Sunday, May 31, 2009

Pituitary Blog Alert, May 31, 2009

Miss Diagnosis: Cardiology, Add Another Doc
By Hi, I'm Rene


The surgical removal of the pituitary adenoma is performed by a technique called a transsphenoidal operation. The word 'transsphenoidal' describes the path the surgeon follows to reach the pituitary gland. The word comes from 'trans', ...
Miss Diagnosis - http://missdiagnosis-rene.blogspot.com/

Friday, May 29, 2009

Cushing's? Blood pressure issue

Dear Dr. Donohue: I am a 42-year-old male who has had high blood pressure for the past two years. I have been on many medicines, but my pressure does not go much lower. I do not smoke or drink. No one else in my family has high blood pressure. I am about 25 pounds overweight. My doctor mentioned that I might have secondary high blood pressure. What is that? -- R.B.

Dear R.B.: Ordinary high blood pressure, or hypertension, is essential hypertension -- high blood pressure that comes on its own. Secondary high blood pressure is an elevation of pressure due to another process.

A leading cause of secondary high blood pressure is a narrowed kidney artery. Because of the narrowing, the kidney thinks the body's blood pressure is too low. It begins to turn out large quantities of renin, a kidney-made chemical that raises blood pressure. This kind of high blood pressure is known as renovascular hypertension. It can be cured by relieving the blockage in the kidney artery.

Adrenal gland tumors, Cushing's disease and a very unusual tumor called a pheochromocytoma are other causes of secondary high blood pressure.

The bright side of secondary high blood pressure is its curability when the "secondary" process is treated.

Your young age and the fact that your pressure does not respond to the drugs well are two factors that suggest a secondary process might be going on Even though you did not ask, you can help yourself by losing the extra 25 pounds of weight you carry. Diet and exercise do work. You can also do yourself good by reducing greatly the amount of salt in your diet.

Proof of secondary high blood pressure involves some complicated tests, so do not be surprised if your doctor arranges them for you.

From http://www.heraldtribune.com/article/20090529/COLUMNIST/905291000/2127?Title=Blood-pressure-issue

Help raise awareness for rare diseases (like Addison's and Cushing's!) http://ping.fm/IMOCg

A Novel Approach to Self-Empowered Healthcare

Learn about Cushing's and share your symptoms at http://curetogether.com/Cushings-Disease/

Cushing's Disease is an endocrine disorder caused by high levels of cortisol in the blood from a variety of causes. It is relatively rare, affecting 10-15 out of every million people. (Sources: Wikipedia, NIDDK)

At this writing 6 CureTogether members report having Cushing's Disease. The most common symptoms are: Weak muscles, Irritability, Bruise easily. The most common treatments are: Pituitary surgery, Radiation, Cortisol-inhibiting drugs.

Have you been diagnosed with Cushing's Disease?

See how your symptoms compare with others.

Not sure if you have it?

Look at the list of Cushing's Disease symptoms to see how well your symptoms match.


Or, if you think it might be something else, enter your symptoms below to see a list of matching conditions:.

Want to know how to feel better?

