. This is why calcium should be taken spaced away from multi-vitamin tablets, because both compete for absorption, and so you end up not getting the maximum benefit from either.
4. There is a limit to how much calcium the body will absorb at any one time. This is why no more than 500mg of calcium should be taken at one time.
vitamin d 400-800IU, because it increases calcium absorption from the gut and reabsorption from the kidneys. This actually works not so much directly, but rather because it prevents secondary hyperparathyroidism that would lead to bone demineralization.
The exact dose of the Vitamin D depends upon the blood levels you achieve - the body only begins to store Vitamin D in fat and muscle tissue once blood levels reach 40ng/ml, and for some people only at 50ng/ml (i.e. those people are still using up Vitamin D as fast as they can make it or get it until this blood level).
In 2007, a study of 93 Hawain surfers found that none had blood levels of Vitamin D higher than 65ng/ml. It therefore recommended that optimal blood levels are 60ng/ml, and stated that the only way to achieve levels above this is to take a drug.
Thus, the optimal level of Vitamin D is 40-60ng/ml (100-150nmol/L).
As for the level at which you have deficiency, it is argued between 20 and 30ng/ml.
A summary table is:
25 (OH) D Level
ng/ml
(used in USA)
nMol/L
(international)
Deficient
less than 8
less than 20
Insufficient
8-40
20-100
Optimal
40-60
100-150
High
60-90
150-225
Toxic
greater than 90
greater than 225
Blood levels are often measured in nmol/L. The conversion is that 30ng/ml= 75nmol/L.
So, practically, what to do about borderline levels? Use PTH as the umpire!
There are several types of Vitamin D that can be bought:
cholecalciferol (D3) This is the same chemical as the vitamin D that is made in the skin from cholesterol.However, we get it bytaking lambs wool and melting it down to fat. The cholecalciferol is then extracted from the fat. Therefore it is not kosher or halal. It is the preferred form to take because it sustains blood levels the longest.
Ergocalciferol (D2), we get by subjecting fungi to radiation. Because it comes from plants, it is kosher. It is broken down by the body more quickly than cholecalciferol.
calcidiol. This is the same chemical that is made in the liver from cholecalciferol (the liver hydroxylates the cholecalciferol). We make it synthetically.
calcitriol. This is the same chemical that is made in the kidneys from calcidiol (the liver hydroxylates the calcidiol). This is the drug most likely to cause hypercalcaemia. In addition, your “vitamin D” blood level measurement will not change at all because what we measure in the blood is calcidiol (25-OH Vitamin D). Quite importantly, no trials of calcitriol have ever shown it to decrease fracture rates or even bone density.
calcitriol analogues. These drugs are equally most likely to cause hypercalcaemia. In addition, your “vitamin D” blood level measurement will not change at all.
So, one way to think of things is to say that cholecalciferol is natural vitamin D and all other compounds are either metabolic products or chemical modifications.
These other compounds are more likely to lead to hypercalcaemia, which then results in adynamic bone disease. To prevent this, keep an eye on the calcium-phophate product:- calcium times phosphorus must not exceed 70 mg2/dL2.
How much cholecalciferol to give?
The currently recommended limit for supplementation is 2000IU/day (50 micrograms). However, this doesn’t make a lot of sense because the body makes 10000IU of cholecalciferol with a ½ hour of sun exposure to the whole, nude body. Thus, 10,000IU/day has been suggested as the new upper limit of safety. Importantly, all known cases of vitamin D toxicity with hypercalcemia have involved intake of or over 1,000 micrograms/day (40,000 IU).
Vitamin D is essentially the backbone of osteoporosis management.
It has other benefits:
-intake of an additional 1,000 international units (IU) (or 25 micrograms) of vitamin D daily reduced an individual's colon cancer risk by 50%, and there is an inverse relationship of colon cancer with blood levels of 80 nmol/L or higher, a total 72% risk reduction.
