UNIVERSITA’ CATTOLICA DEL SACRO CUORE

“A. Gemelli” School of Medicine and Surgery

Medicine and Surgery Degree Program

Department of Trauma and Orthopedics Surgery

Head of department: Professor Giulio Maccauro

EUTHYROID SICK SYNDROME IN ELDERLY PATIENTS

WITH PROXIMAL FEMUR FRACTURE: CLINICAL

OUTCOMES AND PATHOPHYSIOLOGICAL IMPLICATIONS

Supervisor Co-supervisor:

Prof. Carlo Perisano Prof. Giulio Maccauro

Candidate:

Giacomo Dughiero

4450250

Academic year 2019-20

1
“Years ago, anthropologist Margaret Mead was asked by a student
what she considered the first sign of civilization in a culture.
The student expected Mead to talk about first hooks or clay pots or
grinding stones.
But no, Maed said that the first sign of civilization in an ancient
culture was a femur that had been broken, then healed. Mead
explained that in the animal kingdom if you break your leg you die.
You cannot run from danger, get to the river for a drink or hunt
food. You are meat for prowling beasts. No animal survives a
broken leg long enough for the bone to heal.
A broken femur that has healed is proof that someone has taken
time to stay with the person who has fallen, has bound up the
wound, has carried the person to safety and has tended the
person through recovery.
‘Helping someone through difficulty is where civilization starts’ said
Mead.
We are at our best when we serve others. Be civilized.”

- Dr. Ira Byock

2
Index

1: INTRODUCTION ..................................................................................................................... 4
1.1: PROXIMAL FEMUR ANATOMY........................................................................................................ 4
1.1.1: Bone landmarks ............................................................................................................. 4
1.1.2: Hip muscles .................................................................................................................... 7
1.1.3: Hip vascular supply ........................................................................................................ 9
1.2: FEMORAL FRACTURES ................................................................................................................ 10
1.2.1: Epidemiology and risk factors ...................................................................................... 10
1.2.2: Clinical and radiological evaluation ............................................................................. 11
1.2.3: Hip fracture classification ............................................................................................ 14
1.2.4: Hip fracture treatment ................................................................................................. 19
1.2.5: Complications .............................................................................................................. 27
1.3: THE THYROID GLAND ................................................................................................................. 32
1.4: THE PARATHYROID GLANDS ........................................................................................................ 36
1.5: CALCIUM METABOLISM .............................................................................................................. 39
1.6: VITAMIN D ............................................................................................................................. 40
1.7: EUTHYROID SICK SYNDROME (ESS) .............................................................................................. 41

2: MATERIALS AND METHODS ................................................................................................. 43

2.1: STATISTICAL ANALYSIS ............................................................................................................... 46

3: RESULTS ............................................................................................................................... 47
3.1: CHANGES IN VITAMIN D VALUES.................................................................................................. 48
3.2: CHANGES IN PTH VALUES .......................................................................................................... 49
3.3 NUMBER OF TRANSFUSIONS ........................................................................................................ 51
3.4 TYPE OF FRACTURE .................................................................................................................... 53
3.5 INFECTION INCIDENCE ................................................................................................................. 54

4: DISCUSSION ......................................................................................................................... 55
4.1 ESS ........................................................................................................................................ 55
4.2 CALCIUM METABOLISM ............................................................................................................... 56
4.3 TYPE OF FRACTURE .................................................................................................................... 59
4.4 NUMBER OF TRANSFUSIONS ........................................................................................................ 60
4.5 INFECTIONS .............................................................................................................................. 62

5: CONCLUSIONS...................................................................................................................... 64
TABLES .................................................................................................................................... 66
BIBLIOGRAPHY ........................................................................................................................ 69

3
1: INTRODUCTION

1.1: Proximal Femur anatomy

The hip is a ball and socket synovial joint where the pelvic acetabulum and

the head of the femur articulate with each other. The acetabulum, a cup-

shaped surface of the pelvic girdle, is deepened by the presence of a

fibrocartilaginous collar, the acetabular labrum. The capsule of the joint

attaches proximally to the edge of the acetabulum and distally to the

intertrochanteric line anteriorly and the femoral neck posteriorly.

1.1.1: Bone landmarks

The femur is the longest and strongest bone in the human body. It is made

by a distal and proximal epiphysis and a central body or femoral shaft.

