Download MetabolIsM, enDocrInology & DIabetes DePartMent of Internal MeDIcIne facUlty thyroid Problems:

M etabo li s m , E n d o c r i n o lo g y & D i a b etes
D e pa rtm e n t of I n te r n a l Me di c i n e Fac ulty
Thyroid Problems:
More than the Usual Pain in the Neck
It’s shaped like a bow tie, and it sits right where such
a tie would be worn—at the front of the throat. But the
thyroid gland is anything but decoration.
In fact, it’s one of the master glands of the body,
sending out signaling hormones that help control
everything from heart rate and blood pressure to our
body temperature, metabolism, and weight.
But as with many organs in the body, things can go
wrong. In fact, the thyroid gland is the single most
common organ to be attacked by autoimmune disease.
That’s part of the reason that the thyroid is so
interesting to doctors and scientists in the division
of Metabolism, Endocrinology & Diabetes (MEND),
like Ronald Koenig MD, PhD. Of all the physicianscientists in the MEND division, Dr. Koenig uniquely
specializes in two widespread and terribly serious
thyroid problems: abnormal thyroid hormone levels
in critically ill patients, and thyroid cancer, which
kills more than 1,500 Americans yearly.
“Doc, I can’t understand it, if the
problem is not in my thyroid, then
why are my thyroid hormone levels
so low?”
Through research, Dr. Koenig and others
have found that abnormal thyroid gland
function is linked to many other illnesses
that seemingly have nothing to do with it. It’s
often associated with a profound downward
spiral in a patient’s health status—particularly in
critically ill patients in the intensive care unit.
Amazingly, virtually every patient with any serious
disease or injury develops thyroid dysfunction during
the course of their illness. Once upon a time, this
might even have been a good evolutionary strategy,
allowing our ancestors to conserve energy when they
were seriously sick or injured.
Above: Each ball represents one thyroid cancer patient
in Dr. Koenig’s study, and the colors represent different
types of thyroid cancer. For example, the orange balls are
papillary thyroid cancers, the green are follicular thyroid
cancers that lacks the PPFP fusion gene, and the red are
follicular thyroid cancers with the PPFP fusion gene. The
positions of the balls represent the patterns of genes turned
on or off in the cancers—the closer the balls, the more similar the patterns of gene expression. The red balls are far
removed, indicating their unique pattern of gene expression, due to the unique properties of PPFP.
Left: Ronald Koenig, MD, PhD
Row 1:
Halter, Brosius, Cooney, Del Valle, Rabbani, Berling, Todd, Osta, Slocum, Margolis, Owyang, Arvan
Row 2:
Platchek, Choski, Abdallah, Kolman, Gandhi, Nichols, Vazirani, McMahon, Kazanjian, Laing, Graham, Grum, Moseley, Baker, Trese, Bakhru, Vredeveld, Wang
Row 3: Tahir, Jordan, Chang, Kim, Bonham, Marks, Proud, Boldenow, Wyckoff, Howe, White, R. Parekh, Muza-Moons, Sisson, Zen, Welch, Bittenbender, Working, Greenstone
Rows 4-5: Mahmood, Park, McCune, Oman, Stardsta, Krijanovkis, Van Poznak, Schneider, Yung, Esfandiari, Lundy, Kuhne, McNamara, Jongnarangsin, Jensen, Buckley, Nichani,
Roychowdhury, Chakrabarti, Dele-Michael, Good, V. Parekh, Rubenfire, Blayney, Meddings, Reineck, Keirns, Aaronoff, Young, Peters-Golden, Markovitz, Engleberg,
Miller, Petty, Burnstein, Akin, Barnes, Pickrul, Griggs
Rows 6-7: Leichtman, Rao, Norman, Awais, Segal, Fernandez, DeBenedet, Bogdasarian, Dave, Shiran, Zhang, Chick, Weber, Mangrulkar, Gafoor, Kaul, Gitlin, Flanders, Curtis,
Buschur, Cease, Piersma, Rich, Hyzy, Moore, Huffnagle, Grant, Plaisance.
Table of Contents
But in the modern era of intensive-care unit medicine,
physicians are beginning to suspect that the mechanism works against us.
Chair’s Report . . . . . . . . . . . . . . . . . . . . . . 2
In fact, low thyroid hormone levels in critically ill patients have been shown to correlate directly with risk of
death. Whether it’s patients with chronic heart or liver
disease, or intensive-care patients trying to fight off an
infection, levels of the thyroid hormone called T3 often
drop far below normal. And the lower their T3, the
more likely the patient is to die from their illness.
Administration . . . . . . . . . . . . . . . . . . . . . . 6
Dr. Koenig’s team is working to explain the roots of
“non-thyroidal illness syndrome”—the formal name
for this phenomenon. To find out
why T3 levels drop, Dr. Koenig
and his associate Jingcheng Yu,
MS, have led an effort to study
specific molecules in the body
that underlie the syndrome.
