One of the most challenging cases I have ever been asked about was regarding a 31 year old Caucasian man. When he walked into the Rheumatology clinic, referred by his GP with arthralgias and a raised, fluctuating CK, even the junior doctors felt he was a straightforward case of acromegaly. He had the classical facies, a large tongue that he felt was "growing" and tingling in his hands. CK fluctuated between 270 and 2000, yet muscle power, EMG and muscle biopsy were normal, as were numerous tests for metabolic myopathy.
He also reported more than one episode of near loss of consciousness. He saw the neurologists with this, who felt this was syncope. A tilt table test showed a sharp drop in BP while upright, associated with tachycardia.
Baseline IGF-1 and timed levels of Growth Hormone after stimulation with glucose were normal. MRI of pituitary revealed a microadenoma.
ECG was not done.
Echo was reported as normal. However, when you looked at the detail, the LV size was the upper limit of notmal, the left atrium was dilated and the E:A ratio at the mitral inlet was at the upper limit of normal at 1.48.
Nerve conduction studies showed no evidence of entrapment neuropathy at the wrist. Autoimmune screen, including every conceivable autoantibody in the book, was negative. Inflammatory parameters were normal.
Can you suggest a diagnosis?
Sunday, 30 June 2013
Sunday, 23 June 2013
Tuesday, 18 June 2013
A Young Man With Hypercalcaemia
A 32 year old man is referred by his GP with hypercalcaemia. Corrected serum calcium is 2.75 mmol/l (11 mg/dl). Serum PTH is raised at 105 pg/ml (normally up to~70). Serum phosphate is normal. Serum 25(OH)D levels are at the upper limit of normal. Chest Xray is normal, as is a myeloma screen. Alkaline phosphatase is not raised. Renal function is normal, with an egfr of >90 ml/min.
What's the likely diagnosis?
What's the likely diagnosis?
Saturday, 8 June 2013
Trivial Signs?
I recently saw a middle aged man with a swelling at the base of his left middle finger. Just that. Nothing else. He didn't even have much pain. His GP had sent him to Rheumatology because he couldn't explain the symptoms.
He looked well. The left middle MCP was swollen. All other joints were normal. He had had lots of bloods in primary care, including FBC, U&Es, LFTs, ESR, CRP, Rheumatoid factor- all normal. A plain X-ray had revealed an odd looking cyst in the head of the 3rd metacarpal, but all else was normal.
There was no history of trauma.
Thoughts?
He looked well. The left middle MCP was swollen. All other joints were normal. He had had lots of bloods in primary care, including FBC, U&Es, LFTs, ESR, CRP, Rheumatoid factor- all normal. A plain X-ray had revealed an odd looking cyst in the head of the 3rd metacarpal, but all else was normal.
There was no history of trauma.
Thoughts?
Monday, 1 April 2013
Hypokalaemia & Hypertension
A relatively common problem in clinical practice is the young subject with hypertension in association with hypokalaemia and metabolic alkalosis. Physicians should resist the temptation of labeling this subset as "Essential Hypertension". A definitive diagnosis can be achieved with a bit of perseverance.
As medicine evolves, new paradigms displace old ones. Primary hyperaldosteronism was thought to be exceedingly rare. Not so. It is now recognised that 10-15% of subjects with hypertension have primary hyperaldosteronism. This is particularly true in young subjects, subjects with a strong family history of hypertension and those with hypokalaemia.
Yet, too much reliability has been placed on the presence of hypokalaemia as a marker of this condition. In fact, less than 50% of subjects with primary hyperaldosteronism have hypokalaemia. The rest are normokalaemic. Therefore it is important to have a high index of suspicion in young subjects, those with a strong family history of early onset hypertension, those with family history of stroke before age 40, and those with refractory hypertension, i.e. subjects whose BP remains uncontrolled despite three anti-hypertensives, including a diuretic.
The assessment should begin by measuring the ratio of plasma aldosterone to plasma renin activity (PRA). A ratio of >30 with an absolute concentration of aldosterone of>415 pmol/l and in particular, a completely suppressed PRA is virtually diagnostic of primary hyperaldosteronism.
The most common cause of this condition is idiopathic adrenal hyperplasia (IHA), causing bilateral hyperplasia of the adrenals, accounting for 65% of cases. Around 30% of cases are due to unilateral adrenal adenomas. The other 5% comprises 3 rare disorders- hereditary hyperaldosteronism types 1,2 and 3.