Look at treatments others have tried and see stats on how satisfied they are.

~~~~~~~~~~~~~

Have you heard of CureTogether? We recently stumbled across this website and after trying it out, decided that it most definitely rates a closer look.

cure-together

CureTogether describes itself as a place to help people “anonymously track and compare health data, to better understand their bodies, make more informed treatment decisions and contribute data to research”.

While the site is still new, it’s gaining momentum with more than 3,000 members. The website is “currently funded by its founders, and does not host or receive funding from advertising”.

They have a simple profile where you can start by adding data you want to track such as weight, caloric intake, sleep, and excercise. A nice feature is that you can add anything else you would like to keep track of such as mood or water intake - anything you think is important for your particular situation.

Something we really like is that you can view and edit this data on your Google search page (to learn how to use iGoogle, click here).

igoogle

On your bio page, you can tell your story and add details such as location, avatar (picture) and date of birth. This is, by default, kept completely private though you have the option to share your details anonymously.

So far there are 289 conditions on the site and CureTogether highlights the “most active”. Back pain, anxiety, and depression are among the top five. Click on back pain and you will get a list of user generated symptoms. You can check off whether or not you’ve experienced it as well as the severity level. If you don’t see something that you are experiencing, it’s easy to add it.

add-a-symptom

Next are treatments. What have you tried so far? For back pain ice packs, stretching, and vicodin are some of the options. Again, it’s easy to add to the list. Now you can document what you think (or know) causes it. Does your back hurt after sex, after sitting for long periods of time, or from an injury?

treatments

The related conditions portion list the most commonly reported ones first. The fact that anxiety is number one and depression number two for back pain gives us some food for thought! This ability to compare user data is where CureTogether really shows its potential usefulness.

A this point, you can view resources, document how you are feeling (much like Facebook updates, this allows you to share status updates with your friends), invite friends, or revisit any of your health pages.

For those living with chronic pain, or even those who just want to keep track of their day to day health, CureTogether offers some unique tools.

Check out their site here and let us know if it works for you!

Cushing's locations page updated, new people added. http://ping.fm/pHFE2

Upcoming Cushing's Book

This project was started in June 2008 and put on hold due to several "life issues", one of them being the enormous amount of time it takes to apply for non-profit status.

Here are some of the thoughts and ideas that will be in the book when finished, hopefully by December 2009.

MaryO: some people have articles on the website like http://www.cushings-help.com/helpful_hints.htm and these:

On the website here

Discuss here at http://cushings.invisionzone.com/index.php?showtopic=32996

Bilateral Adrenalectomy for Refractory Cushing Disease: A Safe and Definitive Therapy

Philip W. Smith MDa, Corresponding Author Contact Information, E-mail The Corresponding Author, Kristin C. Turza MDa, Cullen O. Carter MDa, Mary Lee Vance MDc, Edward R. Laws MD, FACSb and John B. Hanks MD, FACSa

aDepartment of Surgery, University of Virginia, Charlottesville VA

bDepartment of Neurological Surgery, University of Virginia, Charlottesville VA

cDepartment of Medicine, University of Virginia, Charlottesville VA

Received 14 October 2008; 

revised 29 January 2009; 

accepted 2 February 2009. 

Available online 24 April 2009.

From http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T91-4W4S38W-2&_user=10&_coverDate=06%2F30%2F2009&_rdoc=11&_fmt=high&_orig=browse&_srch=doc-info(%23toc%235101%232009%23997919993%231116105%23FLA%23display%23Volume)&_cdi=5101&_sort=d&_docanchor=&_ct=46&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=8a88e97748d1e2e6d927094213d964bc

Background

Refractory Cushing disease (CD) is associated with considerable morbidity and mortality. Bilateral adrenalectomy (BA) offers effective permanent treatment. Both open and laparoscopic approaches have been used, but longterm comparisons are few.

Study Design

We reviewed 40 consecutive BA for refractory CD from 1995 through 2007. Surgical results were evaluated. A Short Form-36 Quality-of-Life (QOL) survey was performed.

Results

Eighty-five percent (34 of 40) of patients were women, and median age was 41.9 years (range, 22.2 to 78.3 years). All had persistent CD after transsphenoidal operation (mean, 1.7; range, 1 to 3). Median followup was 5.0 years. Thirty-eight percent (15 of 40) of procedures were performed laparoscopically; 1 was converted to open. There were no operative or 30-day mortalities, and there was 1 90-day mortality. Morbidities occurred in 7 of 40 (18%) patients. Median length of stay was shorter in the laparoscopic group (4 versus 6 days; p < 0.001). All patients achieved clinical reversal of hypercortisolism, including the 5 (13%) with ectopic adrenal tissue. Elevated serum ACTH (> 200 ng/mL) was present during followup in 33% (13 of 40). A QOL survey demonstrated 86% of patients felt good to excellent compared with 1 year pre-BA. Chronic fatigue was present most or all of the time in 46%, and patients were below population norms on 7 of 8 Short Form-36 scales. No difference was evident in QOL between laparoscopic and open adrenalectomy.

Conclusions

Our experience demonstrates excellent survival and clinical results, despite the inherent risk in patients with CD. There are persistent fatigue and QOL deficits that are not ameliorated by laparoscopic compared with open resection.

Abbreviations: BA, bilateral adrenalectomy; CD, Cushing disease; NS, Nelson syndrome; QOL, quality of life; SF-36, Short Form-36 Quality-Life-Survey; TSS, transsphenoidal surgery

Article Outline
Methods
Results
Discussion
Author Contributions
References

Thumbnail image

Figure 1. Survival after bilateral adrenalectomy.

View Within Article


Thumbnail image

Figure 2. Short Form-36 Quality-of-Life normative-based scoring, summary results.

View Within Article


Table 1.

Patient and Prior Treatment Characteristics for Study Groups

View table in article

BMI, body mass index (calculated as kg/m2); TSS, transsphenoidal surgery; XRT, radiation therapy.

View Within Article


Table 2.

Operative Characteristics and Outcomes for Patients in Study Groups

View table in article

EBL, estimated blood loss; LOS, length of stay.

low asterisk Excludes a single patient from the open adrenalectomy group with 3,700 mL EBL.

View Within Article

Disclosure Information: Nothing to disclose.

Corresponding Author Contact InformationCorrespondence address: Philip W Smith, MD, Department of Surgery, University of Virginia, Box 800709, Charlottesville, VA 22908

Thursday, May 28, 2009

Deletereous Effects of Glucocorticoid Replacement on Bone in Women after Long-Term Remission of Cushing's Syndrome

María-José Barahona1, 33962mbc@comb.es   N Sucunza1, nsucunza@hmanacor.org   E Resmini1, eresmini@santpau.cat   JM Fernández-Real2, jmfernandezreal.girona.ics@gencat.cat   W Ricart2, wricart.girona.ics@gencat.cat   JM Moreno2, h416ummn@htrueta.scs.es   T Puig3, tpuig@santpau.cat   AM Wägner1, awgn@steno.dk   J Rodriguez-Espinosa1, jrodrigueze@santpau.cat   J Farrerons4, jfarrerons@santpau.cat   SM Webb1, swebb@santpau.cat

1Endocrinology and Medicine Departments and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, Barcelona; Hospital Sant Pau, Universitat Autònoma de Barcelona

2Endocrinology Department, Institut d'Investigació Biomèdica de Girona (IDIBGI) and CIBER Fisiopatologia de la Obesidad y Nutrición CB06/03/010; Hospital Josep Trueta, Girona

3Epidemiology Department, Hospital Sant Pau, Universitat Autònoma de Barcelona, Spain

4Internal Medicine Department, Hospital Sant Pau, Universitat Autònoma de Barcelona, Spain

 

Corresponding author: María-José Barahona, Department of Endocrinology, Hospital Mútua de Terrassa, Pl Dr Robert 5, 08221 Terrassa, Barcelona, Spain. Tel: +34-93-7365050. Fax: +34-93-7365059. Email: 33962mbc@comb.es

Funding: Supported by a grant from the Instituto de Salud Carlos III (FIS 05/0448). M.J. Barahona was supported by a fellowship from CIRIT (FI 03/1102).

Conflict of Interest: The authors do not have any conflicts of interest.

Abstract

Objective: Endogenous hypercortisolism as well as high dose and long-term glucocorticoid (GC) therapy reduce bone mass. Patients in remission after successful treatment of Cushing's syndrome (CS) often present hypoadrenalism and require long-term GC replacement. The aim of our study was to evaluate whether this GC “replacement” had any further effect on bone in women after long-term remission of CS.

 