Unfortunately, critically ill patients are not an easy group with
which to perform molecular research studies. Instead, using sick
mice as a model for sick humans,
Dr. Koenig’s team is drilling down
to the level of specific proteins
and cell signals in a way that
would not otherwise be possible.
Virtually every
patient with
any serious
disease or injury
develops thyroid
dysfunction
during the
course of their
illness.
They’re focusing on the interaction between three
key molecules: T3 thyroid hormone; a liver protein
known as SRC1 that helps T3 exert its control over
the body; and inflammation which causes cell signal
molecules called cytokines.
Normally, the liver plays a key role in the body’s
production of active T3 by converting a precursor
molecule called T4 after it is released into the bloodstream by the thyroid. But certain cytokines inhibit
the liver’s ability to make this conversion—especially
when a person suffers serious infection or other illness or injury, which causes cytokine release.
Clinical Programs . . . . . . . . . . . . . . . . . . . . 4
Faculty Affairs . . . . . . . . . . . . . . . . . . . . . . 7
Research Programs . . . . . . . . . . . . . . . . . . . 8
Veterans Affairs . . . . . . . . . . . . . . . . . . . . . 9
Graduate Medical Education . . . . . . . . . . . . 10
Undergraduate Medical Education . . . . . . . . 11
Allergy & Clinical Immunology . . . . . . . . . . 12
Cardiovascular Medicine . . . . . . . . . . . . . . 16
Gastroenterology . . . . . . . . . . . . . . . . . . . 20
General Medicine . . . . . . . . . . . . . . . . . . . 24
Geriatric Medicine . . . . . . . . . . . . . . . . . . . 28
Hematology/Oncology . . . . . . . . . . . . . . . . 32
Infectious Diseases . . . . . . . . . . . . . . . . . . 36
Metabolism, Endocrinology & Diabetes . . . . 40
Molecular Medicine & Genetics . . . . . . . . . . 42
Nephrology . . . . . . . . . . . . . . . . . . . . . . . 46
Pulmonary & Critical Care Medicine . . . . . . . 50
Rheumatology . . . . . . . . . . . . . . . . . . . . . 54
Development . . . . . . . . . . . . . . . . . . . . . . 58
Honor Roll . . . . . . . . . . . . . . . . . . . . . . . . 58
Leadership in Professional Societies . . . . . . 62
Editorships & Editorial Boards . . . . . . . . . . 65
Major Faculty Awards . . . . . . . . . . . . . . . . 67
To outsmart these effects, Koenig’s research team has
developed a way to increase expression of the SRC1
gene, which enhances the action of the remaining T3.
Study Sections & Federal Advisory Boards . . . . 68
Thus far, this experimental gene-therapy approach
has proved effective in preventing non-thyroidal
illness syndrome in mice that were given a toxin that
ordinarily would have made them very ill, with an
associated low T3 level. Next, the team is testing the
gene therapy approach against infections, to see if
the protective effect can be replicated.
Standing Committees . . . . . . . . . . . . . . . . 72
Honorary Societies . . . . . . . . . . . . . . . . . . 70
Executive Officers & Regents . . . . . . . . . . . 72
Continued on page 40
Internal Medicine Annual Report 2007 • 1
M etabolism, Endocrinolog y & D iabetes
Peter Arvan, MD, PhD
Division Chief/Professor
Emeritus Faculty
Stefan S. Fajans, MD (active)
Ralph F. Knopf, MD (active)
Sumer B. Pek, MD (active)
Professor
Ariel L. Barkan, MD
Charles F. Burant, MD, PhD
William F. Chandler, MD (secondary)
Roger J. Grekin, MD
Milton D. Gross, MD (secondary)
William H. Herman, MD, MPH
Ronald J. Koenig, MD, PhD
David E. Schteingart, MD
Adjunct Professor
Henry G. Bone, III, MD
Douglas A. Greene, MD
Associate Professor
Thomas J. Giordano, MD, PhD (secondary)
Gary D. Hammer, MD, PhD
Craig A. Jaffe, MD
Arno K. Kumagai, MD
Robert W. Lash, MD
Ormond A. MacDougald, PhD (secondary)
Richard M. Mortensen, MD, PhD (secondary)
Martin G. Myers, Jr., MD, PhD
Massimo T. Pietropaolo, MD
Adjunct Associate Professor
Martin J. Stevens, MD
Assistant Professor
Annette M. Chang, MD, MS
Tae-Hwa Chun, MD, PhD
Liselle Douyon, MD
Nazanene H. Esfandiari, MD
Diane C. Fingar, PhD (secondary)
Jennifer R. Franzese, MD
Roma Y. Gianchandani, MD, MBBS
Elif A. Oral, MD
Rodica Pop-Busui, MD, PhD
Jennifer A. Wyckoff, MD
Research Assistant Professor
Heike Muenzberg, PhD
Ghada A. Soliman, MD, PhD
Instructor
Crystal M. Holmes, DPM
Clinical Lecturer
Angela R. Subauste, MD
Israel Hodish, MD, PhD
Adjunct Lecturer
Susan L. Johnson, MD
Vivian H. Lin, MD
Research Investigator
Yigang Chang, MD
Arun K.Das, PhD
Mayumi Inoue, MD, PhD
Stephen I. Lentz, PhD
Ming Liu, PhD
Nathan Qi, PhD
Bin Xu, PhD
40 • University of Michigan
Continued from page 1
Although human clinical trials are several years away,
this remarkable research is revealing clues as to why
non-thyroidal illness syndrome occurs, and it may
have important implications for survival from otherwise lethal illness.
