CPC 2016: Chronic Indolent Pheochromocytoma, Hypertension, and Diabetes Mellitus

CPC 2016: Chronic Indolent Pheochromocytoma, Hypertension, and Diabetes Mellitus

November 7, 2019 0 By Bertrand Dibbert


– [Panelist] Now move to the
second presentation and we hope for similar fascinating discussion, and this is a case of chronic indolent pheochromocytoma which caused medically
controlled hypertension but treatment resistant diabetes mellitus. And we have, this is presented
on behalf of doctors, Lee Park Na Kim Lee and Park, please. – Thank you very much. Good afternoon everyone. You must be bored to see pheochromocytoma might be too easy to be
presented in this situation, but for me it took nine years from first meeting this patient
and final diagnosis. And when I heard pheochromocytoma from preoperative consultation, I was very embarrassed and shocked because I did
some risky procedure to her so please hear our case and think and tell us which time you can diagnose pheochromocytoma
from this patient. – Hello it is an honor
for me to be presenting at the ISH. I’m Hyun-Jung Lee from Seoul National University Hospital. Our patient was a 47 year old female and she visited the
emergency room on 2006 March. Her main complaint was dyspnea
which started two months ago. She was a previously healthy woman and two months ago,
after upper respiratory infection symptoms of cough, myalgia, and epigastric pain, dyspnea of NYHA functional
class II to III developed with intermittent chilling sense. She was managed at the
local clinic for asthma but she had no improvement in symptoms. One month ago, she underwent operation for anal hemorrhoids and she bled rather severely and received transfusion. Three days ago before the visit, her cough and dyspnea aggravated and she went to the local hospital and was diagnosed with
possible heart failure and was referred to their emergency room. She had nothing special in
her past medical history. She was a housewife and she did not smoke or drink alcohol. She had nothing of interest
in her family history. On interview, she had general weakness, easy fatigability and she
had anorexia indigestion. And she had some weight loss. She had cough and dyspnea which aggravated on supine position and on exertion. On physical examination, she
had normal blood pressure at 129/86 millimeters mercury and her heart rate was slightly elevated at 113 beats per minute and she was breathing rather fast at 22 times per minute. Her body temperature and
oxygen saturation were normal. Her height was 161 centimeters and her weight was 67 kilograms and she was overweight. She was slightly anemic
and icteric on examination and she was not dehydrated. On auscultation, we could
hear coarse breath sounds with crackles on the
right lower lung field and right beat heart beat
with a soft systolic murmur. She had a soft flat abdomen
without any tenderness and no visible edema or cyanosis. This is her initial laboratory findings. On ABGA done on room air, she had normal O2 pressure and she showed signs of hyperventilation. She had slight leukocytosis with a normal segment
fragmentation fraction and her total bilirubin was
elevated at 2.6 milligrams per deciliter and her
liver enzymes were elevated at 930 units per liter and ALT 1868 units per liter. Her PT INR was elevated at 1.59 and her urine was rather concentrated and albuminuria was two positive. Her BNP level was 2002
picograms per milliliter. Her hemoglobin A1C level was 6.8% and her fasting blood sugar was 142 milligrams per deciliter and she was newly diagnosed
with diabetes mellitus. Her thyroid function was normal and her hepatic serology was normal. Her initial chest x-ray showed cardiomegaly and pulmonary congestion with right pleural effusion. Her initial electrocardigoram showed sinus tachycardia with
ST elevation at V1 to V3 and ST depression at V6 suggesting left ventricular hypertrophy. Her initial echocardiogram was as follows. She had dilated LV cavity with an end systolic
dimension of 61 millimeters and end diastolic dimension
of 72 millimeters. Her wall thickness was normal. She showed secondary mitral regurgitation due to tethering and her ejection fraction
was decreased at 28%. There was global
hypokinesia as you can see. A myocardial SPECT was done to check for cause of heart failure and there was no significant
perfusion decrease suggesting ischemic heart disease. – Yes from this point until this point, I thought this patient is
usual dilated cardiomyopathy who aggravated by upper
respiratory infection. Although she has newly
onset diabetes mellitus EKG shows the ST elevation
reciprocal change. We ruled out coronary
artery disease presence by SPECT but there is no no specific regional
wall motion abnormality. But now in this point we
know the final diagnosis. If you check the clinical
manifestation of pheochromocytoma one of many manifestations is heart failure with hypertension, that comes from direct myocyte injury. And typical pattern of