Methods: Thirty-seven women (mean age: 50 ± 14 years, 27 of pituitary and 10 of adrenal origin) with cured CS (mean time of cure: 11 ± 6 years), 14 with active CS and 85 sex, BMI and age-matched controls, were enrolled. Bone mineral density (BMD) and bone mineral content (BMC) were measured by dual-energy x-ray absorptiometry scanning. Bone biochemical markers were also measured. Duration and dose of GC replacement, and duration of endogenous hypercortisolism were calculated.

 

Results: Cured and active CS patients had less BMC, BMD and osteocalcin than controls (p<0.01). These differences were observed in estrogen-sufficient women, but not in those with estrogen- deficiency. Duration of GC treatment (mean: 42 months (2-420)) and endogenous hypercortisolism (mean: 70 months (13-241)) negatively correlated with BMC and lumbar spine BMD. After regression analysis, the main predictor of abnormal BMC and BMD was the duration of GC replacement (p<0.01).

 

Conclusions: Patients treated for CS persistently have less bone mass despite long-term cure. Both duration of endogenous hypercortisolism and mainly exogenous “replacement” therapy with GC, negatively affect the bone mass. Thus, the additional deleterious effect of GC for the treatment of adrenal axis suppression should be considered.

 

From http://www.jbmronline.org/doi/abs/10.1359/jbmr.090505

Wednesday, May 27, 2009

RT @jensmccabe Hospitals, what would you do if a national law were passed making variance reporting part of patients' records? http://ow.ly/9uVU

Outcome of transsphenoidal surgery for Cushing's disease: A high remission rate in ACTH-secreting macroadenomas

Edward Fomekonga, Dominique Maiterb, Cécile Grandinc and Christian Raftopoulosa, Corresponding Author Contact Information, E-mail The Corresponding Author

aDepartment of Neurosurgery, Cliniques, Cliniques Universitaires Saint Luc Brussels, Université Catholique de Louvain, Belgium

bDivision of Endocrinology and Nutrition, Cliniques Universitaires Saint Luc Brussels, Université Catholique de Louvain, Belgium

cDepartment of Neuroradiology, Cliniques Universitaires Saint Luc Brussels, Université Catholique de Louvain, Belgium

Received 15 April 2008; 

revised 2 December 2008; 

accepted 24 December 2008. 

Available online 5 February 2009.

Abstract
Objective

Although numerous studies have shown that transsphenoidal surgery is the best initial treatment for Cushing disease offering 59–95% of success, fewer information is available on the long-term outcome in the subgroup of patients harboring ACTH-secreting macroadenomas. The aims of this study were to analyze our 10-year experience with transsphenoidal surgery in Cushing's disease and to examine whether remission rates were different between micro- and macroadenomas.

Patients and methods

Forty consecutive patients with proven Cushing's disease (28 microadenomas, 12 macroadenomas [diameter: 10–25 mm], 3 patients with no visible adenoma at MRI) underwent transsphenoidal surgery (TSS) assisted by neuronavigation in our center between 1996 and 2007. The diagnosis was made using standard endocrinological criteria including bilateral inferior petrosal sinus sampling (BIPSS) with CRH stimulation in all patients with discordant or equivocal biochemical and radiological testing. Morning serum cortisol was measured during the first week postoperatively, and a complete endocrine evaluation was made in all patients at 6–8 weeks. Remission at follow-up was defined as a normal postoperative 24-h urinary free cortisol (UFC) or continued need for glucocorticoid hormone replacement after TSS.

Results

Overall, 32/40 patients (80%) were in remission after one or more TSS. Interestingly, a very good remission rate (92%) was observed in the subset of macroadenomas, similar to that found in the group of microadenomas (84%, NS), while no post-surgical remission was observed in the 3 patients with no visible adenoma at MRI (p < 0.01). Of the 8 patients not in remission after repeated TSS surgery, 3 underwent radiation therapy and three had bilateral adrenalectomy, allowing remission of their hypercortisolism. There was minor morbidity and no death.

Conclusion

While our overall results are in accordance with other published series, we show here that ACTH-secreting pituitary macroadenomas are usually not associated with a bad outcome, in contrast with patients with no visible adenoma at preoperative MRI.

Keywords: ACTH; Cushing's disease; Macroadenoma; Microadenoma; Neuronavigation; Transsphenoidal surgery

Article Outline
1. Introduction
2. Patients and methods
2.1. Patient population
2.2. Endocrine evaluation
2.3. Preoperative imaging
2.4. Surgical procedures
2.5. Histopathology
2.6. Postoperative evaluation and follow-up
2.7. Statistics
3. Results
4. Discussion
5. Conclusion
References

 

From http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T5F-4VJ4FSN-2&_user=10&_coverDate=06%2F30%2F2009&_rdoc=10&_fmt=high&_orig=browse&_srch=doc-info(%23toc%235001%232009%23998889994%231024731%23FLA%23display%23Volume)&_cdi=5001&_sort=d&_docanchor=&_ct=19&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c4d08d114675404a89d36791ea547ac0

Monday, May 25, 2009

Maybe Cushing's will Be Included? New institute will study rare diseases

From http://www.reuters.com/article/healthNews/idUSTRE54J7F220090520?feedType=nl&feedName=ushealth1100&sp=true

By Maggie Fox, Health and Science Editor

WASHINGTON (Reuters) - A unique new institute will look for ways to treat rare and neglected diseases and take the first and riskiest steps toward bringing new drugs to market, U.S. health officials said on Wednesday.

Congress has provided $24 million a year for five years to start the Therapeutics for Rare and Neglected Diseases Program, or TRND at the National Institutes of Health, acting NIH director Dr. Raynard Kington told reporters in a telephone briefing.

The program will use taxpayer money to get drugs through the most costly and dangerous phase of development, known as the "Valley of Death" because so many fail there.

It will publish details of failures as well as successes to guide other researchers, the NIH said.

"Twenty-five to 30 million Americans suffer from rare or neglected diseases," Kington said.

A rare disease is one that affects fewer than 200,000 Americans, and NIH estimates there are about 6,800 of these conditions, ranging from multiple symmetric lipomatosis or Madelung's disease, characterized by large fat deposits around the neck and nervous system abnormalities, to pseudomyxoma peritonei, in which tumor cells swell up the abdomen.

Only about 200 of these conditions, many of which affect fewer than a dozen people, have treatments.

"We don't know yet exactly which diseases this program will take on," Dr. Alan Guttmacher, acting director of the National Human Genome Research Institute, told the briefing.

He said the new institute would be opportunistic, pouncing on promising research studies, some of which may be funded by advocacy groups for rare diseases.

Often drug companies are afraid to take on this work, Guttmacher added. "Getting a promising chemical through the pre-clinical stages of drug development is fraught with failure," Guttmacher said.

"It is colloquially called the "Valley of Death." This stage of drug development can take two to four years of work, costs tens of millions of dollars," and still fail, he added.

90 PERCENT FAILURE

The NIH estimates that up to 90 percent of all potential drugs fail to make it from the lab into human volunteers for safety testing.

The group will publish details even of failures -- something that rarely happens in the world of medical publishing now and a focus that can sometimes lead researchers to cover up or minimize dangers.

"We are going to tell everyone what we are doing," said Dr. Christopher Austin of the NIH Chemical Genomics Center. "That alone will be revolutionary." Early-stage research is often considered proprietary by companies.

One project that may get funding -- a potential new drug to treat schistosomiasis, which is not rare but is considered a "neglected" tropical disease. The parasite kills 280,000 people a year.

A researcher came to the NIH to test a promising new drug and the team published a study last year showing the compound -- still known only by its chemical name 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide -- may work.

"When we go to this point there were no resources to carry this project forward. This, I think, is one of the projects that we are going to put into the trend queue," Guttmacher said.

(Editing by Paul Simao)

Sunday, May 24, 2009

Hypercoagulable state in Cushing's syndrome: a systematic review.

From http://www.unboundmedicine.com/medline/ebm/record/19454584/full_citation/Hypercoagulable_state_in_Cushing%27s_syndrome:_a_systematic_review_

Author(s) :   van Zaane B, Nur E, Squizzato A, Dekkers OM, Twickler MT, Fliers E, Gerdes VE, Büller HR, Brandjes DP
Institution    Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands; Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Clinical Medicine, University of Insubria, Varese, Italy; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands; Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.


