Whole Genome Sequencing - Yes or No?

One of the most significant scientific developments over the past decade has been the ability to rapidly sequence the entire human genome. The success of this technology has led to a rapid increase in the detection and diagnosis of genetically inherited diseases. One use has been to identify specific disease causing mutations, while another use has been to identify susceptibility loci and polymorphisms which combine to increase a patient's risk of developing a disease which may be caused by not one, but many genes. It can also help to predict how a patient will respond to certain types of medications (pharmacogenomics). 

So should we sequence every person's genome? There are obvious arguments for: personalised medication, screening for disease etc. However the counter-arguments are also significant ie. screening for diseases which cannot be treated. There is risk of harm by screening a person's entire genome. For example, it may suggest that a patient has a predisposition to certain conditions and may lack clinical significance. Would it be useful to know that you carried a gene for an inherited condition? This could lead to a world of 'genetic compatibility' testing between partners before having a child. It would be useful for doctors to know if patients are going to respond / not respond to certain drugs eg. warfarin or chemotherapy before they are prescribed. 

A number of ethical implications need to be considered: for example how will implications for relatives be handled - who owns the genetic information? How can we ensure that the information obtained is kept private and not shared with research or pharmaceutical organisations? The discovery that a patient may be at a slightly increased risk of coronary heart disease could lead to a rise in un-necessary investigations (particularly in the private sector) eg. unnecessary imaging, while a result showing low risk could also be harmful, leading to a person becoming too relaxed about their health and abandoning healthy diet and exercise as it is felt un-necessary due to low genetic risk. At the moment, in my opinion there is too much risk of harm to be caused by screening everyone's human genome. However once our knowledge expands and our ability to handle the information improves, I honestly believe that in my lifetime it will become routine medical practice (ie. genome sequencing at 18th birthday or on registering with a new GP practice).

One of the big medical news stories last week was the revelation by Hollywood actress Angelina Jolie that she had undergone a double mastectomy to prevent her risk of developing breast cancer, caused by her carrying the BRCA1 gene. I think it is highly commendable that she went public with this - helping to increase awareness of the risk of breast cancer. The question this raises and which is the title of the article in the BMJ this week which I am referring to is the 'who owns our genes?' question. Unbelievably, in the US it costs about $3000 to undergo testing for BRCA1 and BRCA2 because one biotechnology company owns the patent and hence has a monopoly over the testing (the company's share prices jumped 3% after Jolie's announcement). These patents are set to expire in 2014 as it has now been argued in the US Supreme court that human genes are 'natural' and therefore cannot be patented. 

Is Patient Involvement the Key to Improvement?

Would you recommend this hospital to your friends and family?

One of the suggestions which came from the recent enquiry into Mid-Staffordshire was that patients be asked for feedback on their experiences. The value of this would in theory be to help identify areas of under-performance. Although this measure has been introduced without a great deal of evidence to back it, on the surface it appears sensible. Patient experience in hospital is of course likely to vary enourmously from patient to patient, but this method could pick up trends and help to highlight areas needing improvement.

But what if we take this a step further. What if the solution to improving healthcare is by asking patients what they want to get out of their interaction with the medical services. The old 'ideas, concerns and expectations' set of questions was drilled into us at medical school (although from personal experience it is all to often left out of consideration). The focus of the BMJ this week is on this concept, empowering patients to take responsibility in working in partnership with doctors.

Working in collaboration with our patients is by no means a new idea, but perhaps a fresh reminder is necessary. Social media and networking could be one way of doing this - examples are given of patients who are able to reach thousands with their blogs describing their experiences. For example 'rheumatoid arthritis warrior' Kelly Young shares her online blog rawarrior.com with almost 2% or patients with RA in the US. 

Patient support groups are plentiful, and are able to connect patients to share experiences, and perhaps more doctors should be engaging with these communities. Where the patient brings the value of their personal experience, the doctor can bring their knowledge of medicine and treatment. A doctor for example could help to prevent conversations from going down incorrect paths and share up to date knowledge of treatments (allowing information to filter down from clinical research to the lay person).