diabetes function is Takotsubo cardiomyopathy, but as you see this patient
has no sign of Takotsubo but a global dysfunction. So in this point, my diagnosis dilated cardiomyopathy aggravated by urine infection. So initial assessment is
dilated cardiomyopathy and congestive hepatopathy
and diabetes mellitus. We treated him because
her blood pressure is low, we made dobumatine, off dobumatine and he got the improvement of symptom. At the discharge, blood pressure was 90/74 and pulse rate is still high. So we started Carvedilol, all Carvedilol without compounding any
alpha blocking agents. So we made ionotropic and beta blocker and for heart failure management. In this point, I want to ask how was this patient safe with ionotropics so we all know sympathomimetics may stimulate catecholamine release which might be very harm to the patient but however, long-term chronic exposure to the catecholamine make desensitization so make little impact for further increase in catecholamines. I did not do it on purpose but I made many mistakes, so how is the chairperson’s opinion? Can you detect the
pheochromocytoma in this patient? – [Panelist] Okay this is
now open for discussion and we hope we will have
some discussants coming to the microphones. Clearly very difficult but as
you told us at the beginning, pheochromocytoma is a great mimic, yes and I think you’ve just
discovered this patient at the time where this
great mimicry was already very advanced. I presume this pheochromocytoma
has been present for quite a while and that’s why dilated cardiomyopathy, the destruction, the
destructive changes of cardiomyocytes due to
excess of catecholamines which you haven’t measured yet because blood pressure was
completely normal or low. So any ideas, any suggestions
from the audience please? I know it is late but we need your help. No? I think you explained everything so could we hear a little more? – Yes. – I will tell you about her
outpatient clinic course. Her blood pressure and
pulse rate was normalized at the outpatient clinic and she was kept on Carvedilol 6.25 milligrams twice daily, Losartan 50 milligrams daily and Toarasemide 5 milligrams daily for around two years and
she was quite stable. On the second year, her blood pressure started to increase and Nifedipine was added. Also her blood sugar levels were started to be a little high and were not improved through lifestyle modification so metformin was added. On the two year follow-up
electrocardiogram and chest x-ray, you can
see diffuse T inversion on her electrocardigoram but her chest x-ray shows improvements with disappearance of cardiomegaly
and pulmonary congestion. Follow-up echocardiography was done and her LV cavity size was normalized and her ejection fraction was recovered from 28% to 73%. Secondary MR disappeared and her ejection fraction was normalized but apical akinesia was still left. As we continued to follow her up at the outpatient clinic, her blood pressure and pulse rate and hemoglobin A1C level
started to slowly rise. Blood pressure medication was changed to amlodipine plus Valsartan and Sitagliptin was added and
then the dose was increased. Carvedilol was initially discontinued due to concern that it
might aggravate hypoglycemia but she showed increase in blood pressure and pulse rate so bisoprolol
2.5 milligrams daily was added again. Her blood pressure was
stable with that medication but her blood glucose
levels continued to rise. On the fifth year, her
glucose levels started increasing very steeply and her HbA1c suddenly rose up to 9.3%. So glimepiride was added. After three months hemoglobin
A1c levels decreased once more to 7.3%. During this time, the
blood pressure was stable. At five years, we
performed another follow-up and her electrocardiogram
was totally normalized and her chest PA was normal. On the echocardiography, you can see that the function
was continuously normal and the cavity size was normal and also apical akinesia disappeared and there was no regional
wall motion abnormality. At the outpatient clinic, blood pressure continued to rise and started raising once more. We added thiazide and spironolactone and then increased the beta blocker dosage to Carvedilol 25 milligrams twice daily. Hemoglobin A1c levels were stable on metformin, Sitagliptin, and Glipizide but rather high at 7.7%. – When we screened secondary hypertension, pheochromocytoma always maybe first one to ruled out but in here, pheochromocytoma is coming close to secondary hypertension. Only 0.2% of all hypertension patients and eplerenone resistant hypertension the prevalence is 1%. But in contrast, among pheochromocytoma patient, majority have sustained or
paroxysmal hypertension. It cannot be discriminated clearly whether there is subtle
difference in hypertension pattern according to mainly
secreted catecholamine. Noradrenaline dominant type, it may increase peripheral
vascular resistance. So sustained hypertension
