Metabolomic Biomarkers in Urine of Cushing’s Syndrome Patients

Posted on January 29, 2017 by MaryO
Int. J. Mol. Sci. 2017, 18(2), 294; doi:10.3390/ijms18020294 (registering DOI)

Alicja Kotłowska 1,* , Tomasz Puzyn 2, Krzysztof Sworczak 3, Piotr Stepnowski 4 and Piotr Szefer 1

1 Department of Food Sciences, Faculty of Pharmacy, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland
2 Laboratory of Environmental Chemometrics, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland
3 Department of Endocrinology and Internal Medicine, Medical University of Gdańsk, ul. Dębinki 7, 80-211 Gdańsk, Poland
4 Department ofEnvironmental Analytics, Institute for Environmental and Human Health Protection, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland
* Author to whom correspondence should be addressed.
Academic Editor: Ting-Li (Morgan) Han
Received: 5 December 2016 / Revised: 9 January 2017 / Accepted: 19 January 2017 / Published: 29 January 2017
(This article belongs to the Section Molecular Diagnostics)
Download PDF [1853 KB, uploaded 29 January 2017]

Abstract

Cushing’s syndrome (CS) is a disease which results from excessive levels of cortisol in the human body. The disorder is associated with various signs and symptoms which are also common for the general population not suffering from compound hypersecretion. Thus, more sensitive and selective methods are required for the diagnosis of CS.

This follow-up study was conducted to determine which steroid metabolites could serve as potential indicators of CS and possible subclinical hypercortisolism in patients diagnosed with so called non-functioning adrenal incidentalomas (AIs).

Urine samples from negative controls (n = 37), patients with CS characterized by hypercortisolism and excluding iatrogenic CS (n = 16), and patients with non-functioning AIs with possible subclinical Cushing’s syndrome (n = 25) were analyzed using gas chromatography-mass spectrometry (GC/MS) and gas chromatograph equipped with flame ionization detector (GC/FID). Statistical and multivariate methods were applied to investigate the profile differences between examined individuals. The analyses revealed hormonal differences between patients with CS and the rest of examined individuals.

The concentrations of selected metabolites of cortisol, androgens, and pregnenetriol were elevated whereas the levels of tetrahydrocortisone were decreased for CS when opposed to the rest of the study population. Moreover, after analysis of potential confounding factors, it was also possible to distinguish six steroid hormones which discriminated CS patients from other study subjects.

The obtained discriminant functions enabled classification of CS patients and AI group characterized by mild hypersecretion of cortisol metabolites. It can be concluded that steroid hormones selected by applying urinary profiling may serve the role of potential biomarkers of CS and can aid in its early diagnosis.

 

Keywords: Cushing’s syndrome; metabolomics; multivariate analysis; biomarkers; steroid hormones; urinary profiling; gas chromatography; linear discriminant analysis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

From http://www.mdpi.com/1422-0067/18/2/294

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Imaging Technique Measures Tumor Stiffness to Aid Surgical Planning

Posted on January 28, 2017 by MaryO

screenshot-2017-01-27-11-04-44

 

Important steps in planning tumor surgery include identifying borders between tumor and healthy tissue and assessing the tumor stiffness, e.g. hard and calcified or soft and pliant. For decades, tumors near the surface of the body have been evaluated for stiffness by simple palpation—the physician pressing on the tissue. Because tumors within the skull cannot be palpated, researchers used Magnetic Resonance Elastography (MRE) to assess pituitary tumor stiffness by measuring waves transmitted through the skull into pituitary macroadenomas (PMAs). MRE reliably identified tumors that were soft enough for removal with a minimally-invasive suction technique versus harder tumors requiring more invasive surgery.

“The group developed brain MRE several years ago and is now successfully applying it to clinical diagnosis and treatment,” explained Guoying Liu, Ph.D., Director of the NIBIB Program in Magnetic Resonance Imaging. “This development of a new imaging technique followed by its practical application in surgical planning for better patient outcomes is an outstanding example of one of the main objectives of NIBIB-funded research.”

