Back in September 2018, we realized there was no literature analyzing the

relationship between hip fractures and ESS, even though ESS had been already
studied in a variety of other settings.
So we asked ourselves: “Is the thyroid profile of elderly patients with hip fracture
relevant?”
We decided to start patient’s recruitment and a year and later we started to gather
the first results.
Let’s first address the two conditions separately.

Proximal femur fracture is a very common condition in the elderlies.

In the population over 65, where the prevalence of osteoporosis and the risk of falls
are quite high, 1/100 people suffer a hip fracture every year. This population subset
has a lot of risk factors for osteoporosis: scarce physical activity, nutritional
deficiencies and chronic medical conditions.
Female to male ration is 3:1, highlighting the underlying profound bone weakness
that develops following the drop in estrogens concomitant with menopause. This
difference though tends to disappear in the over 80 population.
Cases of hip fracture are always increasing. Even though in developed countries
incidence tends to decrease, our population ages at a much faster pace, keeping the
absolute number of hip fractures per year on the rise.

Social impact of hip fracture is quite high: 1/3 people die within one year, 40% of
patients will never walk unaided again and 60% will still require assistance a year
after the event.
Moreover, 1 in 3 patients is admitted to long term care in the first year, increasing
the risk of healthcare associated infection and contributing to the social
abandonment of the elderlies.
The economic burden of this condition is also very relevant, as each patient costs
50.000 $ to the US NHS, for a total yearly expense of 6 billion $ and 3.4 million
hospital bed days.

As for proximal femur fracture classifications many are valid, but we decided to use
the AO/OTA foundation classification, which is quite precise.

As we can see from the picture it divides hip fractures into three broad categories:
31 A refers to fractures of the trochanteric area, 31 B to fractures of the cervical
area and 31 C to fractures of the head of the femur.

3 MIN

Euthyroid sick syndrome is a thyroid profile imbalance in the absence of an

underlying thyroid pathology. In particular the early stage of the syndrome presents
decreased levels free T3, which is the cornerstone of the condition, together with
normal values of free T4 and TSH.
These instead tend to decrease in prolonged illnesses.

Why does this syndrome develop?

Literature is still not clear about this question: ESS has been linked to inflammatory
cytokines, particularly IL-6, and it seems the initial response limits catabolism, which
is increased in conditions of stress for the organism, thus having a beneficial effect.
Some studies though found ESS to be a predictor of poor prognosis in severely ill
patients, leaving this question unanswered: is ESS adaptive or maladaptive?

Regarding its treatment, scientific evidence only points towards the administration
of T3 in specific settings, as patients under intensive care and particular cases of
heart failure.
Some studies even found treatment of ESS to be detrimental to the patient’s health
status.
So the question stands: how and when does ESS need addressing in the context of
elderlies with hip fracture?

In order to better appreciate the results we got from the study, it’s also important to
address the effects thyroid hormones, PTH and vitamin D have in general, and more
specifically how they affect calcium homeostasis, the immune system and
erythropoiesis.

Thyroid hormones are generally attributed the non-specific effect of increasing

metabolism, but actually, they also have specific actions depending on the target
organ or system on which they act.
For what we are interested in, we need to know that thyroid hormones exert
responses in various immune cells and play an important stimulatory role on
erythropoiesis.

As for PTH, its main role is related to calcium metabolism. As you can see from the
image on the left, low levels of blood calcium, stimulate production and releasd of
PTH from parathyroid glands. The hormone, in turn, acts at three levels: on the
bone, increasing bone resorption, on the kindey, increasing calcium reabsorption
and on the intestine, modulating the activity of vitamin D.
The final effect of these 3 actions is to increase circulating calcium, which is
fundamental in a variety of electrophysiological processes.

Last but not least Vitamin D. Receptors for vitamin D are found in almost every cell
in the body, meaning it has a role in a lot of physiological processes throughout the
organism. What interests us in the context of this study is that vitamin D plays a
pivotal role on calcium homeostasis, increasing calcium absorption at the level of
the intestine.
Moreover, Vitamin D is an immunomodulator and it has a supportive role in
erythoropoiesis.

