̽��ֱ�� of Cambridge - Morris Brown

New research leaves tumours with nowhere to hide

Anonymous — Thu, 24 Sep 2015 09:25:29 +0000

̽��ֱ��small tumours concealed in the adrenal gland are “unmasked” in early pregnancy, when a sudden surge of hormones fires them into life, leading to raised blood pressure and causing risk to patients.

New research published today in the New England Journal of Medicine conducted by a team led by Professor Morris Brown, professor of clinical pharmacology at Cambridge ̽��ֱ�� and a Fellow of Gonville & Caius College, identifies this small group of lurking tumours for the first time, and explains why they behave as they do.

̽��ֱ��study means that, when patients are found to have high blood pressure early in pregnancy, doctors will now be encouraged to consider that the cause could be the tumours, which can be easily treated. Currently, adrenal tumours are not usually suspected as the cause of high blood pressure in pregnancy, and so go undiagnosed.

Brown and an international group of PhD students including first-author Ada Teo of Newnham College used a combination of state-of-the-art gene “fingerprinting” technology and old-fashioned deduction from patient case histories to work out that the otherwise benign tumours harbour genetic mutations that affect cells in the adrenal gland.

̽��ֱ��mutation means the adrenal cells are given false information and their clock is effectively turned back to “childhood”, returning them to their original state as ovary cells. They then respond to hormones released in pregnancy, producing increased levels of the salt-regulating hormone aldosterone.

Aldosterone in turn regulates the kidneys to retain more salt and hence water, pushing up blood pressure. High blood pressure – also known as hypertension – can be fatal, since it greatly increases the risk of stroke and heart attack.

̽��ֱ��new findings build on a growing body of research focusing on the adrenal gland and blood pressure. Sixty years ago, the American endocrinologist Dr Jerome Conn first observed that large benign tumours in the adrenal gland can release aldosterone and increase blood pressure (now known as Conn’s Syndrome).

Brown and his team have previously found a group of much smaller tumours, arising from the outer part of the gland, that have the same effect. ̽��ֱ��latest discovery drills down still further, revealing that roughly one in ten of this group has a mutation that makes the cells receptive to pregnancy hormones.

Brown said: “This is an example of what modern scientific techniques, and collaborations among doctors and scientists, allow you to do [through a form of genetic fingerprinting]. Conditions are often around for 60 years which we have had no explanation for, and now we can get to the heart of what has gone wrong.”

But the discovery also relied on what doctors call “clinical pattern recognition” – using experience to spot similarities. Brown was able to link together the cases of two pregnant women almost ten years apart and a woman in early menopause. All suffered high blood pressure, leading him to screen their adrenal tumours and identify a matching genetic mutation.

Pregnant women found to have the newly identified subset of tumours can now be identified more readily, and the tumours either treated with drugs or potentially even removed.

̽��ֱ��research was funded by the Wellcome Trust, National Institute for Health Research, British Heart Foundation and A* Singapore.

Hidden tumours that cause potentially fatal high blood pressure but lurk undetected in the body until pregnancy have been discovered by a Cambridge medical team.

Conditions are often around for 60 years which we have had no explanation for, now we can get to the heart of what has gone wrong

Morris Brown

11C metomidate PET CT of small Conn's tumour

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Old drug performs new tricks

Anonymous — Mon, 21 Sep 2015 08:24:54 +0000

Spironolactone, one of a range of drugs given according to doctors' preference to patients with resistant hypertension (high blood pressure that doesn't respond to a standard drug treatment), is in fact "outstandingly superior" to the alternatives, researchers have found. They recommend it should now be the first choice for such patients, and say that – for most – this well-known but under-valued drug will bring their condition fully under control.

̽��ֱ��discovery could have a profound impact globally, since hypertension, a major contributor to stroke and heart disease, is so common, affecting as many as one in three adults in some countries. It challenges what the authors describe as "a growing perception" that severe hypertension was beyond the control of existing drug treatments, and gives more clues into what causes the condition.

̽��ֱ��latest research, published today in the Lancet to coincide with their presentation to the British Hypertension Society, emerged from the PATHWAY-2 trial, part of the PATHWAY programme of trials in hypertension funded by the British Heart Foundation and led by Professor Morris Brown, professor of clinical pharmacology at Cambridge ̽��ֱ�� and a Fellow of Gonville & Caius College.

̽��ֱ��findings are drawn from what authors Brown and Professor Bryan Williams of ̽��ֱ�� College London describe as an experimental "shoot-out" between three different drugs used by doctors for years to treat patients if the standard initial cocktail of three hypertension drugs do not work.

Spironolactone 'slugged it out' against a betablocker (bisoprolol) and an alpha-blocker (doxazosin) in the trial, which took six years and involved 314 patients in 14 different centres.

̽��ֱ��patients all suffered from resistant high blood pressure that had not responded to the standard treatment for hypertension: a combination of three drugs (an ACE-inhibitor (or angiotensin-receptor blocker), a calcium channel blocker and a thiazide-type diuretic). They continued with this basic combination throughout, but each of the three trial drugs – and a placebo – was added one at a time, in random order, for 12 weeks each.

In what is known as a "double blind" trial, neither the patients nor the researchers knew which patient was taking which drug when. In a pioneering step, the study also used patients' own blood pressure readings taken at home to minimise so-called "white coat syndrome", in which the stress of being in a clinic causes blood pressure to rise artificially.