is usual phenotype but adrenaline dominant type, it may increase cardiac output. So episodic paroxysmal
hypertension more common. So paroxysmal hypertension majority occurs at least weekly. And generally several minute to one hour. Patient from time to time,
she may have in outpatient clinic. She complained of headache, but she didn’t take her
blood pressure in the home. And every time she visited my clinic, blood pressure is in pretty normal ranges. So in this point, still I cannot catch the whether headache is
some episodic symptom of pheochromocytoma. In this point, we think beta blocker, we all know beta blocker is very dangerous because beta blocker should
never be the initiated until there is sufficient
adrenoreceptor blockade because blockade of beta-2 adrenoceptor may impair vasodilator function. They may further increase
in blood pressure. But cardioselective beta
blockers or alpha blocking activity make some good
but even Carvedilol their alpha blocking potency is very less than beta blocker efficacy. So in text book, it clearly shows even Labetalol and
Carvedilol, their use alone is contraindicated. We go on. Hemoglobin A1c is somewhat stabilized but there is still
increase in Hemoglobin A1c. So I think when I see the
Hemoglobin A1c level over 9%, I think it is time to start insulin. I asked coworker endocrinology department is it is really good
to change the the hands and hear the second opinion. They showed from time to time there is microscopic hematuria. So he took the computer tomography. This time I screamed. I find the larger pheochromocytoma. So hormonal evaluation. There is epinephrine,
adrenaline dominant type but noradrenaline is still increased and renin, aldosterone are increased. PET scan, there is messy and
there is no other finding. So in outpatient clinic course, echocardiography normalized after first episode of heart failure. Marginally controlled blood
pressure and pulse rate responded to beta blockers. Diabetes mellitus
progressively uncontrolled despite followed medication. Incidentally pheochromocytoma diagnosed after computer tomography due to incidental microscopic hematuria. In this point, I hope
to ask your opinion. What time is the timing I can diagnose earlier than the nine years follow-up? – [Panelist] Okay this is open and whilst everybody is thinking, I think it is very, very difficult in this case because you’ve never really
managed to have hypertension until very, very late. So my question is during
observation of this patient, have you ever done either ambulatory blood pressure monitoring or home blood pressure monitoring, any out of office blood pressures because perhaps this could
have picked up things earlier? – Yes I didn’t think about doing ambulatory blood pressure because the anti-hypertensive
medication regime is not so heavy, so the usual two or
three strong medications so I didn’t took ambulatory
blood pressure monitoring. – [Panelist] Okay any
points, yeah we’ve got Garry. – I don’t know when you
could’ve made this diagnosis. You had to get lucky I think to make it but it is interesting reflecting on the pharmacology of Carvedilol that she wasn’t hypertensive until you improved her ventricular function to the point that she could sustain an
elevated blood pressure and then it was fortunate that a drug which is predominantly a beta blocker with a little bit of alpha blockade didn’t increase her blood pressure further because she was predominantly
secreting adrenaline when you came to get some catecholamine, so it’s been a course which could’ve been very different if it had
been a different kind of pheochromocytoma. – [Panelist] Okay we have another comment. Please introduce yourself. – There are two questions. You’ve had a lot of tests done but what was her fundoscopy like right from the start and
subsequent examinations and what happened to the raised PT which was in the first testing done right at the start? She had a raised INR. Was that investigated? – Yes the first, until this timing I didn’t think she is hypertension patient but a hypertensive heart failure patient. So regrettably I didn’t see
the retinal examination. It is my fault. And can you ask me once
more second question. – The INR was raised right
at the first initial INR, PT, prothrombin time. – PT is about 80%, so
INR basically is over one but less than two. So 80% of normal range, so I thought that was part
of congestive hepatopathy. Her PT was normalized after discharge. – [Panelist] Thank you. – [Panelist] The right microphone please. – I have a question. Now we brush back her history. In the second examination,
there is a Q wave inversion in EKG and some more apical aneurysm. And there is enough reason to perform a coronary angiography because she has a diabetes and hypertension. So how about the cardiac enzyme or her symptom or did you ever perform the coronary angiography? – Very good question. In the first time, in terms of diagnosed
heart failure etiology, I can do the coronary