- people with low levels of vitamin D had a 62% higher risk of a cardiovascular event than those with normal vitamin D levels. Low levels of vitamin D have also been implicated in hypertension, elevated VLDL triglycerides, and impaired insulin metabolism. Cholesterol levels were found to be reduced in gardeners in the UK during the summer months, and heart attacks peak in winter and decline in summer in temperat but not tropical latitudes.
The drawbacks of Vitamin D:
It can cause kidney stones, at least for people on modern American diets. The reason this has come up is because a recent study found the relative risk for people taking 400 units of vitamin D and 1,000 mg of calcium daily was 17% higher than in the placebo group. Also, at least two studies have linked kidney stones to latitude, with an increasing incidence of stones at lower latitudes. One also directly linked stones to sunlight. A Saudi Arabian study found kidney stones were more common in the summer. Eleven of 45 lifeguards in Israel had kidney stones, which is twenty times the rate of the general population. The largest study that looked at the risk of kidney stones with vitamin D came out of Harvard. They studied 45,616 men over 14 years for a total of 477,000 person-years of follow up. They found no increased risk of kidney stones with vitamin D intake but did not look at sun exposure or 25(OH)D levels. Of interest, they found three things in your diet that protect against kidney stones: high potassium (46% lower relative risk), high magnesium (29% lower relative risk), and high fluid intake (29% lower relative risk). For younger men, higher dietary calcium was associated with a reduced risk of kidney stones (31% lower relative risk). It seems likely that physiological vitamin D intakes will result in a higher relative risk for kidney stones for people on modern American diets (low potassium, low magnesium, high refined carbohydrates, high sodas, and a high acid residue). Today, humans live in a state of low-grade metabolic acidosis, mainly caused from a modern diet of high animal protein, refined sugars, refined grain, and sodas—instead of an ancient diet of moderate protein and whole grain and lots of vegetables and fruit. The low-grade acidosis in modern humans leaches calcium from our bones, increases the amount of calcium in our urine, and causes kidney stones, hypertension, and even stroke. Also, vitamin D does not work as well in metabolically acidotic people. For those of you who just can't eat five to nine servings of vegetables and fruit a day, 25 mEq of effervescent potassium bicarbonate every day in the form of a supplement is a good idea, as long as you are not taking a medication (usually for hypertension) that inhibits potassium excretion by the kidney.
SOURCES OF VITAMIN D:
1. Sun
If there is whole body exposure to summer midday sun for 10-15 minutes that produces a faint skin redness, then this is equivalent to 15,000 IU of cholecalcieferol orally!
Thus, if there is exposure of 15% of the skin surface (=hands, face and arms) such that you are 1/3 of the way to redness, then this is equivalent to 1000 IU. The time required is:
Importantly, you don't want too much exposure, because the previtamin D that is formed in the skin, if exposed to more UV, gets degraded.
2. Vitamin D tablets
3.Multi-vitamin tablets
In multi-vitamin preparations, you will usually get 10mcg of Vitamin D3 - this will only give you 400IU (1mcg=40IU). Thus, two multi-vitamin tablets/day will give the 800IU that are thought to be the minimum daily requirement.
4. Food
Milk is fortifed with Vitamin D - it has no natural Vitamin D, and this is why neither cheese nor yoghurt will supply Vitamin D. To get 800IU you need to drink 8 glasses/day of milk. However, this has the drawbacks of:
a) milk has a high protein content and this can increase blood acidity thereby leading to leaching of the bones.
margarine is fortified
One tablespoon (15 grams) of cod liver oil will provide 1,400 IU of Vitamin D. However, the drawback of this is the high levels of Vitamin A that it also provides - up to 4000IU, and high Vitamin A levels are linked to increased fracture risk. For this same reason, fatty fish such as salmon, herring and mackerel provide vitamin D
liver and eggs provide vitamin D
bisphosphonates
weekly Alendronate – for men, the data we have is in primary OP from a meta-analysis. It showed a reduction in vertebral fractures over just calcium and vitamin d. Non-vertebral fracture refuction was not statistically significant.
weekly Risedronate – 5mg of risedronate led to less non-vertebral fractures.