Source:    J Clin Endocrinol Metab 2009 May 19.


Abstract:    CONTEXT: It has been debated whether an increased risk of venous thromboembolism (VTE) exists in patients with Cushing's syndrome (CS).


OBJECTIVE: We aimed to summarize published literature on the effects of endogenous hypercortisolism on coagulation and fibrinolysis, as well as on the clinical outcome of VTE.


DATA SOURCES: We searched the MEDLINE and EMBASE databases up to July 2008. Review of reference lists further identified candidate studies.


STUDY SELECTION: Two investigators independently performed study selection and data extraction. Eligible studies had to include CS patients and either evaluate hemostatic parameters in comparison with control persons or post-treatment levels, or describe the occurrence of VTE.


DATA EXTRACTION: The Newcastle-Ottawa Scale was used to assess study quality. A scoring system divided studies into categories of low, medium and high quality.


DATA SYNTHESIS: Of 441 identified publications, 15 reports were included. They contained information on 8 cross-sectionals, 2 intervention- and 8 cohort studies. No high quality studies were identified. Hypercoagulability was suggested by high levels of factor VIII, IX and von Willebrand factor and evidence of enhanced thrombin generation. A risk of 1.9% and 2.5% was reported for VTE not provoked by surgery, whereas risk of post-operative VTE varied between 0 and 5.6%, with one outlier of 20%. VTE was reported as cause of death in 0-1.9% of CS patients.


CONCLUSIONS: Available studies suggest a high risk of venous thrombosis in patients with Cushing's syndrome. Glucocorticoid-induced hypercoagulability as well as surgery and obesity almost certainly contribute to this thrombotic tendency.


Language    ENG
Pub Type(s)    JOURNAL ARTICLE
PubMed ID    19454584

Free Book: MANAGEMENT OF PITUITARY TUMORS

Publisher: Humana Press
Number Of Pages: 322
Publication Date: 2003-05-14
Sales Rank: 1327003
ISBN / ASIN: 1588290530
EAN: 9781588290533
Binding: Hardcover
Manufacturer: Humana Press

Studio: Humana Press

Leading physicians share their clinical experiences in treating endocrine adenomas in United States and the United Kingdom. Discussion of treatments for prolactinoma, acromegaly, Cushing’s disease, and nonfunctioning endocrine tumors, and preoperative techniques. The clinician’s discernment of the illness, describes the undergo of diagnosis, treatment, and follow-up.

Comprehensive and accessible, Management of Pituitary Tumors: The Clinician’s Practical Guide brings information about endocrine tumors, both for novices in the specialties that control these cases, and for endocrine specialists.

 

http://www.cushings-help.com/downloads/Management_of_Pituitary_Tumors.pdf

Pituitary-thyroid feedback in a patient with a sporadic activating TSH-R mutation

From http://www.unboundmedicine.com/medline/ebm/record/19454581/full_citation/Pituitary_thyroid_feedback_in_a_patient_with_a_sporadic_activating_TSH_R_mutation:_implication_that_thyroid_secreted_factors_other_than_thyroid_hormones_contribute_to_serum_TSH_levels

Title:    Pituitary-thyroid feedback in a patient with a sporadic activating TSH-R mutation: implication that thyroid-secreted factors other than thyroid hormones contribute to serum TSH levels.


Author(s)    Gelwane G, de Roux N, Chevenne D, Carel JC, Léger J
Institution    Pediatric Endocrinology Department, Centre de Référence Maladies Endocriniennes de la Croissance and Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 690, Pediatric Biochemistry and Hormonology Unit, Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Université Paris-Diderot Paris 7, Paris, France.


Source:    J Clin Endocrinol Metab 2009 May 19.


Abstract:    Context: Constitutive mutations of the TSH receptor gene are a rare cause of severe congenital hyperthyroidism. Persistent TSH suppression has been described in euthyroid Graves' disease patients treated with antithyroid drugs. An ultra-short negative feedback loop affecting TSH secretion by activating the pituitary TSH receptor with TSH receptor autoantibodies has been suggested as a possible mechanism of TSH suppression in these patients.

Objective and Design:  To determine whether TSH suppression also occurs in euthyroid treated patients with non-autoimmune hyperthyroidism. We investigated the outcome of pituitary-thyroid feedback in a patient carrying an activating mutation of the TSH-R gene, in an observational prospective study. Repeated clinical investigations from birth until the age of 14 years are presented for the patient on drug treatment and following radical treatment.


Results: TSH was consistently undetectable or present at very low concentrations in the serum for several years, although FT4 and FT3 concentrations remained mostly in the normal range. Moreover, serum TSH concentrations increased only slightly when serum FT4 concentrations fell below normal levels. During drug treatment, serum TSH concentrations expressed as a function of serum FT4 and FT3 concentrations were significantly lower than those for control or congenital hypothyroid populations. By contrast, after radical treatment, serum TSH levels increased, reaching the normal range, and low serum FT4 and FT3 concentrations were associated with appropriate increases in serum TSH concentrations.


Conclusion: These data provide insight into the regulation of serum TSH concentrations and suggest an alternative mechanism, in addition to serum thyroid hormone levels, for adjusting TSH secretion.


Language    ENG
Pub Type(s)    JOURNAL ARTICLE
PubMed ID    19454581

New helpful endo added to Akansas http://ping.fm/eBLMC

Saturday, May 23, 2009

Cushing's and Adrenal Cancer:

Hope dies last

A 37-year-old father of two faces the dilemma of a rare cancerous disease

By Douglas Todd, Vancouver SunMay 23, 2009 at http://www.vancouversun.com/Health/Hope+dies+last/1623098/story.html

Max Rose and his wife, Stefanie WyerRose and their two sons, Cooper and Fisher, in their North Vancouver home.

Max Rose and his wife, Stefanie WyerRose and their two sons, Cooper and Fisher, in their North Vancouver home.

Photograph by: Ward Perrin, Vancouver Sun, Vancouver Sun

One of the hardest things for Max Rose to face is that he no longer has the strength to keep up with his two preschoolers, including carrying them up the stairs of the home he built in North Vancouver.

It's especially painful for the 37-year-old construction superintendent to deal with the fact one of his sons will soon be learning to ride a bicycle.

"I won't be able to run after him. That's going to be tough. I think of all the things I'd like to do with my sons, and hopefully I'll be able to. But still."

Max, who was supervising more than 100 trades workers on Vancouver's Olympic village project before he took medical leave late last year, is receiving intravenous chemotherapy for an extremely rare and virulent disease.

It's called adrenal cortical cancer.

Its rarity is part of what makes it so devastating. Since so few people are attacked by adrenal cancer, there has been virtually no research into targeted ways to treat it.

Adrenal cortical cancer strikes only one or two people per million. There are only about 600 patients throughout Canada and the U.S.

Adrenal cancer is considered an "orphan" disease because pharmaceutical companies calculate there is not enough money to be made researching drugs to combat it.

Still, U.S. Democratic Senator Edward Kennedy, who has brain cancer, is among the people leading legislative efforts that might address the dilemma of those battling rare and ultra-rare cancers.

The fight against the clock is on for Max and those who love him.

Last November, when doctors finally figured out why Max was suddenly gaining weight, feeling tired and bruising easily, his adrenal cancer was discovered to be stage four, the most serious stage.

Since the cancerous tumours were too advanced for surgery, he was told it would be unusual for him to live more than a year. His treatment is considered palliative.

Max was undergoing his third round of intravenous chemotherapy when I talked to him and his wife, Stefanie WyerRose, in the combined living- room/kitchen of their airy home.

"I'm trying to stay as positive as I can. I can do that or I can be negative and curl up in the fetal position and give up, which I'm not going to do," said Max, sitting on a couch with energetic Cooper, 2, and Fisher, 1, bustling nearby.

Members of Max's extended family, including his father Chris Rose, a former Vancouver Sun editor, are doing everything they can to improve his chances.

Max's wife of six years, who overcame her own bout of skin cancer almost five years ago, has been doggedly researching adrenal cancer and pressing for more research and better treatment regimens.

But Max and those who care about him are coming face-to- face with a major obstacle in the Canadian and international medical communities.

It relates to the ethics of triage.

That's the system of medical rationing that began on battlefields, where emergency doctors, nurses and resources were often in short supply.