angiography in this patient but initial cardiac enzyme
is completely normal. There is no sign of elevation. Second one is response is quite rapid, so based on these two findings, I ruled out the possibility
of coronary artery disease. – Sometimes pheochromocytoma
produce cortisol. In the middle of the
examination, her lab data, is there any hypokalemia
developed or not? – No there is no kind
of hypokalemia because as I used the thiazide diuretics and I always check the natrium column, but there is no range of derangement. Thank you. – [Panelist] Okay so do we
have the rest of the story? I think we are ready for
the rest of the story? – But it took nine years from
first meeting this patient and final diagnosis, but all this is related
with pheochromocytoma. For example diabetes
is maintained six years but after operation there is no sign of any diabetes mellitus. In this point, check about
the prevalence of diabetes in pheochromocytoma. Pheochromocytoma is one of
the most higher prevalence of secondary glucose intolerance
in endocrine disorder. So majority of patient have hypoglycemia but usually milder course. Especially adrenaline dominant type is more higher affinity for beta receptor by binding beta receptor they increase gluconeogenesis and decrease the insulin release. That two mechanisms is the main mechanisms of pheochromocytoma
associated hypoglycemia. When I added sulfonylurea
only one tablet per day, her Hemoglobin A1c level
decreased by two points. It is unusual. Usually put on sulfonylurea is only 1% hemoglobin A1c decreased. So that may be rejuvenating insulin releases from the beta cell. After find out the pheochromocytoma, at the time we did good. Alpha blocker, we
covered the alpha blocker and we sufficiently supplied six liters per day one
day before operation so there is no hypertensive
episodes during operation. So adequate hydration
is very important point. And regarding preoperative alpha blocking there is still confusion
whether alpha blocker is better or phenoxybenzamine is better. One of good point of phenoxybenzamine is BP control but phenoxybenzamine is not a familiar anti-hypertensive agent. Doxazosin is familiar. Doxazosin is still associated
with less pronounced BP approximation. So in that case, we use doxazosin but current standard
treatment of pheochromocytoma in my hospital is phenoxybenzamine. So gross specimen. Some malignant portion
and whole benign portion. Even there is some malignant foci. Patient is very indolently
may course of nine year and adrenaline dominantly secreting type pheochromocytoma causing
transient heart failure and diabetes mellitus. And after operation, both
condition completely disappeared. She had follow-up without any medication. In the final discussion point, I would like to ask your opinion what is the adequate
preoperative prevention strategy between alpha blocker
and phenoxybenzamine? – [Panelist] Okay in our
center, we would have normally used phenoxybenzamine because that’s how it’s always been done but I don’t think there is any evidence that one is truly better than the other. But it is quite good
to lower blood pressure preoperatively and as you
did maybe it doesn’t matter which drug but to truly
control blood pressure to the millimeter during surgery to avoid any big blood
pressure differences both up and down. Any other opinions? They agree. They agree. There is one question
that just came to my mind this very moment. Has she had a pregnancy before because in a woman
occasionally pheochromocytoma comes to light during pregnancy especially if there are any procedures such as caesarean section etcetera sometimes traumatically. Was she ever pregnant or not? – No she has no experience of pregnancy. One year before heart
failure of the patient, she got hemorrhoid operation
under local anesthesia but hopefully there is no
stage of pheochromocytoma during local anesthesia and operation. – [Panelist] I think in this case, we need to blame the patient. She made it so difficult for you to make the diagnosis that I
think you need to feel completely free of any guilt. Any other comments from
the audience please. No? So you have the final diagnosis which we all agree with and there are no more comments. So if you would like to summarize and we will be closing the session. – Yes, final diagnosis
adrenaline predominantly secreting subtype pheochromocytoma, causing transient heart
failure and diabetes mellitus. Through this conference, I hope to again keep in mind pheochromocytoma have
clearly multiple faces. So in any case of clinical uncertainty we think the possibility
of pheochromocytoma. Thank you very much. – [Panelist] Thank you very much. That’s fantastic presentation. (clapping) Could I thank all presenters? I think we had a very good although greatly attended session. We will work on this for next time and could we have all discussants please to give your names and emails to Denise. Thank you very much for attending this and have a nice evening. (clapping)