Acute and chronic gout

The following is based on the Malaysian Clinical Practice Guidelines for Management of Gout (Published in October 2008)

1. The first line treatment for acute gouty arthritis is non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, diclofenac and indomethacin. Aspirin is not recommended because it increases uric acid levels in the blood unless given in very high doses.

Question: A patient with acute gouty arthritis has peptic ulcer disease and hence cannot be prescribed any of the traditional NSAIDs. What can be done for pain relief in this situation?

Answer: We can use either COX-2 (cyclooxygenase 2) inhibitors like Celecoxib or Etoricoxib. We can also use Colchicine. A third option for pain relief, particularly in elderly people and in those who have renal disease, is the use of glucocorticoids. Short courses of oral prednisolone are effective in providing pain relief. Intra-articular injections of corticosteroids are also helpful.

2. Long term therapy with Allopurinol to reduce serum uric acid levels should be initiated in those who have chronic gout – that is, those who have experienced 3 or more episodes of acute gouty arthritis in a year, those who have erosive gouty arthritis, those who have tophi, and those who have uric acid nephropathy or uric acid stones.

Question: How is Allopurinol prescribed?

Answer: Allopurinol should be started in a low dose of 100 to 150mg once a day. After 3 to 4 weeks, the dose can be increased to usual maximum dose of 300mg per day. In those who have renal impairment, the dose of Allopurinol should be appropriately reduced. For example, if a patient with gout has end stage renal failure, the dose of allopurinol should not exceed 100mg once in 2 to 3 days. If a patient with gout has Stage 3 CKD, the maximum dose should not exceed 200mg per day. The usual dose of 300mg per day should only be prescribed for those with normal renal function.

Question: Can Allopurinol be prescribed for those with asymptomatic hyperuricemia?

Answer: It is not necessary to prescribe Allopurinol for all asymptomatic people with elevated uric acid levels because most of them will never suffer from gout. However, if the uric acid level is very high (about twice the upper limit of normal), it is better to prescribe allopurinol to reduce the risk of developing nephropathy. Prophylactic use of allopurinol is also recommended when a rapid increase in serum uric acid  is anticipated – as in treatment of leukemias and lymphomas.

Question: Since allopurinol has the potential to cause severe allergic reactions and bone marrow depression, is there an alternative drug for reducing serum uric acid?

Answer: Probenecid is also a uric acid lowering drug. Unlike allopurinol, probenecid increases the excretion of uric acid in the urine. Hence probenecid is not recommended for those who have uric acid nephropathy or uric acid nephrolithiasis. Ideally, urinary excretion of uric acid should be measured and probenecid should be prescribed only for those who do not have elevated urinary uric acid levels. 

Question: Will allopurinol therapy increase the risk of acute gouty arthritis?

Answer: Yes, there is an increased risk of acute arthritis during the initial period after allopurinol is initiated. That is why one should not prescribe allopurinol during an acute episode. To minimise acute episodes while initiating allopurinol therapy, low doses of colchicine (0.5mg twice a day) can be given. Colchicine can be stopped when the patient has not suffered acute arthritis for 6 months or when serum uric acid levels are normal for one month.

Question: Should allopurinol be stopped when a person, who is already on allopurinol, develops acute gouty arthritis?

Answer: No. Allopurinol need not be stopped in this situation. 

Question: What is risk when Allopurinol is prescribed along with Ampicillin?

Answer: There is an increased risk of developing a skin rash due to allopurinol.

Question: What is the risk of prescribing allopurinol with warfarin?

Answer: There is the risk of bleeding because allopurinol reduces the metabolism of warfarin and increases its half-life.

3. Polyarticular gout mimics rheumatoid arthritis. Gouty arthritis can lead to osteoarthritis.

Question: How do the subcutaneous tophi in gout differ from the subcutaneous nodules of rheumatoid arthritis?

Answer: Tophi are painless while rheumatoid nodules are generally painful.