Type 1 hereditary hyperaldosteronism is a fascinating condition. Also called glucocorticoid remediable aldosteronism (GRA), this rare autosomal dominant condition is due to the fusion of two genes- CYB11B1 and CYB11B2, whereby the enzyme aldosterone synthase comes under the control of ACTH. Thus, aldosterone is made in the zona fasciculata rather than zona glomerulosa and is suppressible by steroid therapy. Half of these subjects have a normal serum potassium.
Type 2 is simply an inherited predisposition to adrenal adenoma or hyperplasia.
What if the plasma renin and aldosterone are both raised? Think of renovascular hypertension, renin secreting tumours, coarctation of aorta and subjects on diuretics.
Then there are those whose plasma renin and aldosterone are both suppressed. These subjects have a non-aldosterone related cause for their hypertension such as hypercortisolism due to Cushing's syndrome, Syndrome of Apparent Mineralocorticoid Excess (SAME), or excessive liquorice intake, certain causes of congenital adrenal hyperplasia such as 11-beta hydroxylase deficiency, deoxycorticosterone secreting tumours and Liddle's syndrome.
Two inherited conditions deserve special mention. SAME is a rare autosomal recessive condition due to inherited deficiency of 11-beta hydroxysteroid dehydrogenase deficiency. This is a renal enzyme that converts cortisol to inactive cortisone. When this enzyme is deficient or inhibited by liquorice, or overwhelmed by excessive production of cortisol, as in Cushing's syndrome (particularly due to ectopic ACTH production from small cell or other tumours), cortisol is freed up to act on the mineralocorticoid receptors and mimic the action of aldosterone. These patients tend to have a very low serum potassium.
The other inherited disorder with suppressed aldosterone and renin levels is Liddle's syndrome. This is an autosomal dominant condition where epithelial sodium channels responsible for reabsorption of tubular sodium at the expense of potassium remain constitutively open due to inability to remove the beta or gamma subunits of these channels. The removal of these channels from the tubular epithelium depends on an uniquitin ligase called Nedd, which is defective in Liddle's patients. Intuitively, direct potassium channel blockers such as amiloride and triamterene work well in the treatment of hypertension in Liddle's syndrome, while aldosterone antagonists such such as spironolactone do not. It's worth remembering that as in GRA, over half of subjects with Liddle's syndrome have normal serum potassium.
In subjects with high aldosterone:PRA ratio, the next test is salt loading to see if the serum aldosterone levels are suppressible. This can be done as an inpatient after infusing IV saline, or as an outpatient, after loading for 3 days with oral salt tablets. Subjects with primary aldosteronism will not suppress their aldosterone levels after salt loading.
Such subjects should then have a CT scan to pick up an adrenal adenoma putatively responsible for the excess aldosterone. If the CT does not show an adenoma, and irrespective of the CT results in subjects over the age of 40, most authorities would recommend that patients should have adrenal vein sampling for aldosterone:cortisol ratio to distinguish functional adenoma from IHA. Subjects under 40 with an obvious adenoma on CT should be directly considered for surgical adrenalectomy. Conversely, those with IHA would benefit from medical management with spironolactone.
Acknowledgement: uptodate.com
As medicine evolves, new paradigms displace old ones. Primary hyperaldosteronism was thought to be exceedingly rare. Not so. It is now recognised that 10-15% of subjects with hypertension have primary hyperaldosteronism. This is particularly true in young subjects, subjects with a strong family history of hypertension and those with hypokalaemia.
Yet, too much reliability has been placed on the presence of hypokalaemia as a marker of this condition. In fact, less than 50% of subjects with primary hyperaldosteronism have hypokalaemia. The rest are normokalaemic. Therefore it is important to have a high index of suspicion in young subjects, those with a strong family history of early onset hypertension, those with family history of stroke before age 40, and those with refractory hypertension, i.e. subjects whose BP remains uncontrolled despite three anti-hypertensives, including a diuretic.
The assessment should begin by measuring the ratio of plasma aldosterone to plasma renin activity (PRA). A ratio of >30 with an absolute concentration of aldosterone of>415 pmol/l and in particular, a completely suppressed PRA is virtually diagnostic of primary hyperaldosteronism.
The most common cause of this condition is idiopathic adrenal hyperplasia (IHA), causing bilateral hyperplasia of the adrenals, accounting for 65% of cases. Around 30% of cases are due to unilateral adrenal adenomas. The other 5% comprises 3 rare disorders- hereditary hyperaldosteronism types 1,2 and 3.