The two-headed PPFP was thought to cause cancer by
blocking the activity of the normal protein counterparts.
But Koenig’s team’s gene expression analysis revealed
just the opposite—that biological activity was actually
abnormally enhanced by the two-headed protein.
“I was referred to see you because my doctor says I
have a thyroid nodule that could be cancer…”
The U-M team published its first findings in 2006, and
is now actively pursuing promising leads. In one curious twist, one of the proteins whose activity is boosted
by PPFP may be attacked by a class of drugs currently
used to treat diabetes. The possibility of leveraging
drugs that were developed for unrelated endocrine
disorders in the treatment of thyroid cancer is a decidedly positive development.
Fortunately, the vast majority of thyroid nodules
diagnosed each year are not cancers. However, like
many other glands, the thyroid is prone to developing cancerous cells that multiply, alter their function,
and in some cases spread to other areas of the body,
becoming lethal.
Even so, the news is generally good for the 33,000
people diagnosed with thyroid cancer every year.
Modern treatments have paved the way for outstanding long-term survival in most patients—with a more
favorable outcome than for any other metastasizing
solid tissue cancer.
For years, U-M has offered a specialized thyroid cancer clinic at its Comprehensive Cancer Center, where
MEND endocrinologists work closely with radiation
oncologists, surgeons, nuclear medicine specialists,
and others to optimize each patient’s care.
At the same time, Dr. Koenig and his team are developing new tests that may someday allow doctors to
better distinguish different forms of thyroid cancer
from one another, to identify those thyroid tumors
that are likely to be the most aggressive, and to identify in advance those patients most likely to develop
certain inherited forms of the disease.
Michigan offers an ideal place to tackle these problems, due to a partnership between the research team
and numerous U-M thyroid cancer patients who have
allowed the team’s researchers to look in detail at
their DNA, and search for genetic “fingerprints” that
describe their particular form of thyroid cancer. This
effort, which has engaged the advanced capabilities of
the U-M gene expression facility, was made possible in
part by the Marilynn Collins Thyroid Cancer Fund, created in memory of a patient who died from the disease.
Dr. Koenig and his colleagues—including Thomas
Giordano, MD, PhD, of the Department of Pathology, Rork Kuick, MA, of the Cancer Center, and their
collaborator Yuri Nikiforov, MD, PhD, of the University of Pittsburgh—have been actively pursuing one
particular kind of “genetic shuffling” that can be detected in half of all cases of follicular thyroid cancer,
the second most common form.
This shuffling involves transfer of genetic material
between chromosomes 2 and 3, creating an abnormal
hybrid gene called PPFP, and resulting in production
of a two-headed protein that combines the properties
derived from the two different parent genes.
Dr. Koenig’s research team, including Yu and Ericka
Diallo, MS, has been developing a strain of mice that
express PPFP in the thyroid, and might be used as a
model for human follicular thyroid cancer. This will
allow further study of PPFP in the
living thyroid, and will accelerate
the development of drug therapies
to be used against it. Additionally, in collaboration with Cancer
Center director Max Wicha, MD,
and graduate student Dang Linh
Vu Phan, the team is searching for
stem cells that may underlie thyroid
cancer development.
Modern
treatments have
paved the way
for outstanding
long-term
survival in most
patients—with a
more favorable
outcome than
for any other
metastasizing
solid tissue
cancer.
At the same time, the team is
vigorously pursuing other genetic
phenomena that might cause an
additional type of thyroid cancer.
Their goal is to develop precision
“biomarkers”—simple blood tests
that can catch thyroid cancers early
and identify the type so that treatment can be tailored to the individual patient. This effort is aided
by sophisticated DNA technology
that looks for genetic mutations
and patterns across a large number
of cancer patients. In fact, this year
Drs. Nikiforov, Giordano, and Koenig discovered a
rare genetic feature in one U-M patient with papillary
thyroid cancer—the most common type. This unusual
finding may illuminate the search for a common pathway in all papillary thyroid cancer.
Dr. Koenig’s status and stature have been growing at
U-M for the better part of two decades. As the director of the U-M Medical Scientist Training Program,
Dr. Koenig is also deeply involved in the growth and
development of our next generation of physician
scientists. Perhaps one of them will be the one to cure
thyroid cancer, for good.
Internal Medicine Annual Report 2007 • 41