MRE is a special magnetic resonance imaging technique that captures snapshots of shear waves that move through the tissue and create elastograms—images that show tissue stiffness. John Huston III, M.D., Professor of Radiology at the Mayo Clinic in Rochester, MN, and senior author of the study, explains how MRE works. “MRE is similar to a drop of water hitting a still pond to create the ripples that move out in all directions. We generate tiny, harmless ripples, or shear waves, that travel through the brain of the patient. Our instruments measure how the ripples change as they move through the brain and those changes give us an extremely accurate measure–and a color-coded picture–of the stiffness of the tissue.”

MRE data enables non-invasive surgical planning

Ninety percent of PMAs are soft—nearly the consistency of toothpaste. Therefore, without MRE, surgeons would routinely plan for a procedure called transphenoidal resection that employs very thin instruments that are threaded through the nasal cavity to the pituitary gland at the base of the skull, where suction is used to remove the tumor. However, in about 10% of the cases, the surgeon will encounter a hard tumor. At that point an attempt is made to break-up the tumor—essentially chipping away at it with sharp instruments. If that is not successful, the surgeon must perform a fully-invasive craniotomy that involves removing a piece of the skull bone in order to fully expose the tumor.

The more extensive procedure means added risk and discomfort for patients, and up to a week-long recovery in the hospital compared to the transphenoidal approach that allows patients to leave the hospital in a day or two. Using MRE, hard PMAs can be identified and the more extensive craniotomy can be planned before starting the surgery, which makes the more invasive procedure less taxing for both the surgeon and patient. Similarly, MRE showing a soft PMA gives surgeons confidence that the nasal entry and removal by suction will be successful-eliminating the likelihood that the surgeon may need to perform a second fully-invasive craniotomy.

In the study of PMA reported in the January 2016 issue of the journal Pituitary, the group performed pre-surgical MRE evaluation of the PMAs of 10 patients.The MRE measurements were compared to tumor classifications made by inspection of the tumor during surgery. The surgeons categorized six tumors as soft and four tumors as medium. No tumors were deemed to be hard. The comparison of the MRE results and reports of stiffness by the surgeons when the tumor was removed and inspected were in close agreement, which was confirmed by statistical analysis.

Future plans

Although brain MRE is not yet widely available, Huston explained that the surgeons at the Mayo Clinic are now routinely using MRE to plan the best procedure for the removal of PMAs as well as several other types of brain tumor. And, even though this study of the 10 PMA patients is a very small set, Huston believes that as Mayo surgeons continue to use MRE in planning, the technique will likely begin to be adopted by other surgical centers.

Huston explained that an important aspect of some of the other brain tumor types, which the surgeons are finding extremely useful, is the ability of MRE to identify tumor adhesion to the brain. Adhesion refers to whether the brain tumor and healthy brain tissue are connected by an extensive network of blood vessels and connective tissue. This is in comparison with a tumor that is in the brain but is isolated from healthy tissue.

When MRE is used to analyze this aspect of the tumor, it clearly identifies those that are non-adhered, showing a border around the tumor through which there are no vascular connections. Conversely, MRE of adhered tumors show no border between the tumor and healthy brain, indicating extensive vascular and soft tissue connections between brain and tumor. Mutual blood vessels make removal of adherent tumors much more difficult, with a much higher chance of damage to healthy tissue and potential loss of function for the patient.

Huston and his colleagues are continuing to apply MRE, often called “palpating by imaging” to diagnosis of other brain disorders. In addition to characterizing focal brain disorders such as tumors, the group is testing the potential for MRE to provide diagnostic information about diffuse brain disease, and are currently using MRE brain stiffness patterns to identify different types of neural disorders including dementia.

This research was funded by the National Institutes of Health through the National Institute of Biomedical Imaging and Bioengineering grant EB001981.

Magnetic resonance elastography detects tumoral consistency in pituitary macroadenomas. Hughes JD, Fattahi N, Van Gompel J, Arani A, Ehman R, Huston J 3rd. Pituitary. 2016 Jun;19(3):286-92

From http://www.rdmag.com/news/2017/01/imaging-technique-measures-tumor-stiffness-aid-surgical-planning

Filed under: Cushing's, Diagnostic Testing, pituitary, Treatments | Tagged: , , , , , , | 2 Comments »

Topical Ocular Glucocorticoid Leads to Cushing’s Syndrome in 9-Year-Old

Posted on January 21, 2017 by MaryO

In a case report published online January 19 in Pediatrics, iatrogenic Cushing’s syndrome (CS) is described in a 9-year-old girl who received topical ocular glucocorticoid (GC) treatment for bilateral iridocyclitis.