Triage ethics developed with harsh simplicity: The soldiers considered most treatable were helped first. Those with the most grievous wounds were left until last, since their chances of survival were already poor.

Triage thinking continues to influence the apportioning of medical resources in North American society, where dollars are not infinite.

Sometimes it's called the ethics of scarcity.

Still, people like Stefanie are working hard for Max and others with adrenal and related rare cancers -- to raise their odds.

They have allies throughout the world. They also have ideas for reform.

RANDOM MISFORTUNE

There are so many difficult things about the life-and-death struggle Max and his family are enduring. Most are existential: the pure random misfortune of being struck with this unusual cancer of the adrenal endocrine glands, which are located above the kidneys.

Max's adrenal tumours were found last fall to have spread to his left liver and lungs.

Other difficulties relate to the medical system. For reasons related to the rarity of adrenal cancer, Max wasn't diagnosed early.

If medical personnel had discovered sooner that his symptoms, including Cushing's syndrome, were signalling something more serious, the cancer would have been more treatable.

When Max was interviewed in late March in his home in south Lonsdale, a cherry tree was blossoming in the yard. Corners of the shiny hardwood floors were covered with the toy trucks and diggers that, true to their dad's vocation, Max's sons like so much.

Max misses his career at Metro-Can Construction Ltd. He has supervised the building of Vancouver's Chan Centre for the Performing Arts, SkyTrain extensions and other high-profile projects.

"It's really hard not working. I worked with those guys for 15 years. I made longtime friendships."

The cheery brightness of the living room, and the innocent lack of awareness of the children, belied Max and Stefanie's inner struggles.

Despite his fatigue, Max was gracious, quick-witted and brave. And he and Stefanie had one bit of good news to pass on, the first in months.

A CT scan had shown that one of Max's adrenal gland tumours had shrunk by three centimetres. Another one, on his liver, may also have decreased.

The fairly standard cancer treatment Max has been receiving from his oncologist, Dr. Sasha Smiljanic, was having some effect. But the treatment is not particularly targeted to adrenal cancer, since the disease is not well understood.

Max's prognosis remains grim. "It's like somebody pulled a rug out from underneath your feet." To add to the extended family's plight, Max's stepfather has grave prostate cancer.

Stefanie, who works as a judicial assistant at B.C. Supreme Court, wears a purple "AC Warriors" bracelet to highlight the cause of adrenal cancer.

The family has been joined in the campaign to raise awareness for it and other rare diseases by two of the few British Columbians struggling with adrenal cancer.

Megan McNeil, 18, of North Delta, has recorded a song with Nickelback producer Garth Richardson to support cancer victims. It's titled, The Will to Survive. (Unlike Max, McNeil has been able to benefit from surgery.)

Another British Columbian with adrenal cancer, Victoria-based wildlife biologist Karen Truman, is raising money for the B.C. Cancer Agency, but said she's disappointed she's not allowed to divert the money to rare-cancer programs.

Both Max's family and Truman discovered on their own that a scientist at the University of Michigan, Dr. Gary Hammer, is one of the few experts on adrenal cancer in the world.

Truman, whose stage two adrenal cancer is not as advanced as Max's, paid out of her own pocket to fly to Michigan. Max paid to have his pathology report sent there.

Hammer, who is experimenting with genetically based treatments for adrenal cancer, provided the medical analysis that led to Max's current chemotherapy regimen, which he receives at Lions Gate Hospital.

Smiljanic, the oncologist who treats Max, says "there is a really heated debate" about whether rare-cancer patients like Max should receive travel costs to visit specialized treatment centres.

"In the policy area, the question is where do you draw the line?" said Smiljanic.

The B.C. Cancer Agency, said Smiljanic, has 40 to 50 oncologists treating patients with breast, colon and other common cancers with programs "that are the envy of other parts of the world."

But Canadians with rare cancers aren't in as strong a position as those with common cancers, in part because they "don't have a strong lobby group," said Smiljanic, who never had a patient with adrenal cancer until he met Max.

If Smiljanic was in Max's shoes, he'd consider enrolling in an experimental clinical trial for adrenal cancer, such as those at the University of Michigan. Max, however, would have to pay for his own travel and accommodation.

'A PRICE ON LIFE'

Simon Fraser University applied ethicist Mark Wexler has nothing but empathy for Max and his family.

They are doing their duty, he said, which is to do whatever they can to quickly get the best possible treatment.

However, Max is running into a wider ethical conflict: Even though our culture says every human life is "invaluable," society still places limits on how much to spend on an ailing individual.

"Some people ask, 'Isn't it hypocritical to admit we actually put a price on life?' " said Wexler.

But the hard reality is that society does put an economic value on a human life -- in a way reminiscent of so-called lifeboat ethics.

If there is only so much room in a lifeboat to save those who are drowning, if there is only so much money to help the sick, Wexler said society is forced to decide who is allowed on the lifeboat.

University of Victoria medical ethicist Eike Kluge agrees with Wexler that health care systems can't devote unlimited resources to people with rare cancers, while taking away from broader programs.

Kluge, who is being treated for prostate cancer, feels wholehearted sympathy for Max. Still, the professor of applied ethics said: "I often have to tell my students that not everything that is tragic is unethical."

Dr. Charles Blanke, who heads the B.C. Cancer Agency's systemic therapy program, said one of the hardest questions the organization has to face is how to fairly parcel out limited resources "so everybody gets at least a share of the pie."

Even though the B.C. Cancer Agency is covering Max's chemotherapy and will pay for out-of-province treatment, Blanke said the B.C. government won't pay for Max's travel and accommodation costs to attend clinical trials.

If Max isn't able to finance his own travel to specialized treatment programs, Blanke said Max could complete his chemotherapy treatment and then, depending on the outcome, seek a referral to the Vancouver Cancer Centre.

Some oncologists at the Vancouver Cancer Centre focus on rare cancers, Blanke said, and could, "on a case-by-case basis," try to provide targeted or even "highly experimental" treatment.

Still, the problem remains that adrenal cancers, unlike common cancers, don't have proven treatment programs.

LEVEL THE PLAYING FIELD

In a North American society that so strongly emphasizes economic gain, patients with rare diseases can be left behind, said the University of Michigan's Hammer.

In an effort to aid those with rare cancers, Hammer has been busily consulting with officials connected to the proposed Cancer Alert Act in the U.S.

The Alert Act is being brought before the House of Congress by Kennedy and Republican Senator Kay Hutchinson. It calls for increased funding for research and treatment of cancer, including rare and ultra-rare cancers.

It makes sense, Hammer said, that armies of researchers around the world are focusing on common cancers, like that of the breast and prostate. Breast cancer takes the lives of about 45,000 North Americans a year, while prostate cancer kills roughly 30,000.

"But it leaves other patients with rare cancers as orphans, with little hope for research into their diseases let alone treatment. How do you level the playing field somewhat?

"And how do you do that without breaking the bank? Our society and medical system shouldn't be based on only the survival of the fittest, on only social Darwinism."

Hammer has a series of arguments for increasing society's emphasis on rare cancers, which include those of the adrenal glands, saliva glands and tongue.

Hammer's first argument is that some of the most important advances in the field of cancer have been made studying rare cancers.

Discovering a targeted genetic-based therapy for adrenal cancer, which Hammer is working on through two clinical trials, could also help those with testicular and ovarian cancers.

Secondly, Hammer believes financial incentives could encourage research into uncommon diseases.

Government regulators, for instance, could approve rare-cancer drugs that are proven to shrink tumours even if they do not ensure long-term survival.

Pharmaceutical companies, he added, could also be given longer times to hold exclusive patents on drugs they discover to treat rare diseases.

Perhaps most importantly, Hammer calls for the establishment of rare-cancer "centres of excellence."