Question: Is it possible to differentiate gouty arthritis from osteoarthritis with an x-ray of a painful joint?

Answer: Yes. The joint space is preserved in acute gouty arthritis while the joint space is narrowed in osteoarthritis.

4. A normal serum uric acid in a person with acute arthritis does not exclude gout.

Question: Can a therapeutic response to colchicine be used to diagnose gout?

Answer: Yes. Acute gouty arthritis responds within 48 hours to colchicine.

5. Alcohol should be restricted or avoided in all patients with gout.

Question: Why is alcohol restriction necessary in gout?

Answer: Alcohol reduces the excretion of purines. Uric acid is the result of purine metabolism.

6. Drugs that increase uric acid levels can provoke acute gouty arthritis.

Question: A patient with diabetes, hypertension and ischemic heart disease experiences frequent gouty arthritis. Which of her medications may need to be changed?

Answer: Is she on thiazide diuretics for hypertension and low dose aspirin for heart disease? If yes, these should be changed.

7. Food that is high in purine content should be avoided by those who have gout.

Question: Should eggs be avoided by those who have gout?

Answer: No. Eggs have low purine content.

Question: Should mushrooms, beans and peas be avoided by those who have gout?

Answer: These foods have moderate purine content and should be eaten less frequently than usual.

Question: Can those with gout eat red meat, anchovies and sardines?

Answer: These are food items with high purine content and should be avoided.

Cyanosis without hypoxia

Clinically evident cyanosis is often due to increased levels of reduced hemoglobin in the blood caused by cardiac or pulmonary diseases. Recently a 23 year old woman presented with cyanosis of the tongue and finger tips. She was not anemic or icteric. She did not have any cardiac or pulmonary disease. Her capillary oxygen saturation was 93 percent. When a few drops of her blood (dark brown in colour) were spilled on a white filter paper, no change in colour was noted after adequate exposure to the atmosphere.

This provoked a discussion on the causes of cyanosis without hypoxia.

We discussed methaemoglobinemia as a possible cause. Methaemoglobinemia is a condition where the hemoglobin molecule has a ferric iron instead of the normal ferrous iron. This condition can occur following exposure to drugs like nitrites, sulphonamides and some chemical dyes. When iron is in the ferric state, hemoglobin does not easily release its oxygen to tissues. Methaemoglobinemia can also be due to inherited disorders: deficiency of the enzyme within red cells that normally converts iron from a ferric state to a ferrous state - an enzyme called methaemoglobin reductase - can result in methaemoglobinemia. Another reason is the presence of an abnormal hemoglobin called Hemoglobin M.

Our patient however did not have methaemoglobin reductase deficiency. Her hemoglobin electrophoresis showed the presence of the hemoglobin variant called Hemoglobin M. And that explained why she had cyanosis without hypoxia.

The Mantoux tuberculin skin test - interesting facts

The Mantoux test or the Tuberculin Skin Test (TST) is one of those tests that most doctors will do when faced with a patient who is suspected of having tuberculosis. The test involves the intradermal injection of 0.1ml of a protein called tuberculin purified protein derivative. The test is interpreted as positive or negative according to the size of induration on the skin (not erythema), measured perpendicular to the long axis of injection, between 48 and 72 hours after the injection.

The TST is not a very sensitive test. In those who are not suffering from any kind of disease that compromises their immunity, the test has a sensitivity of about 95 percent. This means that this test may miss one out of every twenty previously healthy people who develop tuberculosis. The sensitivity of the TST drops to 80 percent when an immunocompromised person develops tuberculosis. This means that for people with HIV, the TST is not reliable in excluding tuberculosis because it can be negative in 1 in 5 people with HIV infection who develop tuberculosis.

The size of induration required for a positive TST depends on who is being tested. An induration of 5mm is adequate if the person is immunocompromised in any way through disease or from medication. Otherwise an induration of 10mm is required for the test to be regarded as positive.