Daisuke Fukuhara, MD, PhD, from the Kyorin University School of Medicine in Mitaka, Japan, and colleagues present the case of a 9-year-old girl suffering from idiopathic uveitis. She arrived at the ophthalmology department with a complaint of painful eyes, and was diagnosed with bilateral iridocyclitis and started on betamethasone sodium phosphate eye drop treatment.

The authors note that the patient was referred to the pediatric department with stunted growth, truncal obesity, purple skin striae, buffalo hump, and moon face six months after initiation of topical ocular GC treatment. She was diagnosed with iatrogenic CS as her serum cortisol and plasma adrenocorticotropic hormone levels were undetectable. The clinical symptoms of CS were improved after the doses of topical ocular GC were reduced. On genetic analysis, the patient was found to have a single heterozygous nucleotide substitution in the 3′ untranslated region of the NR3C1 gene.

“However, additional investigations are required to determine if our findings can be extrapolated to other patients,” the authors write. “In conclusion, clinicians should be aware that even extremely low doses of topical ocular steroid therapy can cause iatrogenic CS.”

Full Text (subscription or payment may be required)

From http://www.empr.com/news/iatrogenic-cushings-syndrome-topical-ocular-glucocorticoid-iridocyclitis/article/632840/

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A Letter To Patients With Chronic Disease

Posted on January 10, 2017 by MaryO

MaryO’Note:  Dr. Rob was interviewed by Robin (staticnrg) and Mary O’Connor (MaryO) October 2, 2008 on BlogTalkRadio Cushing’s Help

Listen to this interview here: http://www.blogtalkradio.com/cushingshelp/2008/10/03/robin-staticnrg-and-mary-oconnor-maryo-interview-dr-rob-1

July 14, 2010
by Rob Lamberts

Dear Patients: You have it very hard, much harder than most people understand.  Having sat for 16 years listening to the stories, seeing the tiredness in your eyes, hearing you try to describe the indescribable, I have come to understand that I too can’t understand what your lives are like.  How do you answer the question, “how do you feel?” when you’ve forgotten what “normal” feels like?  How do you deal with all of the people who think you are exaggerating your pain, your emotions, your fatigue?  How do you decide when to believe them or when to trust your own body?  How do you cope with living a life that won’t let you forget about your frailty, your limits, your mortality?

I can’t imagine.

But I do bring something to the table that you may not know.  I do have information that you can’t really understand because of your unique perspective, your battered world.  There is something that you need to understand that, while it won’t undo your pain, make your fatigue go away, or lift your emotions, it will help you.  It’s information without which you bring yourself more pain than you need suffer; it’s a truth that is a key to getting the help you need much easier than you have in the past.  It may not seem important, but trust me, it is.

You scare doctors.

No, I am not talking about the fear of disease, pain, or death.  I am not talking about doctors being afraid of the limits of their knowledge.  I am talking about your understanding of a fact that everyone else seems to miss, a fact that many doctors hide from: we are normal, fallible people who happen to doctor for a job.  We are not special.  In fact, many of us are very insecure, wanting to feel the affirmation of people who get better, hearing the praise of those we help.  We want to cure disease, to save lives, to be the helping hand, the right person in the right place at the right time.

But chronic unsolvable disease stands square in our way.  You don’t get better, and it makes many of us frustrated, and it makes some of us mad at you.  We don’t want to face things we can’t fix because it shows our limits.  We want the miraculous, and you deny us that chance.

And since this is the perspective you have when you see doctors, your view of them is quite different.  You see us getting frustrated.  You see us when we feel like giving up.  When we take care of you, we have to leave behind the illusion of control, of power over disease.  We get angry, feel insecure, and want to move on to a patient who we can fix, save, or impress.  You are the rock that proves how easily the ship can be sunk.  So your view of doctors is quite different.

Then there is the fact that you also possess something that is usually our domain: knowledge.  You know more about your disease than many of us do – most of us do.  Your MS, rheumatoid arthritis, end-stage kidney disease, Cushing’s disease, bipolar disorder, chronic pain disorder, brittle diabetes, or disabling psychiatric disorder – your defining pain –  is something most of us don’t regularly encounter.  It’s something most of us try to avoid.  So you possess deep understanding of something that many doctors don’t possess.  Even doctors who specialize in your disorder don’t share the kind of knowledge you can only get through living with a disease.  It’s like a parent’s knowledge of their child versus that of a pediatrician.  They may have breadth of knowledge, but you have depth of knowledge that no doctor can possess.