Once the resulting data had been analysed, it emerged that almost three quarters of patients in the trial saw a major improvement in blood pressure on spironolactone, with almost 60% hitting a particularly stringent measure of blood pressure control. Of the three drugs trialled, spironolactone was the best at lowering blood pressure in 60% of patients, whereas bisoprolol and doxazosin were the best drug in only 17% and 18% respectively.

"Spironolactone annihilated the opposition," said Brown. "Most patients came right down to normal blood pressure while taking it."

He added: "This is an old drug which has been around for a couple of generations that has resurfaced and is almost a wonder drug for this group of patients. In future it will stimulate us to look for these patients at a much earlier stage so we can treat and maybe even cure them before resistant hypertension occurs."

Doctors appear to have been wary of giving patients spironolactone because it raises the level of potassium in the body. But the study revealed the rise to be only marginal and not dangerous.

̽��ֱ��causes of resistant of hypertension are still poorly understood, but one theory is that the condition could be the result of sodium retention: too much salt in the body.

Spironolactone is a diuretic and helps the body get rid of salt. In the trial, it worked even better than average on patients whom tests showed had high salt levels. Brown said the findings appeared to confirm that, in most patients with resistant hypertension, excessive salt was the problem, probably caused by too much of the adrenal hormone aldosterone.

Instead of seeing the treatment-resistant form of high blood pressure as simply the result of having the condition for a long time or of poor treatment, it should be regarded as a different sub-group of hypertension which would need different investigations and treatments, Brown said.

Patients with the most dangerous type of high blood pressure will be able to receive far more effective treatment after Cambridge-led research reveals the powers of a "wonder drug" that has lain under the noses of doctors for 50 years.

jasleen_kaur

Sphygmomanometer

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New test could help thousands of patients with high blood pressure

gm349 — Wed, 30 Nov 2011 16:01:56 +0000

A new test developed by researchers at the ̽��ֱ�� of Cambridge could help doctors diagnose thousands of people with the most common curable cause of high blood pressure (hypertension). Research funded by the British Heart Foundation (BHF) and National Institute for Health Research (NIHR), showed a high-tech PET-CT scan could detect Conn’s syndrome, which causes up to five per cent of hypertension cases.

Around 12 million people in the UK are diagnosed with hypertension, a condition which greatly increases the risk of having a heart attack or stroke. For most people with hypertension there is no single underlying cause, but in a small minority there is a specific condition that causes blood pressure to rise. One of these conditions is called Conn’s syndrome – the most common curable cause of high blood pressure.

Conn’s syndrome is difficult to diagnose but an accurate diagnosis often leads to successful treatment. It’s caused by a benign tumour called an adenoma – about the size of a 5-pence coin – in one of the adrenal glands, which lie close to the kidneys. ̽��ֱ��tumour causes the over-production of a key blood pressure-regulating hormone called aldosterone. It can be treated either by surgically removing an affected gland, or by using a drug to block the effects of aldosterone.

̽��ֱ��new test, studied in 44 patients at Addenbrooke’s Hospital in Cambridge, scans the abdomen using ‘positron emission tomography with x-ray computer tomography’ technology, better known as a PET-CT and more commonly used in cancer diagnosis. ̽��ֱ��researchers developed a special radioactive tracer called 11C-metomidate, which lights up culprit adenomas in the scan. ̽��ֱ��test takes around 45 minutes.

̽��ֱ��current standard test for Conn’s syndrome relies on taking blood samples from a vein supplying the adrenal gland to measure the aldosterone level, a complex and difficult procedure which often fails to confirm the diagnosis. However, the researchers showed that their scan picked up adenomas causing hypertension in the majority of study patients, making it a potentially useful alternative to the standard test.

Morris Brown, Professor of Clinical Pharmacology at the ̽��ֱ�� of Cambridge, who led the study, said: “We were excited to see our technique work so well, and shortcut the delays and discomforts associated with the alternative test. We’re using PET-CT on our patients already, but we also plan a larger study to work out who will benefit the most. ̽��ֱ��test could be especially important for older patients – we often see growths in the adrenal glands during a routine CT scan. Often these growths are not Conn’s adenomas, but it’s difficult to be sure and they create a lot of anxiety in patients and doctors. In the future PET-CT could be a quick way to reassure a lot of patients without the need for detailed investigations.”

Dr Shannon Amoils, Research Advisor at the BHF, said: “Conn’s syndrome is the most common curable cause of high blood pressure. And although it affects only a small fraction of people with hypertension, it’s almost certainly more widespread than we previously thought. There are drugs that can control the high blood pressure caused by Conn’s syndrome, but the only cure is surgery, so making the diagnosis is very important. This new approach, using a PET-CT scan, offers real hope that more people with Conn’s syndrome will be accurately diagnosed in the future.”

Chris Wood, 56, who was diagnosed as having Conn’s syndrome by the new test, said: “When I had blood tests before, the results were never clear. I enrolled in Professor Brown’s study I had the scan, which took less than an hour, and immediately after the scan they showed me the pictures of the lump in my adrenal gland that was causing the problem. Getting the definitive diagnosis is fantastic because it removes all the worry, and because I’m on much much less medication than I had been for 15 years. I feel absolutely great.”

̽��ֱ��study was published online in the Journal of Clinical Endocrinology and Metabolism. ̽��ֱ��work was funded mainly by the BHF and the National Institute for Health Research (NIHR), the research funding arm of the NHS.

Scan can detect 5p-sized growth that causes hypertension.

̽��ֱ��test could be especially important for older patients – we often see growths in the adrenal glands during a routine CT scan.

Morris Brown, Professor of Clinical Pharmacology at the ̽��ֱ�� of Cambridge

Morris Brown

Conn's adenoma

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