What have body building and sickle cell got in common? Well it’s a complicated story that starts nearly 40 years ago with the discovery of a simple chemical, nitric oxide. Nitric oxide is a very powerful vasodilator, meaning that it is able to relax the muscles in the walls of blood vessels, the blood vessel gets bigger, or dilates, resulting in a dramatic increase in blood flow and the delivery of oxygen to the tissues.
Muscle blood flow is important to body builders. If blood flow through the muscles is maximised, then more oxygen is delivered and they can exercise for longer, resulting in a more rapid increase in muscle size. The increased blood flow also removes lactic acid, one of the by products of muscle activity which, if it builds up results in muscle pain which limits further contractions.
Blood flow is also important in sickle cell. It is restricted blood flow, due to clumping together of sickled red cells, which results in the repeated attacks of pain, or vaso-occlusive crises, which are typical of the disease.
So, how is nitric oxide involved in sickle cell?
Nitric oxide is normally produced by the endothelial cells, which line the walls of blood vessels, from a precursor chemical called, L-arginine. Arginine is an amino acid, one of the building blocks of proteins and, is in turn, made from another amino acid, L-glutamine, by a series of chemical reactions, which occur in the wall of the small intestine and in the kidney. Normally a surplus of arginine is produced but, if the body’s requirements are increased, then there may not be enough to go round. Sickle cell disease is thought to be a condition where this is the case.
Not only is there an increased need for arginine in sickle cell disease but it appears that sickle cell has a variety of negative effects on the supply of arginine. Firstly, the red cell lifespan is shortened and when red cells break down, or haemolyse, they release an enzyme, arginase, which destroys any L-arginine in the bloodstream. Secondly, the hemoglobin released into the blood when the red cells break down binds to and destroys nitric oxide. Lastly, one of the chemical reactions producing arginine in the body occurs in the kidneys. Kidney disease is common in sickle cell and this probably results in reduced arginine synthesis.
In addition to dilating blood vessels and improving blood flow via nitric oxide, arginine also has other important effects in sickle cell, including reducing inflammation, inhibiting the clumping together of platelets and preventing the thickening of blood vessel walls by reducing the growth of smooth muscle cells and collagen. All these factors are important in the many complications of sickle cell disease.
In summary then, the synthesis of L-arginine is disrupted in sickle cell disease and there is not enough to go around. It also appears that arginine has some important positive benefits in sickle cell. Adults with sickle cell have low levels of arginine in the blood all the time and in both adults and children arginine levels fall further during a painful crisis. The lower the levels the more severe the crisis and the more likely it is that the patient will require admission to hospital. Patients with the lowest levels of arginine are more prone to attacks of the acute chest syndrome, a series complication of sickle cell. So, arginine really does seem to be important, which begs the question, could taking supplements of arginine be useful in sickle cell?
That brings us back to the body builders. Body builders often take oral arginine supplements before and after exercise to allow them to exercise harder and for longer and so speed up muscle development.
Long term supplementation with arginine appears to be safe. Our normal daily intake of arginine is about 2.0-7.0 grams from foods such as, seeds and nuts, seafoods, spinach, meat and dairy products. Generally, body builders double this, taking an extra 6.0 grams a day, but doses of up to 21.0 grams daily (divided into three doses of 7.0 grams each) can be safely given in a variety of conditions and these larger doses are probably necessary to maximise the beneficial effects.
There are difficulties with this however. Taking doses of this size involves a large number of tablets to be swallowed every day and this makes the treatment difficult to stick to over time. Although arginine can also be given by an intravenous infusion, this usually requires some sort of venous access device and this makes outpatient treatment difficult.
Is there any evidence that arginine supplementation is actually helpful in sickle cell?
1. Doctors in California, USA published a paper last year showing that IV arginine (100mg/kg given three times a day) given to children admitted to hospital with a painful crisis resulted in remarkable 54% reduction in the amount of strong pain killers used by the children and lower pain scores when they were discharged home. There was also a trend to a shorter stay in hospital for those children treated with arginine.
2. Chronic leg ulcers are one of the most distressing complications of sickle cell disease, they are painful, slow to heal and very difficult to treat. In 2010, doctors from Boston, USA published the results of a trial of intravenous arginine (500mg/kg/day; given 5 days a week for 12 weeks) in patients with severe, long standing leg ulcers. After 3 months treatment 78% of ulcers had healed compared with only 24% in a group similar patients who were only given standard treatment.
3. Pulmonary hypertension (PHT) is a recently recognised, serious complication of sickle cell disease, where the blood pressure inside the lungs reaches very high levels. There was hope that arginine would prove to be an effective therapy but results have been disappointing and contradictory. One trial showed a modest 15% reduction in lung blood pressure, but other studies showed no effect at all.
4, Priapism is a sustained, painful erection of the penis, a common complication in men and boys with sickle cell, which is sometimes difficult to treat. There have not been any formal studies of the use of arginine to treat priapism but anecdotal case reports suggest that it may be of benefit.
There is therefore reasonable evidence that treatment with arginine may be helpful in the management of painful crises and leg ulcers and some evidence that it may also be helpful in PHT and priapism.
However, the situation is clearly complicated. Treatment with arginine does not always result in an increase in the level of arginine in the blood and giving nitric oxide instead does not mimic the success of arginine, suggesting that other factors apart from dilation of blood vessels are at play. There is a pressing need for more research to define the place of arginine in management and to devise new ways of administering the drug.
One interesting possibility is the use of arginine in combination with hydroxycarbamide. A group working in Fortaleza, Brazil reported interesting, preliminary results in 2012 with low dose oral arginine (250mg daily for 90 days). Patients treated with both arginine and hydroxycarbamide showed a bigger increase in foetal haemoglobin levels than patients treated with hydroxycarbamide alone. It may be that one way forward is to investigate combination therapy.
A randomised, placebo controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalised with vaso-occlusive pain episodes. Morris CR, Kuypers FA, Lavrisha L et al. Haematologica, 2013; volume 98, pages 1375-1382.
A randomised phase II trial of arginine butyrate with standard therapy in refractory sickle cell leg ulcers. McMahon L, Tamary H, Askin M et al. British Journal of Haematology, 2010; volume 151, pages 516-524.
L-arginine as an adjuvant drug in the treatment of sickle cell anaemia. Elias DBD, Barbosa MC, da Silva Rocha LB, et al British Journal of Haematology, 2012; volume 160, pages 410-412.
Alterations in arginine metabolism in sickle cell disease. Morris CR. Haematology / Oncology Clinics of North America, April 2014, pages 301-321.