So when you approach a doctor – especially one you’ve never met before – you come with a knowledge of your disease that they don’t have, and a knowledge of the doctor’s limitations that few other patients have.  You see why you scare doctors?  It’s not your fault that you do, but ignoring this fact will limit the help you can only get from them.  I know this because, just like you know your disease better than any doctor, I know what being a doctor feels like more than any patient could ever understand.  You encounter doctors intermittently (more than you wish, perhaps); I live as a doctor continuously.

So let me be so bold as to give you advice on dealing with doctors.  There are some things you can do to make things easier, and others that can sabotage any hope of a good relationship:

  1. Don’t come on too strong – yes, you have to advocate for yourself, but remember that doctors are used to being in control.  All of the other patients come into the room with immediate respect, but your understanding has torn down the doctor-god illusion.  That’s a good thing in the long-run, but few doctors want to be greeted with that reality from the start.  Your goal with any doctor is to build a partnership of trust that goes both ways, and coming on too strong at the start can hurt your chances of ever having that.
  2. Show respect – I say this one carefully, because there are certainly some doctors who don’t treat patients with respect – especially ones like you with chronic disease.  These doctors should be avoided.  But most of us are not like that; we really want to help people and try to treat them well.  But we have worked very hard to earn our position; it was not bestowed by fiat or family tree.  Just as you want to be listened to, so do we.
  3. Keep your eggs in only a few baskets – find a good primary care doctor and a couple of specialists you trust.  Don’t expect a new doctor to figure things out quickly.  It takes me years of repeated visits to really understand many of my chronic disease patients.  The best care happens when a doctor understands the patient and the patient understands the doctor.  This can only happen over time.  Heck, I struggle even seeing the chronically sick patients for other doctors in my practice.  There is something very powerful in having understanding built over time.
  4. Use the ER only when absolutely needed – Emergency room physicians will always struggle with you.  Just expect that.  Their job is to decide if you need to be hospitalized, if you need emergency treatment, or if you can go home.  They might not fix your pain, and certainly won’t try to fully understand you.  That’s not their job.  They went into their specialty to fix problems quickly and move on, not manage chronic disease.  The same goes for any doctor you see for a short time: they will try to get done with you as quickly as possible.
  5. Don’t avoid doctors – one of the most frustrating things for me is when a complicated patient comes in after a long absence with a huge list of problems they want me to address.  I can’t work that way, and I don’t think many doctors can.  Each visit should address only a few problems at a time, otherwise things get confused and more mistakes are made.  It’s OK to keep a list of your own problems so things don’t get left out – I actually like getting those lists, as long as people don’t expect me to handle all of the problems.  It helps me to prioritize with them.
  6. Don’t put up with the jerks – unless you have no choice (in the ER, for example), you should keep looking until you find the right doctor(s) for you.  Some docs are not cut out for chronic disease, while some of us like the long-term relationship.  Don’t feel you have to put up with docs who don’t listen or minimize your problems.  At the minimum, you should be able to find a doctor who doesn’t totally suck.
  7. Forgive us – Sometimes I forget about important things in my patients’ lives.  Sometimes I don’t know you’ve had surgery or that your sister comes to see me as well.  Sometimes I avoid people because I don’t want to admit my limitations.  Be patient with me – I usually know when I’ve messed up, and if you know me well I don’t mind being reminded.  Well, maybe I mind it a little.

You know better than anyone that we docs are just people – with all the stupidity, inconsistency, and fallibility that goes with that – who happen to doctor for a living.  I hope this helps, and I really hope you get the help you need.  It does suck that you have your problem; I just hope this perhaps decreases that suckishness a little bit.