We would regard a person as being newly infected with tuberculosis when the tuberculin skin test was negative earlier but is positive now. If such a person has no signs of active tuberculosis (after being investigated), the person will be labelled as having latent tuberculosis.

There are situations where a positive TST is not due to latent tuberculosis or to active tuberculosis. BCG vaccination in childhood can result in a positive test for 3 to 5 years after the vaccination. The test can also remain positive for many years after a person has been successfully treated for tuberculosis in the past.

There is a peculiar phenomenon known as the booster phenomenon where a person may develop a positive test simply because of a tuberculin skin test done earlier within the past one year. This phenomenon is because the TST boosts cell mediated immunity that had previously waned. It occurs in people who had tuberculosis earlier. The danger in not being aware of this phenomenon is that we may label such patients as having latent tuberculosis because of the recent conversion in the TST.

To overcome the problem of misinterpreting the TST in people (like health care workers) who may undergo annual tuberculin skin testing, we can do the two-step tuberculin skin test. The details of how this test is done is given in the reference below.

References:
1. The two-step tuberculin skin test
2. Tuberculin skin testing

The 2013 Nobel Prize in Physiology or Medicine

 Some genetic diseases are caused by defects in the transport of proteins within cells.  An understanding of the mechanisms involving transport of proteins via vesicles was the research work that led to the 2013 Nobel Prize in Medicine / Physiology. (Read about it).  

Genetic diseases can be caused by single gene abnormalities, chromosomal abnormalities or by a combination of genetic and environmental factors. Abnormalities in genes cause diseases in various ways:

1. Excess production of proteins. An example is the fragile X syndrome which shows itself as learning disability or mental retardation and autistic behaviour. This is caused by excess production of a protein that is used in synapses of the brain.

2. Insufficient production of proteins. An example is the group of diseases called glycogen storage disorders which can present with hypoglycaemia, hepatomegaly and/or muscle weakness.

3. Production of an abnormal protein. An example is phenylketonuria which is due to production of an inactive form of the enzyme that hydrolyses the amino acid phenylalanine. This leads to delayed milestones in childhood, seizures, learning disabilities and mental retardation as well as reduced or absent pigmentation of skin, hair and eyes. 

4. Defective transport of proteins. Genetic diseases involving abnormalities in protein transport can manifest in patients as hypopigmentation of skin, defects in cell mediated immunity and/or neurological defects. Bardet-Biedl syndrome where the affected person has mental retardation, retinopathy and is of small stature with poorly developed external genitalia, Charcot Marie Tooth disease and Spinocerebellar ataxias where those affected have ataxic gait along with other neurological abnormalities, Hereditary Spastic paraplegia which causes a pure motor paraplegia, are examples of neurological conditions where the genetic defect affects protein transport within cells. Alzheimer’s disease and Type 2 diabetes mellitus may also have defects in the transport of proteins. The transport of amyloid precursor protein by vesicles has been noted to be defective in the early stages of Alzheimer’s disease.  

Reference: Insights into vesicular transport in inherited diseases

Managing patients with shock

A beautiful review about circulatory shock in the NewEngland Journal of Medicine gives us practical advice for dealing with patients in shock. I summarise here three important learning points from that article. 

1. Diagnosing circulatory shock

Do not define shock only by the presence of arterial hypotension even though a blood pressure lower than 90mm Hg systolic and a mean blood pressure less than 70mm Hg are often present. This is because in those with chronic hypertension, the fall in blood pressure may not reflect the degree of shock. Also, the blood pressure alone may be misleading as it can be low in people who have chronic hypotension or have just suffered a transient episode of vasovagal syncope. The diagnosis of shock needs signs of poor perfusion to tissues and organs. The article tells us to consider the diagnosis of shock when there is tachycardia and signs of poor tissue perfusion as seen through three windows in the body:

                a. The skin: Cold and clammy

                b. The brain: Confusion, disorientation or other signs of altered mental status

                c. The kidney: A urine output of less than 0.5ml per kg per hour.