Type 1 hereditary hyperaldosteronism is a fascinating condition. Also called glucocorticoid remediable aldosteronism (GRA), this rare autosomal dominant condition is due to the fusion of two genes- CYB11B1 and CYB11B2, whereby the enzyme aldosterone synthase comes under the control of ACTH. Thus, aldosterone is made in the zona fasciculata rather than zona glomerulosa and is suppressible by steroid therapy. Half of these subjects have a normal serum potassium.
Type 2 is simply an inherited predisposition to adrenal adenoma or hyperplasia.
What if the plasma renin and aldosterone are both raised? Think of renovascular hypertension, renin secreting tumours, coarctation of aorta and subjects on diuretics.
Then there are those whose plasma renin and aldosterone are both suppressed. These subjects have a non-aldosterone related cause for their hypertension such as hypercortisolism due to Cushing's syndrome, Syndrome of Apparent Mineralocorticoid Excess (SAME), or excessive liquorice intake, certain causes of congenital adrenal hyperplasia such as 11-beta hydroxylase deficiency, deoxycorticosterone secreting tumours and Liddle's syndrome.
Two inherited conditions deserve special mention. SAME is a rare autosomal recessive condition due to inherited deficiency of 11-beta hydroxysteroid dehydrogenase deficiency. This is a renal enzyme that converts cortisol to inactive cortisone. When this enzyme is deficient or inhibited by liquorice, or overwhelmed by excessive production of cortisol, as in Cushing's syndrome (particularly due to ectopic ACTH production from small cell or other tumours), cortisol is freed up to act on the mineralocorticoid receptors and mimic the action of aldosterone. These patients tend to have a very low serum potassium.
The other inherited disorder with suppressed aldosterone and renin levels is Liddle's syndrome. This is an autosomal dominant condition where epithelial sodium channels responsible for reabsorption of tubular sodium at the expense of potassium remain constitutively open due to inability to remove the beta or gamma subunits of these channels. The removal of these channels from the tubular epithelium depends on an uniquitin ligase called Nedd, which is defective in Liddle's patients. Intuitively, direct potassium channel blockers such as amiloride and triamterene work well in the treatment of hypertension in Liddle's syndrome, while aldosterone antagonists such such as spironolactone do not. It's worth remembering that as in GRA, over half of subjects with Liddle's syndrome have normal serum potassium.
In subjects with high aldosterone:PRA ratio, the next test is salt loading to see if the serum aldosterone levels are suppressible. This can be done as an inpatient after infusing IV saline, or as an outpatient, after loading for 3 days with oral salt tablets. Subjects with primary aldosteronism will not suppress their aldosterone levels after salt loading.
Such subjects should then have a CT scan to pick up an adrenal adenoma putatively responsible for the excess aldosterone. If the CT does not show an adenoma, and irrespective of the CT results in subjects over the age of 40, most authorities would recommend that patients should have adrenal vein sampling for aldosterone:cortisol ratio to distinguish functional adenoma from IHA. Subjects under 40 with an obvious adenoma on CT should be directly considered for surgical adrenalectomy. Conversely, those with IHA would benefit from medical management with spironolactone.
Acknowledgement: uptodate.com
Saturday, 23 July 2011
Restaurant Maths
I was at a dinner the other night at a restaurant when we moaned about the fact that the rectangular table was so long that those of us at one end could hardly speak to those at the other. Restaurant designers are acutely aware of the fact for a given perimeter, a circle occupies the greatest area of all possible shapes.
Talk therefore turned to circles and my colleague said the volume of a sphere is obtained by integrating the area of a circle.
I did a quick differentiation in my mind- 4/3 pi r^3 differentiates to 4 pi r^2, so it was easy to prove him wrong.
I just found out why- the area of a sphere is given by 4 pi r^2.
But hey, did you know this? For a cone, sphere and cylinder, where radius equals height:
Volume of a cone= 1/3 pi r^2. h= 1/3 pi r^2.2r= 2/3 pi.r^3 X 1
Volume of a sphere= 4/3 pi r^3= 2/3 pi. r^3 X 2
Volume of a cylinder= pi.r^2.h= pi.r^2.2r= 2/3 pi.r^3 X 3
Therefore the volume of equiradial cone, sphere and cylinder has a ratio of 1:2:3.
The relationshiip between the cone and cylinder is a bit obvious, but I had no idea that you could make a sphere out of 2 cones or a cylinder out of 1.5 spheres. Did you?
Talk therefore turned to circles and my colleague said the volume of a sphere is obtained by integrating the area of a circle.