Sincerely,

Dr. Rob

Post Script: This post has generated a huge amount of conversation and interest (as witnessed by the large number of comments!).  I very much appreciate the dialogue it has spawned both here and across the web.  I’ve subsequently written follow-up posts explaining my thoughts in more detail – largely in response to the comments here.  One of them discusses in more detail my own experiences as a doctor and the second talks of the importance of  knowing and being known.  Reading these will give you a better picture of my thought process and perspective on this.Dr. Rob

From http://more-distractible.org/musings/2010/07/14/a-letter-to-patients-with-chronic-disease

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High cortisol: Symptoms and signs

Posted on January 8, 2017 by MaryO

When we become stressed out bodies release cortisol – the stress hormone – which helps us cope with challenges. Cortisol’s role is to convert protein into energy by releasing glycogen and counteract inflammation. When cortisol is released in the body temporarily, this is okay and won’t have long-lasting detrimental effects to health as it is a natural response to a stressor. But when cortisol levels remain high chronically it can eventually begin to tear your body down thus causing health complications. This is why numerous health experts recommend the reduction of stress as much as possible because in the long run it can harm our health.

High cortisol levels over the long term can destroy healthy muscle and bone, slow down healing, impair digestion, metabolism and mental function, and weaken the immune system. Additionally, adrenal fatigue has been linked to numerous other health conditions including fibromyalgia, hypothyroidism, chronic fatigue syndrome, arthritis, premature menopause, and many others. High cortisol levels are also associated with many unwanted symptoms which we will outline below.

High cortisol symptoms

If you’re concerned about your cortisol levels, the following signs and symptoms associated with high cortisol levels can alert you and prompt you to make the necessary changes in order to reduce cortisol levels.

  • Unexplained weight gain
  • Skin symptoms including acne, skin infections, lesions, thin-appearing skin, bruising, growing facial hair, and reddish purple streaks on skin
  • Muscle and bone symptoms like a deep pain in the bones, weak muscles, chronic backaches, increased risk of bone fractures
  • Gender specific changes such as women developing male-pattern hair growth, irregular menstrual cycles, low libido, infertility
  • Neurological symptoms such as depression, irritability, headaches, chronic fatigue, and anxiety
  • High blood pressure (hypertension)
  • Poor sleep or lack of sleep
  • Swelling of hands and feet

If you notice any of the above symptoms, you may want to have your cortisol levels checked to confirm diagnosis. Living with high cortisol levels over the long term can have detrimental effects on a person’s health. Treating high cortisol as soon as possible can lower the risk of long-term health problems.

Causes of high cortisol

There are two main causes of high cortisol: Chronic stress and more rarely, Cushing’s disease. Cushing’s disease is caused by a hormone-secreting tumor on the adrenal gland which results in the release more cortisol than required.

Living with chronic stress also leads to high cortisol because the release of cortisol is a natural response from the body when it is stressed. The hypothalamic–pituitary-adrenal [HPA] axis is what regulates the timely release of cortisol during acute stress, but when stress becomes chronic the feedback from the HPA becomes damaged and so cortisol continues to be released.

Conditions that can contribute to chronic stress and high cortisol include:

  • Depression
  • Panic disorder
  • Generalized anxiety disorder
  • Post traumatic stress disorder (PTSD)
  • Anorexia nervosa
  • Bulimia nervosa
  • Alcoholism
  • Diabetes
  • Severe obesity
  • Metabolic syndrome
  • Polycystic ovary syndrome (PCOS)
  • Obstructive sleep apnea
  • Working in shifts
  • End-stage kidney disease
  • Chronic pain

Tips to lower high cortisol

Here are some tips that can help you lower your high cortisol levels and thus prevent long-term health problems associated with high cortisol. [MaryO’Note:  These will not work if you have active Cushing’s!    You must remove  the source of your Cushing’s first.]

  • Eat a well balanced meal with plenty of fruits and vegetables, avoid sugars, consume low glycemic index foods, avoid processed foods, eat a wide variety of health foods to ensure you receive all essential vitamins and nutrients
  • Exercise on a regular basis
  • Take time out of each day to relax – listen to music, meditate, pray, perform your favorite hobby, anything that promotes relaxation
  • Take up yoga or tai chi
  • Ensure you are getting adequate sleep
  • Drink tea
  • Watch funny videos or hang out with a funny friend
  • Go for a massage
  • Do something spiritual – attend a service
  • Chew gum
  • Limit caffeine intake
  • Stretch

By incorporating these helpful tips into your life you will find that your high cortisol symptoms begin to diminish and your overall health begins to improve.

From http://www.belmarrahealth.com/high-cortisol-symptoms-signs-look/

 

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