Since so few doctors in the world specialize in rare cancers, he thinks society's research and treatment efforts should be focused on leading international centres.

"Patients could be sent to wherever there is a centre of excellence. There could be reciprocal agreements between centres and even states and countries."

Some insurance companies have already financed sending adrenal-cancer patients to Hammer in Michigan. Other patients have paid out of their pockets.

Even though Dr. Smiljanic would support Max going to the University of Michigan, he cautioned it would not necessarily solve Max's rare-cancer dilemma. That's because taking part in clinical trials can be hit and miss.

It's possible, Smiljanic said, Max could end up, without his knowledge, in a "blind" control group that simply receives the "old treatment" for cancer -- not the targeted genetics-based treatments, which are themselves unproven.

Still, such clinical programs are important, at least for others.

"Sometimes the people who take part in clinical trials don't get to reap the benefits themselves," Smiljanic said. "But they will benefit someone in their situation in the future."

FIGHT FOR HIS LIFE

Despite the ethical, financial and political complexities around finding a targeted treatment for people with rare cancers, SFU ethicist Wexler is "totally supportive" of Max's family's efforts to fight for his life.

Families, Wexler said, operate by an unwritten code that says parents should die before their children. Max's loved ones, he said, are utterly justified in seeking help from whatever "deep pockets" they can, including government and private donors.

For his part, Max is not about to give up.

And he says he's not afraid. His attitude, and that of those around him, is reminiscent of the Russian proverb, "Hope is the last to die."

Max notes with a smile that doctors are surprised he has not lost his thick red hair from his chemotherapy treatments. "I tell them it's because I'm too stubborn."

Max also appreciates "the one good thing" to come with his excruciating diagnosis -- he's able to spend extra time with his sons.

Max knows what he's up against with his little-understood disease. He knows how medical rationing works. He's been told his chances.

But he's looking forward to a fishing trip this June near Merritt with his dad, stepbrother and father-in-law. And he's treasuring every moment with his family.

Everyone who cares about Max is yearning for him, and others like him.

They are realistic, but they will never stop hoping.

For many more springs.

Read Douglas Todd's blog at www.vancouversun.com/thesearch

© Copyright (c) The Vancouver Sun

Wednesday, May 20, 2009

May 20, 2009 Cushing's Help and Support Newsletter

In This Issue

Welcome to the latest Cushing's Newsletter!

Cushie Bloggers

Upcoming Interviews

Upcoming Meetings

Podcasts

Cushing's on Facebook and Twitter

Media: Follow up to last week

Want to Volunteer?

Robin writes: Adult Onset Growth Hormone Deficiency: Phenotype and Benefits of Treatment

Video: Cushing Syndrome

Clinical Trials

Help Keep The Cushing's Sites Going

The Endocrine System

Endo News: Diagnosing Cushing’s syndrome

Endo News: Cushing’s syndrome (Hypercortisolism) from NLE Review Bullets

Endo News: Back Pain and Cushing's

Endo News: Pituitary-directed medical treatment of Cushing’s disease

Endo News: About Cushing's from OHSU

Endo News: Untreated Growth Hormone Deficiency Contributes to the Phenotype of Patients With History of Cushing's Disease

Robin writes...

New and Updated Bios
New Bio May 16, 2009
Melanie (Melanie W)
is from Oklahoma. She has many Cushing's symptoms and has been diagnosed with PCOS and mild hypothyroidism so far.
New Bio May 15, 2009
Shirley (SBett)
is from Ronan, Montana. After 6 years her doctor finally found a pituitary tumor on an MRI. She is testing and has high cortisol and growth hormone.
New Bio May 13, 2009
Jodi (Jodi)
is from Rochester, Michigan. She had surgery to remove half her pituitary. She is now having issues with adrenal insufficiency.
New Bio May 12, 2009
angelp (angelp)
is from London, England. She had her first pituitary surgery in January 2009 and a second in March 2009. She will have an adrenalectomy and radiotherapy to remove the rest of her pituitary tumor.
New Bio May 11, 2009
Sue (Sue)
is from Lombard, Illinois. She has many Cushing's symptoms and her cortisol levels are very high but the source of her Cushing's hasn't been found yet.
New Bio May 10, 2009
Kate (kate22)
is from Richmond, Virginia. She is not yet diagnosed with Cushing's but she is testing. She has many Cushing's symptoms.
New Bio May 10, 2009
Angie (dermpat)
is from Melbourne, Australia. She is not yet diagnosed with Cushing's but is testing for cyclic Cushing's.
New Bio May 10, 2009
Vanessa
is from Phoenix, Arizona. She has recently been diagnosed with a pituitary tumor and is looking for an endo.
New Bio May 10, 2009
Rachael (RachaelB)
is from Charlotte, North Carolina. She was recently diagnosed with Cushing's and will be having her pituitary tumor removed in August.
New Bio May 4, 2009
Shiloh (Shiloh)
is from Fort Collins, Colorado. She is not formally diagnosed. She is trying to manage her symptoms with healthy eating, massage and acupuncture.
New Bio May 3, 2009
Luisa (Luisa)
is from Knoxville, Tennessee. She was originally misdiagnosed with PCOS and is testing for Cushing's currently.
New Bio May 1, 2009
Song
is temporarily outside of U.S.A. She is not yet diagnosed. Someone at a party saw her buffalo hump and asked is she knew about Cushing's. Her own research says she might have this and testing shows elevated cortisol.
New Bio May 1, 2009
Alisha (gbsawyer)
is from Kirksville, Missouri. She is not yet diagnosed but has many symptoms and is seeing a new endo.
New Bio April 30, 2009
Lulu
is from Corona, California. She had transnasal surgery 10/2007 and stereotactic surgery 8/2008. Both surgeries have failed. She tried Ketoconozole for a month and ended up in the hospital because the medication was affecting her liver. She is currently doing nothing for her Cushing's.
New Bio April 29, 2009
Melissa (meltizzle)
is from Santa Fe Springs, California. She was recently diagnosed with Cushing's and thinks she had it since 2007.
New Bio April 29, 2009
Aly
is from Arizona. She has had diabetes for 18 years and is a brand new mom. About two years ago she started getting Cushing's symptoms and is scheduling adrenal surgery.
New Bio April 27, 2009
Patty (pattycakes)
is from Cincinnati, Ohio. She has many Cushing's symptoms but doctors are calling her pituitary tumor a Rathke Cleft cyst so she is still trying to get answers.
New Bio April 24, 2009
McCall (McKenzie)
is from Fairfax, Virginia. She was diagnosed with central adrenal insufficiency after an ITT (Insulin Tolerance Test) and is taking 15mg of Hydrocortisone a day for the ACTH replacement therapy. She is wondering if it is possible to have both adrenal insufficiency AND Cushing's.
New Bio April 22, 2009
Kirsty (kirstymnz)
is from Hamilton, New Zealand. Her doctors couldn't find the source of her ectopic Cushing's. She had a lung nodule but removal didn't help so she had a BLA (bilateral adrenalectomy).
New Bio April 22, 2009
Jeff (akflier)
is from Palmer, Alaska. He was diagnosed with pituitary Cushing's in July 2008 and had surgery in August 2008.

New and Updated Bios

Tuesday, May 19, 2009

Diagnosing Cushing’s syndrome

From http://www.onmedica.com/NewsArticle.aspx?id=bed82431-f024-423e-bd4c-7dc0a4fcfbd6

Louise Newson, general practitioner, Solihull. Reviewed by Andrew Krenz, endocrinologist, Southampton.

Tuesday, 19 May 2009.

Key learning points

  • The commonest cause of Cushing’s syndrome is iatrogenic
  • 2% of obese, poorly controlled patients with type 2 diabetes diabetes type 2 diabetics may have Cushing’s syndrome
  • Various biochemical tests are needed for diagnosis; this is complex and requires specialist expertise.
  • The underlying cause of Cushing’s syndrome needs to be determined
  • Treatment and prognosis depend on the underlying cause.
  • Surgery is the treatment of choice for Cushing’s disease i.e. pituitary-dependent

The adrenal cortex produces glucocorticoids including cortisol which affect metabolism of carbohydrate, lipid and protein as well as mineralocorticoids in the form of aldosterone. Both steroid axes are controlled by negative feedback.

Cushing’s syndrome is the term used to describe the clinical state of increased free circulating glucocorticoid concentrations.

Aetiology

Traditionally, the incidence of Cushing’s syndrome is quoted as 1/250,000, with no specific geographical variation. However, more recent data suggest that 3–5% of all obese, hypertensive individuals with type 2 diabetes may have Cushing’s syndrome, and actually experience improve­ment in metabolic control following intervention1. Thus, clinicians should have a high index of suspicion in this patient group.

Cushing's syndrome due to an adrenal or pituitary tumour is more common in females (ratio 5:1). The peak incidence of Cushing syndrome caused by an adrenal or pituitary adenoma is between the ages of 25 and 40 years.