I did a quick differentiation in my mind- 4/3 pi r^3 differentiates to 4 pi r^2, so it was easy to prove him wrong.
I just found out why- the area of a sphere is given by 4 pi r^2.
But hey, did you know this? For a cone, sphere and cylinder, where radius equals height:
Volume of a cone= 1/3 pi r^2. h= 1/3 pi r^2.2r= 2/3 pi.r^3 X 1
Volume of a sphere= 4/3 pi r^3= 2/3 pi. r^3 X 2
Volume of a cylinder= pi.r^2.h= pi.r^2.2r= 2/3 pi.r^3 X 3
Therefore the volume of equiradial cone, sphere and cylinder has a ratio of 1:2:3.
The relationshiip between the cone and cylinder is a bit obvious, but I had no idea that you could make a sphere out of 2 cones or a cylinder out of 1.5 spheres. Did you?
Sunday, 26 June 2011
The Worm That Won Three Nobels
Meet Caenorhabditis elegans, or simply C.elegans. Roundworm extraordinaire, 1 mm long. Multicellular eukaryote. Superstar.
Simple to study, it was the organism that has 35% homology (similarity) to human DNA. The prototype organism, where apoptosis- programmed cell death- was studied. Apoptosis is the reason why the cells of your immune system wither and die in an orderly fashion after killing the bad bugs, rather than running out of control and killing you off instead. When things go wrong with apoptosis, bad things happen- like autoimmune diseases, or cancer. Brenner, Horvitz & Sulston walked with the Medicine Nobel for this work in 2002.
Want to study the function of a particular gene? No problem. Catch a C.elegans, douse it in some double stranded RNA with a complimentary sequence to the bit of DNA you want to study. The dsRNA will home in to the complimentary sequence of the DNA like a long lost brother and join up (hybridise). Result? The protein produced by the gene will be silenced, and presto, because C.elegans stops producing that protein, you know the function of that gene. Cue Nobel for Fire & Mello for Physiology & Medicine in 2006.
Want to label a protein produced by a living organism with a fluorescent biomarker without killing the organism? Try Green Fluorescent Protein or GFP as it's known, first isolated from a jellyfish. Chalfie, Shimomura and Tsien introduced the gene for GFP adjacent to the regulatory sequence (big brother gene) governing the transcription of a certain protein in C.elegans. The protein lit up like Guy Fawkes night under blue light, fluorescing a bright green. It's been used many many times since then to tag proteins, a use that earned the trio, and C.elegans its 3rd Nobel Prize in 6 years, this time in Chemistry, in 2008.
Inspirational worm, C.elegans. Rewarded by my university, the University of Nottingham, with an all expenses paid two week jaunt on The International Space Station to study the effect of zero gravity on muscle. It even has its own social networking site, called- you guessed it- Wormbook.
Simple to study, it was the organism that has 35% homology (similarity) to human DNA. The prototype organism, where apoptosis- programmed cell death- was studied. Apoptosis is the reason why the cells of your immune system wither and die in an orderly fashion after killing the bad bugs, rather than running out of control and killing you off instead. When things go wrong with apoptosis, bad things happen- like autoimmune diseases, or cancer. Brenner, Horvitz & Sulston walked with the Medicine Nobel for this work in 2002.
Want to study the function of a particular gene? No problem. Catch a C.elegans, douse it in some double stranded RNA with a complimentary sequence to the bit of DNA you want to study. The dsRNA will home in to the complimentary sequence of the DNA like a long lost brother and join up (hybridise). Result? The protein produced by the gene will be silenced, and presto, because C.elegans stops producing that protein, you know the function of that gene. Cue Nobel for Fire & Mello for Physiology & Medicine in 2006.
Want to label a protein produced by a living organism with a fluorescent biomarker without killing the organism? Try Green Fluorescent Protein or GFP as it's known, first isolated from a jellyfish. Chalfie, Shimomura and Tsien introduced the gene for GFP adjacent to the regulatory sequence (big brother gene) governing the transcription of a certain protein in C.elegans. The protein lit up like Guy Fawkes night under blue light, fluorescing a bright green. It's been used many many times since then to tag proteins, a use that earned the trio, and C.elegans its 3rd Nobel Prize in 6 years, this time in Chemistry, in 2008.
Inspirational worm, C.elegans. Rewarded by my university, the University of Nottingham, with an all expenses paid two week jaunt on The International Space Station to study the effect of zero gravity on muscle. It even has its own social networking site, called- you guessed it- Wormbook.
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