Engaging patients in decision making could also help to reduce costs through unnecessary over-investigation. Choosing Wisely (www.choosingwisely.com) is an initiative which has been set up in the US which aims to reduce over-investigation of patients and encourages patients and doctors to work together to come up with solutions.

All of these ideas fit perfectly with the GMC guidance on Good Medical Practice and agree with the ethical principles which doctors abide by. I'm pleased to read that this concept is being given increased attention and hope that some of these ideas could help to develop the NHS which I want to be a part of in years to come.

Measles, Acne, Heart Failure and Anti-Depressants

Now that the MRCP exam is out of the way, I've been catching up on few interesting articles which have featured in the BMJ over the past few weeks. 

Measles

This can is a disease which can be effectively prevented by vaccination, yet most of the UK has not reached the levels of immunity necessary to achieve herd immunity (estimated to be around 95% of the population immunised). The number of people not immunised may in fact be greater than known, particularly in the age group of children who should have received vaccination around the time of the widely spread reports about a possible link with autism (a link which has now been rebuked and disproved). Indeed I found out recently that I did not have immunity to measles, and have begun my MMR vaccination schedule to ensure that my risk of catching the disease is diminished. In Swansea this year there has been a surge in the number of cases, and in the north of England there have been 354 cases so far this year (2013). The condition is largely self-limiting but complications can occur including permanent disability and death, and it is highly infectious. And yet an effective vaccine is available. So should we be doing more to prevent this disease? In the US, cases of measles are treated as an emergency, and this may be a contributing factor which has led to the elimination of endemic measles in the Americas. Any child death due to measles should be a 'never' event because it is avoidable. It would be reasonable for me to expect that global eradication of measles will be achieved in my lifetime but we cannot be complacent and must do more as doctors to help eradicate the world from measles permanently.

Acne Vulgaris

Acne vulgaris is a distressing condition which commonly affects adolescents and can have a profound impact on quality of life. It shouldn't be underestimated how often the condition continues into adulthood and permanent scarring may occur. Acne is considered to be severe if there are nodules and cysts present. It is an inflammatory condition of the pilosebaceous unit where there is abnormal keratinocye proliferation, an androgren driven increase in sebum production, proliferation of Propionibacterium acnes and inflammation. Topical retinoids are the mainstay of treatment although oral isoretinoin is the most effective treatment.

Are Anti-Depressants Overprescribed?

There is a strong feeling amongst many doctors that anti-depressants are over-prescribed and a recent poll on the BMJ's website saw 79.3% of respondents vote in agreement. The reasons why are suggested to be due to influences of the pharmaceutical industry, the broad definition of depression and perceived 'quick fix' solutions from patients and doctors. There are however explanations for the increase in anti-depressant prescribing, according to one psychiatrist (who does declare receipt of payment in an advisory role to a pharmaceutical company). He gives the counter-side of the argument in the BMJ this week. His arguments (amongst others) are that anti-depressants are effective in treating depression, and that the increasing numbers of patients taking the medications may reflect improving practice amongst doctors in understanding that patients need to take the medications for at least 6 months for an effect to be seen. 

Investigating Suspected Heart Failure

A review article on the initial investigation of heart failure places a strong emphasis on the use of B-type natriuretic peptide (BNP) as a predictor of disease. A normal 12-lead ECG and BNP has a high negative predictive value for excluding heart failure although this is recommended for use in a non-acute setting. A BNP result of >400pg/mL confers a poor prognosis and it is recommended that these patients are reviewed by a cardiologist within 2 weeks. Echocardiogram does however remain the investigation of choice in confirming the diagnosis of heart failure. It has to be noted though that there are a number of other causes for a modestly raised BNP result, such as COPD, hypoxia and diabetes therefore results need to be interpreted with caution.

MRCP Revision Notes

Another random selection from MRCP Part 1 practice questions - normal updates will resume in May!