The commonest cause of Cushing’s syndrome is iatrogenic from administration of high doses of glucocorticoids.

Causes of Cushing’s syndrome

Causes of Cushing’s syndrome are divided into two groups:

ACTH-dependent disease

  • Pituitary adenoma (Cushing’s disease) – 65% of cases
  • Ectopic ACTH-producing tumours – 10% of cases
  • ACTH administration (rarely given now)

Non-ACTH-dependent causes

  • Adrenal adenomas or hyperplasia – 25% of cases
  • Adrenal carcinomas
  • Glucocorticoid administration

Ectopic ACTH production usually arises from malignancy, especially small cell carcinoma of the lung and carcinoid tumours, especially of the lung.

Figure 1: A hyperplastic adrenal gland taken from a patient with Cushing's syndrome.

cushings-adrenal

Figure 2: An adrenocortical adenoma from a patient with Cushing's syndrome.

cushings-adrenal-adenoma

Clinical features

The predominant clinical features of Cushing’s syndrome are those of glucocorticoid excess as listed in the table below.

Table 1: Symptoms and signs of Cushing’s syndrome.

Symptoms

Signs

Weight gain

Plethora

Depression

Central obesity

Insomnia

Osteoporosis

Amen/oligomenorrhoea

Moon face

Poor libido

“Buffalo hump” / kyphosis

Thin skin / easy bruising

Bruising / striae / thin skin

Hair growth / acne

Hirsuitism / acne

Muscle weakness

Proximal myopathy

Polyuria / polydipsia

Glycosuria

Presentation is common to all aetiologies, although syndromes caused by ectopic ACTH may be a little different. Pigmentation only occurs in patients with ACTH-dependent causes. Pigmentation is most marked with ectopic production of ACTH.

Typical features of ectopic ACTH production include pigmentation (due to melanocyte stimulating hormone production as a byproduct of ACTH synthesis), weight loss, hypokalaemia, metabolic alkalosis and hyperglycaemia. Classical features of Cushing's syndrome, especially weight gain, are often absent. As this tends to occur at a later age than Cushing's disease, if the syndrome develops later in life, a carcinoma should be excluded as an underlying cause.

Note: A cushingoid appearance can be due to alcohol excess (pseudo-Cushing’s syndrome). The pathophysiology of this is poorly understood.

Impaired glucose tolerance or even diabetes mellitus are common, especially in the ectopic ACTH syndrome. Patients also suffer from psychological disturbances where depression and anxiety are common.

Figure 2: A patient with Cushing's syndrome showing signs of acne and hirsuitism.

cushings-hisuitism

Figure 3: Striae in a patient with Cushing's syndrome.

cushings-striae

Investigations

Confirmation of Cushing’s syndrome needs to be performed using investigations, it is not a clinical diagnosis. Most obese, and/or hypertensive patients do not have Cushing’s syndrome2.

It is important to note that random cortisol measurements are of no value in the diagnosis of Cushing’s syndrome.

Oral oestrogens increase cortisol-binding globulin and therefore lead to falsely elevated serum cortisol levels. They should be stopped for six weeks before investigation. It would be prudent to involve a specialist should this situation occur.

The three main investigations to confirm the diagnosis of Cushing’s syndrome include:

  • 24-hour urinary free cortisol (can be checked in primary care)
  • low-dose dexamethasone suppression test
  • midnight plasma or salivary cortisol

The latter two usually require specialist input.

Low-dose dexamethasone suppression test – the two tests commonly used are as follows:

  • 1 mg overnight (dexamethasone, 1 mg, is given at 11:00 p.m. and serum cortisol measured at 9:00 a.m. the next day)
  • 48-hour test (dexamethasone, 0.5 mg, is given at 9:00 a.m., 3:00 p.m., 9:00 p.m. and 3:00 a.m. and serum cortisol measured at 9:00 a.m. at the start and end of the test).

In healthy people, serum cortisol is less than 50 mmol/litre following either test. The 48-hour test is more accurate.

Midnight plasma cortisol – the normal circadian rhythm of cortisol level is lost in Cushing’s syndrome. Following admission to hospital for 48 hours, a single sleeping midnight plasma cortisol level of more than 50 mmol/litre is the most sensitive indicator of Cushing’s syndrome.

Late-night salivary cortisol is an alternative to midnight plasma cortisol, with a slightly lower sensitivity. These samples are easier to obtain as do not require a hospital admission.

Urinary free cortisol – although this test is in widespread use it has a low sensitivity; at least three or four collections are required to avoid missing mild disease. The specificity is also poor as the cortisol levels obtained overlap those found in patients with depression or polycystic ovary syndrome.

Tests to diagnose the cause of Cushing’s syndrome

This can be very difficult as all causes can results in clinically identical Cushing’s syndrome. Differentiation can be difficult even by experts.

Following confirmation of Cushing’s syndrome, the next step is measurement of plasma ACTH.

If plasma ACTH levels are less than 5 pg/ml then a primary adrenal cause is likely. Imaging of the adrenals with CT or MRI is then the appropriate next step3.

If levels of ACTH are persistently more than 15 pg/ml then an ACTH-dependent pathology is likely and the patient will require further investigations as discussed below.

Levels of 5–15 pg/ml require cautious interpretation, because individuals with Cushing’s disease may have plasma ACTH of less than 10 pg/ml. At least two or three estimations are made, to avoid inappropriate classification.

ACTH-dependent Cushing’s syndrome – further tests

Biochemical evaluation, rather than imaging, should be relied on to differentiate pituitary from non-pituitary sources of ACTH with the following tests:

High-dose dexamethasone suppression test

Tumours caus­ing Cushing’s disease (pituitary pathology) typically retain some responsiveness to the suppressive effects of glucocorticoids, whereas tumours causing ectopic ACTH secretion usually do not.

This is the rationale for the high-dose dexamethasone suppression test. In about 80% of patients with Cushing’s disease, cortisol is reduced to less that 50% of the basal level.

Corticotrophin-releasing hormone (CRH) test

CRH stimu­lates release of ACTH from the corticotrophs of the anterior pitui­tary. Patients with Cushing’s disease typically exhibit an excessive increase in plasma cortisol, whereas those with ectopic ACTH secretion usually do not.

Imaging in ectopic ACTH secretion – the most common sites of ectopic ACTH secretion are small cell lung cancers and bronchial carcinoid tumours. High-definition, multi-slice CT of the chest is required. Carcinoid tumours often express somatostatin receptors and may be visualized on radiolabelled octreotide or lanreotide scintigraphy.

Pituitary imaging

If a pituitary source is likely, CT or MRI of the pituitary is the next investigation but sensitivity is not high.

However, around 40% of corticotroph microadenomas are not visualized with a MRI scan and ‘incidentalomas’ are found in 10% of the healthy population. Therefore biochemical assessment of patients is extremely important.

Bilateral inferior petrosal sinus sampling is a highly spe­cialised, invasive investigation, but is the most reliable test for differentiating pituitary and non-pituitary sources of ACTH.
Management

The cause must be addressed.

Iatrogenic

If the cause is iatrogenic, the prescription must be reviewed. There will be a medical need for the steroids but it may be possible to use "steroid sparing" drugs to reduce the dose. More than 7.5 - 10 mg/day (or equivalent in other steroids) may produce Cushings. It is dose-response.

Pituitary Adenoma (Cushing’s disease)

Surgery

Trans-sphenoidal selective microadenomectomy by an experienced surgeon is the treatment of choice in most patients with Cushing’s disease. Long-lasting remission without other pituitary hormonal deficiency is achieved in 50–60% of cases.

Following the operation, ACTH levels fall below normal. This is temporary, but hydrocortisone or prednisolone replacement must be given to avoid acute hypoadrenalism. Most patients can stop this replacement therapy in less than a year. A steroid card including education about intercurrent illness should be given to the patient.

Medical treatment

Medical therapy to lower cortisol may be used in preparation for surgery or after unsuccessful surgery. It may also be used with pituitary radiotherapy. It is only rarely given long-term.

Metyrapone and ketoconazole are often used to inhibit cortisol synthesis. Metyrapone causes an increase in steroid androgenic precursors, and hirsutism is a major adverse effect in women; this does not occur with ketoconazole.

Radiotherapy

Where transphenoidal surgery has failed or in patients who are unsuitable candidates for surgery, radiotherapy is another possible treatment.

Progressive anterior pituitary failure is the major side-effect; growth hormone deficiency is present in almost all patients 10 years after treatment and gonadotrophin deficiency in about 15%. About four years after treatment, 80% of patients are in remission with respect to circulating plasma cortisol levels. Patients must be evaluated by specialist with regular follow up to identify deficiences early.