Bisphosphonates are poorly absorbed, so must be given on an empty stomach. This means that you cannot take your calcium supplementation for 4 hours after taking the bisphosphonate.
Very, very importantly, after 5 years, the fracture rates are as high in the women who keep taking alendronate as in the women who quit.
The drawbacks of bisphosphonates are:
Oesophagitis and oesophageal ulcers that can become strictures.
Gastric ulcers, particularly if taking NSAID’s.
Blood calcium levels fall.
Ocular side effects including pain, blurred vision, conjunctivitis, uveitis, and scleritis have been reported.
Although rare, some patients have experienced severe musculoskeletal pain (bone, joint, and/or muscle pain).
Avascular necrosis of the jaw, especially if poor dental hygiene. It has been estimated that the risk of ONJ is approximately 1 in 10,000 to 1 in 100,000 patient-years in patients taking oral bisphosphonates for osteoporosis.
Increased risk of AF.
There is theoretical concern that prolonged therapy leads to oversuppression of bone turnover ("frozen bone") and increased skeletal fragility. In animal studies, high-dose bisphosphonate accumulation results in microscopic damage.
Individual cases of atypical fracture (particularly sub-trochanteric fractures) and severely suppressed bone turnover in the setting of prolonged bisphosphonate therapy have been reported.
IMor gel or patch testosterone if they are hypogonadal and a man, or oestrogen if they are a woman (without a uterus, else oestrogen-progesterone). If someone is on testosterone then they need a yearly check of their lipids, liver, prostate, and for polycythaemia, all of these being potential side effects of testosterone. Acne is another side effect, as is breast tenderness and sleep apnoea.
Teripatide (synthetic PTH) only if all else fails as it causes osteosarcoma in rats. The combination of PTH with bisphosphonates is not recommended because Several trials have reported that PTH plus alendronate (either started concurrently or prior to PTH) resulted in no additional benefit for spine or hip BMD compared with PTH alone.
Calcitonin,
Thiazides - this will only really work if there is hypercalciuria, which is seen in a surprisingly large proportion of people with idiopathic osteoporosis (20%). It has been shown to improve bone density and to decrease fracture risks in studies on hypertensive patients.
Vitamin K (the vitamin in green, leafy vegetables) has never been studied, but we know that those who have osteocalcin that is decarboxylated - this being a marker of poor vitamin K status - suffer more fractures.
Strontium
Metabolic alkalosis protects bone in the same way that renal tubular acidosis causes bone disease, and perhaps subtle forms of renal acidosis contribute to osteoporosis.
Other things to know:
1. Excess Vitamin A is harmful to bone.
The Institute of Medicine recommendation for Vitamin A is 2330 IU = 700 micrograms (for women) and 3000 IU = 900 micrograms (for men).
One microgram of vitamin A (retinol) = 3.33 international units. Each 12 micrograms of beta-carotene from dietary sources is equal to 1 microgram of vitamin A retinol. If beta-carotene is taken as a supplement in oil, then each 2 micrograms is equal to 1 microgram of vitamin A.
2. Alcohol in small amounts is slightly beneficial to the bone; those who consume 1 unit a day (2 or 3 drinks a week) had higher bone density and a lower fracture rate than teetotallers. Between 1 and 2 units a day there is no increased risk. But above that amount the risk starts climbing.
One unit of alcohol is 8 grams. A "standard drink" is 14 grams, corresponding to a glass of wine, can of beer or a jigger of spirits.
3. An important point about vitamin D supplementation is that because it is stored in fat and muscle, those areas are repleted first. Thus, it can take 4 months for blood levels to begin to rise from supplementation.