4 MIN
After this brief introduction we can start talking about the actual study.

The objectives of the study were to evaluate the impact ESS has on variations of PTH
and vitamin D, postoperative anemia, infections and type of fracture in hip fracture
patients.

Since September 2018, we recruited any patients older than 65 coming to our ER
with a proximal femur fracture. Upon arrival we performed routine hematological
analyses and thyroid profiling. These exams were repeated on the first and third
postoperative days.

Inclusion criteria were: age over 65, proximal femur fracture and ER admission
within 72 hrs from trauma.
The exclusion criteria instead were pre-ecisting thyroid pathology, durgs interfereing
with thyroid function, acute coronary syndrome, active pneumonia, ongoing
neoplastic disease and refusal of surgical intervention.

Our population was made by 79 elderly patients, 20 of which were males.c in line
with the sex-linked epidemiologic data.

49, or 62% of these, were affected by ESS on admission. As we can see from the
table, the only statistically significant result between the two groups after collecting
anthropometric data and routine blood analyses was BMI, proving how
homogeneous the two groups are.
Let’s start by analyzing how ESS impacts calcium metabolism.

Calcium values difference between the two groups is not significant on admission,
but becomes significant on the first postoperative day. Why is that? Well we
analyzed two main players in calcium homeostasis, PTH and Vitamin D, and the
results as you can see are striking. Syndromic patients had an opposite trend for
what concerned PTH changes between admission and first postoperative day.
We can see from the graph, syndromic patients had a reduction of 6.4 pg/mL,
whereas controls had an increase in PTH oh 30.1 pg/mL.
The p value is reported on the table and is 0,001, making this difference statistically
significant.

Another result which is implicated in the variation of calcium is the one regarding
vitamin D. Again we can see how syndromic patients had a drop of 4 ng/mL whereas
controls only 2.2, also this result being significant.

7:10 min

If you look at the graph, you can see how syndromic patients more frequently
suffered lateral, or peritrochanteric fractures with respect to controls. In fact, non-
syndromic participants actually have a higher frequency of cervical fractures.
This is closely related to our results on calcium metabolism: A study from 2010
showed how high PTH positively correlates with an increased risk of lateral fractures
with respect to cervical ones.
This supposedly happens because of microscopic areas of bone weakness that
develop mainly around the trochanters in conditions of high PTH.

Our results are in accordance with these findings but add another important notion:
patients with elevated PTH who suffer lateral fractures are the same ones who
develop ESS after the trauma.

The next important result is the one correlating ESS with postoperative anemia.
After ruling out confounding factors, such as Anticoagulants therapy and duration of
surgery, ESS proved to be a statistically significant predictor of increase need for
transfusions.
As we can see, syndromic patients needed on average 1 full bag of blood more than
controls.
Even though transfusions give major clinical benefits, such as prevention of
postoperative delirium, they also carry a lot of risks and need careful evaluation in
order to avoid putting the patient in harm’s way.

The last result I will present is the relationship between ESS and infections.

Even though this relationship is not statistically significant, we found a higher

incidence of postoperative infecftions in syndromic patients. In particular, the risk of
infecdtion in the syndromic group was 24%, while it was only 11 for controls.

9:15 min

After presenting all these results, our study leaves us both with answers and
questions.

We know syndromic patients can’t develop an appropriate PTH response to the

fracture and hypovitaminosis D, impairing calcium metabolism. Does this have an
impact on long term functional recovery and implant fixation?

We also know from literature that hip fracture correlates positively with
hypovitaminosis D, in fact more than half of our patients presented with below-
range values of vitamin D.

Physiologically, PTH should rise in response to both a fracture and a drop in vitamin
D, mobilizing calcium and facilitating fracture fixation.
Clearly this physiologic process only took place in non syndromic patients, while the
ESS group never developed the appropriate PTH surge.
It seems that these alterations in PTH values also had an impact in the type of
fracture these patients suffered.