2. The VIP rule for resuscitation

This is the Ventilate, Infuse and Pump rule.  Ventilate (when needed) to ensure adequate oxygen intake. In this context we must remember that pulse oximetry is unreliable as a measure of adequate oxygen in the blood when there is peripheral vasoconstriction. So blood gases must be measured for this purpose. 

Fluids must always be infused in patients with shock since even those with cardiogenic shock can benefit from fluid resuscitation. However infusion of fluids must be carefully monitored. A fluid challenge refers to the infusion of 300 to 500ml of fluids (usually crystalloids) over a period of 20 to 30 minutes in order to see whether there is any improvement in one or more of the parameters of circulatory shock. The results of such a fluid challenge can then guide decisions for further infusion of fluids. 

Inotropic agents need to be used when the hypotension is severe or when the response to fluid resuscitation is slow or insufficient.

3. Using inotropic agents in circulatory shock

The authors consider norepinephrine to be the agent of first choice in those with shock whose cardiac output is not decreased. This will be seen in conditions like the early stages of septic shock (distributive shock). In the dose range of 0.5 to 2ug per kg per minute, norepinephrine elevates mean blood pressure without increasing the heart rate. Dobutamine is considered the agent of first choice in those with shock who need an increase in cardiac output. Both dobutamine and norepinephrine can be used together when needed. The authors do not recommend either dopamine or epinephrine as agents of first choice. Dopamine increases the risk of arrhythmias and increases mortality in the acute stage when given to patients with cardiogenic shock. Epinephrine increases the risk of arrhythmias and reduces splanchnic blood flow. These agents can be used as second line agents if necessary. Low dose vasopressin is an agent that can be added to norepinephrine for those with septic shock who have an adequate cardiac output.

Prolonging life and the futility of medical care

We see and interpret the world according to our individual beliefs and values. This difference in interpretation can be seen in the way doctors and lay people make decisions regarding how patients, who are seriously ill and without a chance of cure, have to be managed. When doctors have exhausted all that they have in their therapeutic armamentarium, they speak of poor prognosis and of futility in prolonging life with the use of technology. It sometimes comes as an unpleasant surprise to the doctors when close family members hear them but insist on continuing whatever life-sustaining measures are in place for their loved ones. Doctors tend to feel that such people are in denial of the reality that should be readily apparent to everyone.  In this NEJM article, the author gives us a reason why the loved ones of critically ill patients may differ in their views from doctors. The author tells us that doctors base their reasoning on outcomes for deciding what is important: can the patient be cured or not, is the question for them. For family members, what they do for their loved ones (the process of providing care) is what matters most.  The process of providing care to a loved one can be therapeutic in itself, irrespective of the outcome.  Doctors have outcome-based ethical reasoning on prolonging life while the loved ones of a patient may have process-based ethical reasoning. Doctors need to understand that this is the reason for family members often insisting on continuing futile medical interventions for their loved ones. Instead of labeling such requests as unreasonable and such people as being in denial of reality, doctors should give them time to feel that they have done all that they need to do before letting go of their loved ones.  

Angiotensin receptor blockers: the story continues................

Angiotensin receptors are protein molecules that mediate the effect of the hormone angiotensin 2. These receptors are found in various parts of the body. The existence of angiotensin in the body was recognised by the work of people like Tigerstedt, Bergman and Goldblatt who, in different experiments in the late nineteenth and early twentieth centuries, showed the presence of a vasoconstrictor substance released by the kidneys¹. This substance was named renin and it was soon determined that renin led to the formation of angiotensin 1 and that angiotensin 1 had to be changed to angiotensin 2 in order to be effective. The conversion of angiotensin 1 to angiotensin 2 is facilitated by the enzyme called angiotensin – converting enzyme. Angiotensin 2 exerts its effects on blood vessels and other tissues through receptors called angiotensin receptors. These receptors are also of two types: angiotensin receptor 1 (AT1) and angiotensin receptor 2(AT2). The vasoconstrictor effect of angiotensin 2 is mediated through the AT1 receptor and the angiotensin receptor blockers used clinically are all AT1 receptor blockers.

Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) are both used in medicine for patients with hypertension, cardiac failure, ischemic heart disease and proteinuric-renal disease. Angiotensin receptor blockers score over angiotensin converting enzyme inhibitors in a few ways: they provide a more comprehensive blockade of the renin angiotensin system and they do not affect the serum levels of bradykinin. Hence the effect of angiotensin receptor blockers is more consistent with dose, and bradykinin-related side effects – like cough and angioedema – are not seen².

Angiotensin Receptor Blockers have been shown to protect against myocardial infarctions and strokes in patients who are at high risk for these vascular events. A study reported in 2008 showed the benefit of these drugs in preventing cardiovascular events in patients undergoing long-term hemodialysis ³. A meta-analysis had also shown that ARB can prevent the development of atrial fibrillation in patients with heart failure⁴ and another meta-analysis had shown that these drugs could prevent new onset diabetes in patients who are predisposed to developing diabetes⁵. Hence angiotensin receptor blockers not only reduce blood pressure but also favourably influence cardiovascular risk factors.

There may however be differences in clinical benefit between various angiotensin receptor blockers. A study comparing Losartan, Irbesartan, Valsartan, Candesartan and Telmisartan in patients with heart failure found that Losartan showed poorer survival rates in elderly people with heart failure compared to the other drugs⁶.

Alzheimer’s disease is a common cause of dementia. A pathological finding in this disease is amyloid deposition in the brain.  There is very new evidence, based on autopsies, that those who take angiotensin receptor blockers for hypertension have less amyloid deposition in their brains than those who are on other kinds of antihypertensive drugs⁷ and this actually confirms some earlier anecdotal reports that treatment with angiotensin receptor blockers reduces the likelihood of developing Alzheimer’s disease.  It appears that angiotensin receptor blockers are able to reduce amyloid deposition in the brain by reducing inflammation within the brain.

In conclusion, we have learnt a great deal about the clinical benefits of blocking the renin-angiotensin-aldosterone system (RAAS) in the last decade. Since the ARB class of drugs are more expensive than the ACEI class of drugs, doctors are encouraged to use angiotensin-converting enzyme inhibitors wherever RAAS inhibition is needed and to use angiotensin receptor blockers only when patients are intolerant to ACEI. However, if the recent evidence of the possible benefit of angiotensin receptor blockers in preventing dementia can be verified through other studies, then the drugs in this class will have a distinct edge over their first cousins – the ACE inhibitors.

References:

1. Discovery and development of angiotensin receptor blockers, Wikipedia: http://en.wikipedia.org/wiki/Discovery_and_development_of_angiotensin_receptor_blockers

2. Amy Barreras, et al.Angiotensin 2 receptor blockers. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200815/

3. Effect of angiotensin receptor blockers in patients undergoing hemodialysis http://www.ajkd.org/article/S0272-6386(08)00955-4/abstract

4. Prevention of atrial fibrillation with angiotensin converting enzyme inhibitors and angiotensin receptor blockers http://content.onlinejacc.org/article.aspx?articleid=1136655

5. Angiotensin converting enzyme inhibitors or angiotensin receptor blockers for prevention of Type 2 diabetes http://content.onlinejacc.org/article.aspx?articleid=1136856

6. Angiotensin 2 receptors for the treatment of heart failure http://www.ncbi.nlm.nih.gov/pubmed/17381379

7. Ihab Hajjar, et al. Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series. Arch Neurol 2012; Published online Sept 2012. http://archneur.jamanetwork.com/article.aspx?articleid=1356776#METHODS