Treatment of Hyperlipidaemia - Elevated cholesterol and triglycerides are suggestive of remnant hyperlipidaemia. The most appropriate treatment in this case would be a fibrate. Statins are predominantly used to treat cholesterol. Nicotinic acid lowers cholesterol and triglycerides but it is poorly tolerated (primarily due to cutaneous flushing). Bile acid sequestrants reduce cholesterol but may actually increase triglyceride concentrations and are poorly tolerated. The effects of statins are usually maximal by about 4 weeks after an increase in dose. Fibrates in combination with statins are effective although there is a theoretical risk of myositis when used in combination. In a patient with high cholesterol not responding to a statin, ezetimib may be helpful. Ezetimib inhibits cholesterol absorption from the gut.

Resting Membrane Potential - The resting neurone is polarized (-ve on the inside, +ve on the outside). At rest, the cell membranes are less permeable to sodium than they are to potassium. The outside of the neurone is rich in sodium ions. When stimulated, the neurone permeability changes allowing sodium in and postassium out. The depolarization resulting from this movement causes the generation of an action potential.

Myelodysplastic Syndrome - This is characterised by peripheral cytopenia with marrow full of developing cells. Maturation is abnormal and there is reduced cell survival. It can initially be detected from the presence of abnormal red cell maturation (ie. a raised MCV) in the absence of other causes of anaemia. The most common presenting symptom is fatigue and this condition is far more common in the elderly population.

Rheumatic Fever & Differential - This condition affects children in the age 4-15 group as a result of Group A streptococcal infection. It is common in the middle east, eastern Europe and South America. The arthritis is classically a fleeting migratory polyarthritis affecting the large joints although isolated arthritis is the presenting symptom in 15-40% of cases. Differential diagnosis includes:

Still’s disease (arthritis is usually much more persistent in the affected joint)

Polyarticular juvenile idiopathic arthritis (small joints initially affected, no fever)

Childhood dermatomyositis (age 4-10, classic rash + muscle weakness)

Familial Mediterranean Fever - autosomal recessive in certain ethnic groups, characterised by recurrent attacks of fever, arthritis and serositis. Abdominal or chest pain due to peritonitis / pleurisy may occur.

Chagas Disease - This is a tropical parasitic disease caused by infection with the flagellate potozoan Trypanosoma cruzi. It is associated with sudden cardiac failure due to dilated cardiomyopathy. It is a protozoan parasite, known as the ‘kissing bug’. Patients are often asymptomatic for many years following infection but may develop cardiac failure. It is most prevalent in Central and South America and may cause mega-oesophagus and mega-colon as a complication.

More MRCP Revision

Acute Intermittent Porphyria - Does not typically result in skin manifestations but presents typically in a young woman admitted to hospital with severe abdominal pain, bilious vomiting and postural hypotension. AIP occurs due to the absence of porphobilinogen (PBG) deaminase and the combined oral contraceptive pill can precipitate an attack. Porphyria Cutanea Tarda on the other hand presents with a blistering skin rash on sun exposure, typically precipitated by alcohol.

Marfans Syndrome - This condition follows an autosomal dominant mode of inheritance and is caused by mutations in the fibrillin gene on chromosome 15. The diagnosis is made on clinical grounds. Major diagnostic criteria includes an early diastolic murmur, indicating aortic valve incompetence, likely to be secondary to aortic root dilatation requiring annual cardiology follow-up. Upwards lens dislocation (ectopia lentis) may be seen and minor criteria for diagnosis include arachnodactyly, minor valve prolapse and joint hypermobility.

Familial Hypocalciuric Hypercalcaemia - Is caused by a mutation of the calcium-receptor sensing gene leading to reduced calcium excretion and mild to moderate hypercalcaemia. Renal stones frequently occur in this condition and acute pancreatitis is rare. It is recommended that the patient maintains adequate hydration to reduce their risk of renal stones.