Adrenal tumours

Surgery for adrenal adenomas is usually curative but carcinomas have a much worse prognosis. Adrenal adenomas are usually removed by a laparoscopic unilateral adrenalectomy4.

Micronodular or macronodular hyperplasia is usually treated by bilateral total adrenalectomy as leaving any gland will often lead to recurrence.

Ectopic ACTH production

This may be treated by surgery if the tumour can be located and has not metasasized

Prognosis

Untreated Cushing’s syndrome has a very poor prognosis. Patients with incompletely controlled Cushing's syndrome have a five-fold excess mortality5.

However, with treatment the results are very good unless there is underlying malignancy.

As many studies have shown that a relatively high number of diabetic patients may have unsuspected Cushing's syndrome, one study has even suggested that it may be worthwhile actually screening for Cushing’s syndrome may be feasible at the clinical onset of diabetes6. Clearly this would only be reserved for cases with a high level of suspicion.

Video 1: A summary of Cushing's syndrome occuring in children with discussion about the aetiology.

Video 2: A US based case history illustrating a patients journey through diagnosis of Cushing's disease to surgical treatment on her pituitary gland.

References

1. Catargi B, Rigalleau V, Poussin A et al. Cushing’s syndrome in type-2 diabetes. J Clin Endocrinol Metab 2003; 88: 5808–13.

2. Newell-Price J, Bertagna X, Grossman AB, et al; Cushing's syndrome. Lancet. 2006 May 13;367(9522):1605-17.

3. Rockall AG, Babar SA, Sohaib SA, et al; CT and MR imaging of the adrenal glands in ACTH-independent cushing syndrome. Radiographics. 2004 Mar-Apr;24(2):435-52.

4. Chow JT, Thompson GB, Grant CS, Farley DR et al. Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing's syndrome: a review of the Mayo Clinic experience. Clin Endocrinol 2008;68(4):513-9.

5. Newell-Price J, Bertagna X, Grossman AB, et al; Cushing's syndrome. Lancet 2006;367(9522):1605-17.

6. Reimondo G, Pia A, Allasino B, Tassone F, et al. Screening of Cushing's syndrome in adult patients with newly diagnosed diabetes mellitus. Clin Endocrinol 2007;67(2):225-9.

Further reading

Association for Cushing's Treatment and Help: A support group for people suffering from all forms of Cushing's syndrome.

Pituitary Foundation - Supports pituitary patients and their carers.

Author and reviewers competing interests: none.

Images: Wellcome.

Monday, May 18, 2009

9 new Cushing's bios added. 5 pituitary, 4 not yet diagnosed but testing. http://ping.fm/d1rDq

Health Alert: Adrenal Crisis Causes Death in Some People Who Were Treated With hGH

Recently, doctors conducting the follow-up study of individuals treated with hGH looked at causes of death among recipients and found some disturbing news. Many more people have died from a treatable condition called adrenal crisis than from CJD. This risk does not affect every recipient. It can affect those who lack other hormones in addition to growth hormone. Please read on to find out if this risk applies to you. Death from adrenal crisis can be prevented.

Adrenal crisis is a serious condition that can cause death in people who lack the pituitary hormone ACTH. ACTH is responsible for regulating the adrenal gland. Often, people are unaware that they lack this hormone and therefore do not know about their risk of adrenal crisis.

Most people who were treated with hGH did not make enough of their own growth hormone. Some of them lacked growth hormone because they had birth defects, tumors or other diseases that cause the pituitary gland to malfunction or shut down. People with those problems frequently lack other key hormones made by the pituitary gland, such as ACTH, which directs the adrenal gland to make cortisol, a hormone necessary for life. Having too little cortisol can be fatal if not properly treated.

Treatment with hGH does not cause adrenal crisis, but because a number of people lacking growth hormone also lack ACTH, adrenal crisis has occurred in some people who were treated with hGH. In earlier updates we have talked about how adrenal crisis can be prevented, but people continue to die from adrenal crisis, which is brought on by lack of cortisol. These deaths can be prevented. Please talk to your doctor about whether you are at risk for adrenal crisis.

  • Why should people treated with hGH know about adrenal crisis? Among the people who received hGH, those who had birth defects, tumors, and other diseases affecting the brain lacked hGH and often, other hormones made by the pituitary gland. A shortage of the hormones that regulate the adrenal glands can cause many health problems. It can also lead to death from adrenal crisis. This tragedy can be prevented.
  • What are adrenal hormones? The pituitary gland makes many hormones, including growth hormone and ACTH, a hormone which signals the adrenal glands to make cortisol, a hormone needed for life. If the adrenal gland doesn't make enough cortisol, replacement medications must be taken. The most common medicines used for cortisol replacement are:
      • Hydrocortisone
      • Prednisone
      • Dexamethasone
  • What is adrenal crisis? Adrenal hormones are needed for life. The system that pumps blood through the body cannot work during times of physical stress, such as illness or injury, if there is a severe lack of cortisol (or its replacement). People who lack cortisol must take their cortisol replacement medication on a regular basis, and when they are sick or injured, they must take extra cortisol replacement to prevent adrenal crisis. When there is not enough cortisol, adrenal crisis can occur and may rapidly lead to death.
  • What are the symptoms of lack of adrenal hormones? If you don't have enough cortisol or its replacement, you may have some of these problems:
    • feeling weak
    • feeling tired all the time
    • feeling sick to your stomach
    • vomiting
    • no appetite
    • weight loss

When someone with adrenal gland problems has weakness, nausea, or vomiting, that person needs immediate emergency treatment to prevent adrenal crisis and possible death.

•  Why are adrenal hormones so important? Cortisol (or its replacement) helps the body respond to stress from infection, injury, or surgery. The normal adrenal gland responds to serious illness by making up to 10 times more cortisol than it usually makes. It automatically makes as much as the body needs. If you are taking a cortisol replacement drug because your body cannot make these hormones, you must increase the cortisol replacement drugs during times of illness, injury, or surgery. Some people make enough cortisol for times when they feel well, but not enough to meet greater needs when they are ill or injured. Those people might not need cortisol replacement every day but may need to take cortisol replacement medication when their body is under stress. Adrenal crisis is extremely serious and can cause death if not treated promptly. Discuss this problem with your doctor to help decide whether you need more medication or other treatment to protect your health.

•  How is adrenal crisis treated? People with adrenal crisis need immediate treatment. Any delay can cause death. When people with adrenal crisis are vomiting or unconscious and cannot take medicine, the hormones can be given as an injection. Getting an injection of adrenal hormones can save your life if you are in adrenal crisis. If you lack the ability to make cortisol naturally, you should carry a medical ID card and wear a Medic-Alert bracelet to tell emergency workers that you lack adrenal hormones and need treatment. This precaution can save your life if you are sick or injured.

•  How can I prevent adrenal crisis?

•  If you are always tired, feel weak, and have lost weight, ask your doctor if you might have a shortage of adrenal hormones.

•  If you take hydrocortisone, prednisone, or dexamethasone, learn how to increase the dose when you become ill.

•  If you are very ill, especially if you are vomiting and cannot take pills, seek emergency medical care immediately. Make sure you have a hydrocortisone injection with you at all times, and make sure that you and those around you (in case you're not conscious) know how and when to administer the injection.

•  Carry a medical ID card and wear a bracelet telling emergency workers that you have adrenal insufficiency and need cortisol. This way, they can treat you right away if you are injured.

Remember: Some people who lacked growth hormone may also lack cortisol, a hormone necessary for life. Lack of cortisol can cause adrenal crisis, a preventable condition that can cause death if treated improperly . Deaths from adrenal crisis can be prevented if patients and their families recognize the condition and are careful to treat it right away. Adrenal crisis is a medical emergency. Know the symptoms and how to adjust your medication when you are ill. Taking these precautions can save your life.

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From http://endocrine.niddk.nih.gov/pubs/creutz/alert.htm