Syndromic patients PTH levels positively cvorrelates with lateral fracture, but are
these patients’ thyroid profile already imbalanced before the trauma? Minor
stressors which don’t prompt hospitalization could be the reason for the
development of the syndrome, predisposing the patient to peritrochanteric
fractures.
This would be in line with both our results and the previously confirmed correlation
between high PTH and 31 A fractures. Unfortunately we do not have data regarding
our participant’s thyroid hormones before the trauma, and a population study is
probably needed in order to clarify our findings.

Our population’s age, type of injury, type of surgery and comorbidities, makes them
very susceptible to post-operative anemia.
Anemia of chronic disease is a well defined clinical entity and is mostly present in
subjects who fit perfectly inside our recruitment criteria.
This means our participants probably already present shortened red blood cell
survival, impaired erythropoiesis and impaired iron metabolism.

Fractures and surgical operations both cause hemorrhages and subsequent anemia,
and we know postoperative anemia is associated with a great variety of adverse
outcomes.
ESS increases the risk of these patients to develop anemia, highlighting the inability
of the organism to respond to low hemoglobin levels.
Syndromic patients need, on average, more transfusions than controls… from this
stems the question: should we implement more preventive measures in syndromic
patients in order to reduce the incidence of anemia?

Infections seem to be more frequent in syndromic patients. A study from 2018

found a statistically significant relationship between ESS a postoperative infections
in patients undergoing abdominal surgery. If our results were to be confirmed in a
study with a larger sample size, would it mean that syndromic patients deserve
particular attention in infection prevention?
To sum up, our study found that a substantial subset of elderly patients with hip
fracture develops ESS as a consequence of trauma, showing reduced ability to cope
with stress, higher infection incidence, greater need for transfusions and lower
metabolism.

Our study had some limits, which didn’t allow us to fully delineate the impact ESS
has on these patients.
Our sample size was modest, with 79 patients, and will definitely need an increase in
number in order to have data which are more clear, especially about infections.
Also we do not have the thyroid profile of our patients before the trauma, meaning
understanding the relationship between the syndrome and the type of fracture is
not straight forward and probably needs a population study for confirmation.

Future prospectives in this area are mainly to focus on long term functional recovery
and mortality, in order to understand how ESS in the event of trauma impacts the
life of our patients thrughout the years-

Thanks for your attention.

QUESTION 1: When you presented the patients general data, there was a
statistically significant difference in BMI between the two groups. How do you
explain this difference?

ANSWER1: Thank you for your question. There are some studies in literature that
correlate ESS with malnutrition, so this could be a good reason for syndromic
patients to have a slightly lower BMI. If a population study was to be performed we
could understand if and how lower BMI influences the development of the
syndrome, both after a hip fracture and after minor stressors, shedding light on
some still unknown characteristics of this condition.

QUESTION 2: Is there a higher incidence of surgical complications in the syndromic

group?
ANSWER 2: Thank you for your question. As of now, aside from the higher incidence
of postoperative infections and anemia, we haven’t had an increase in surgical
complications in the syndromic group. However this is a topic that will need to be
addressed in the future, as with a longer follow-up we will also be able to evaluate
the incidence of peri-implant fractures and failure of implant fixation in the two
groups.

GIACCARI 1: ESS is mostly related to systemic disease. Which were the most
common in your study’s participants?

ANSWER G1: Thank you for your question. We actually collected the Charlson
Comorbidity Score which was quite similar between the two groups.
As I said earlier the only statistically significant difference we found in our two
groups for what concerns general data was the BMI. Which was slightly lower in
syndromic patients.
Specifically to answer your question though the two most common systemic
pathologies affecting both categories of participants were Hypertension and
Diabetes.

GIACCARI 2: Do you know if there are any studies on how ESS influences surgical
outcomes?

ANSWER G2: Well this topic is still controversial. There are studies that suggest
administration of T3 before surgery could have a positive impact on surgical
patients, but some others show treatment of ESS to be detrimental in some cases.
One particular study actually found that a specific parenteral nutrition seems to
resolve ESS in most casers, but further evaluation is definitely needed in order to
define a treatment protocol. As of now, treatment with T3 is mostly performed in
intensive care settings and in some cases of cardiac failure, but future studies could
shed light on this topic and who knows, maybe increasing our sample size we will be
able to give a more precise answer in the future.