Sclerosing Cholangitis - Occurs classically in a patient with an inflammatory bowel disease. There is inflammation and fibrosis of the bile ducts with multiple areas of narrowing throughout the biliary system. The patient may be asymptomatic or may present with jaundice, pruritis and intermittent abdominal pain. There is a strong association with inflammatory bowel disease and men are more commonly affected than women.

Hodgkin's Lymphoma - The classic presentation is in a young woman presenting with weight loss and lymphadenopathy. Raised eosinophils in the full blood count are a strong clue towards the diagnosis and lymph node biopsy is necessary to confirm the diagnosis. Prognosis is related to clinical stage, bulk of tumour and histopathology. Presence of the 'Reed-Sternberg' Cell (with giant 'owls eye' nucleoli) are useful diagnostically.

IgA Nephropathy - This would typically occur in a young man who has repeated episodes of painless macroscopic haematuria following a upper respiratory tract infections. On a renal biopsy there will typically be diffuse mesangial proliferation and the condition results in chronic kidney disease in approximately 30% of cases. Heavy proteinuria, raised blood pressure and renal impairment are indicators of a poorer prognosis.

MRCP Revision Notes Random Selection

Aortic Regurgitation

Patients with Marfan’s syndrome are at inceased risk of developing aortic regurgitation. Symptoms include dyspnoea on exertion, syncope, chest pain and congestive cardiac failure. On examination patients have displacement of the apex, prominent S3 sound over the apex, a low pitched apical diastolic rumble (Austin-Flint murmur) and an early systolic apical ejection murmur. CXR may reveal LVH and aortic dilatation. Ideally surgery should be considered before the ejection fraction falls to below 55%.

Complete Heart Block

A basal systolic murmur is consistent with the diagnosis. There is a slow, regular pulse that does not vary with exercise. Usually there is an increase in stroke volume with a large-volume pulse and systolic flow murmur. In an asymptomatic patient, a permanent pacemaker is indicated in second and third degree heart block at the distal conduction system. ‘Cannon waves’ in the JVP occur when the right atrium contracts against a closed tricuspid valve, these occur irregularly in complete heart block. CHB presents with bradycardia, relative hypotension and syncope. The patient needs to be referred for a permanent pacemaker. (Cannon waves are also seen in conjunction with VT)

African Tick Typhus

A man goes to Kruger National Park, saw animals being bitten by mosquitoes and tsetse flies. Returns to the UK and develops fever and a black spot on the thigh as well as a faint macular rash. The most likely diagnosis is African tick typhus. Malaria should be excluded. The organism is Rickettsia conorii. Treatment is with doxycycline which often leads to quick resolution.

Haemochromatosis:

Autosomal recessive disorder more commonly seen in middle aged men. Diabetes, hypogonadism, hepatomegaly and increased skin pigmentation are suggestive of the disorder. Serus iron and ferritin levels are raised. HFE gene, chromosome 6. High transferring saturation and a low total iron binding capacity.

Wallenberg Syndrome:

Left lateral medullary syndrome. Usually die to occlusion of the posterior inferior cerebellar artery or its parent, the vertebral artery. The syndrome leads to ipsilateral pain and numbness on the face, contralateral pain and temperature loss, nystagmus and an ipsilateral Horner syndrome. MRI imaging is the investigation of choice.

Henoch-Schonlein Purpura

A young man is seen in clinic with a rash over his buttocks and lower legs, pain and swelling in both knees. Two weeks previously he had an URTI. He has hypertension. Bloods show a raised IgA + raised ESR – urinalysis shows proteinuria. HSP is characterised by raised IgA levels causing IgA nephropathy. It is a small vessel vasculitis usually occurring in young adults and children.

Type II vs Type I Statistical Error

Type II error occurs when the null hypothesis is wrongly accepted ie. a false negative results – the risk of not detecting a significant difference when there is one. The Type I Error is most closely related to the p value. Standard deviation is the measure of the spread of a sample distribution.