The proximal femur is made, cranio-caudally, by the femoral head and neck,

greater and lesser trochanter. (Figure 1)

Figure 1: proximal femur anatomy

4
The femoral head is intracapsular and spheroidal in shape. It articulates with

the acetabulum and is encircled by the acetabular labrum. Its surface is

smooth and covered by articular cartilage, except for a small area

posteroinferior to the center, the fovea, where the ligamentum teres

attaches.

The femoral neck connects to the head at an angle of 135° on average,

keeping the shaft clear from pelvic bones during movement. The neck

meets the shaft at the intertrochanteric line anteriorly, and the

intertrochanteric crest posteriorly. Since the capsule attaches laterally to the

intertrochanteric line, the anterior surface of the neck is intracapsular.

The greater trochanter is a large quadrangular projection from the junction

of the neck and shaft. Its lateral surface is the only palpable portion of the

femur.

The lesser trochanter, instead, is a posteromedial conical projection at the

junction of the neck and shaft.

The intertrochanteric line is a ridge which descends medially on the anterior

surface of the neck from the greater trochanter to a point anterior to the

lesser trochanter, on the lower border of the neck. This line is the anterior

and lateral limit of the hip capsule.

5
The intertrochanteric crest is a smooth ridge on the posterior surface of the

neck and shaft junction, descending medially from the greater to the lesser

trochanter.

The femoral shaft presents as compact bone with a large medullary cavity,

having a thick wall in the middle where it is narrowest. As the wall becomes

thinner at the extremities, the cavity fills with trabecular bone. Trabeculae

are supportive and connective tissue elements that develop in cancellous

bone. They are disposed following the lines of greatest stress.

According to Wolff’s law, bone withstands both static (generated by gravity)

and dynamic (generated by weight bearing) forces, remodeling itself

anytime these forces change to improve its resistance against that particular

force on that particular segment. (Figure 2)

There are 5 types of trabeculae in the proximal femur:

1. Principal tensile trabeculae

2. Principal compressive/medial compressive trabeculae

3. Secondary compressive/lateral compressive trabeculae

4. Secondary tensile trabeculae

5. Greater trochanter’s trabeculae

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Comprised between the principal compressive, secondary compressive and

primary tensile trabeculae there is Ward’s Triangle, the least dense portion

of the proximal femur which, especially in osteoporotic patients, is more

frequently subject to fractures.

Figure 2: Femoral trabeculae representation of a healthy subject on the left, osteopenic subject on the right.

1.1.2: Hip muscles

Hip muscles are numerous, and their main function is to act on the thigh and

hip to stabilize the joint. For clarity’s sake, we can divide them into 3 groups:

1. Iliopsoas group: It is composed by the iliacus, psoas major and

psoas minor. Their main functions are flexion of the trunk and

thigh external rotation. The psoas major originates from the

lateral surfaces of the vertebral bodies of T12-L3, while the

iliacus originates in the iliac fossa, as they fuse at the level of

the inguinal ligament, they are referred to together as the

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 iliopsoas muscle. They both cross the hip joint to insert into

the lesser trochanter.

2. Gluteal muscles: They comprise large, superficial ones and

the inner hip muscles. The first ones are the gluteus maximus,

medius and minimus and the tensor fasciae latae. Their

functions are hip extension, hip external and internal rotation,

abduction and adduction of the thigh. The gluteus maximus

has a wide origin starting at the gluteal line on the ilium and

ending on the coccyx, it inserts on the iliotibial band and the

gluteal tuberosity on the femur. The gluteus medius originates

on the outer surface of the ilium, it too having a wide origin,

and inserts onto the greater trochanter.

The inner hip muscles are, cranio-caudally: piriformis,

gemellus superior, obturator internus, gemellus inferior,

obturator externus and quadratus femori. They all serve the

same purpose, having as main functions external rotation of

the thigh, abduction of the thigh when the hip is flexed and

stabilization of the femoral head in the acetabulum.

3. Hip adductors: there are six of them and they are all located in

the medial thigh compartment. They all originate from the

pubis, travel across the hip joint, to insert onto the femur. The

gracilis is an exception, as it crosses the knee and inserts onto

the tibia. They are the gracilis, pectineus, adductor longus,

adductor brevis, adductor magnus and adductor minimus.

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1.1.3: Hip vascular supply

As for the vascular supply, the proximal femur has a peculiar organization.

The supply to the femoral head derives from an arterial ring around the neck,

just outside the attachment of the capsule. The main contributors to this ring

are the medial and lateral circumflex femoral arteries. From the ring,

ascending cervical branches enter the capsule becoming the retinacular

arteries, which in turn create the intracapsular subsynovial anastomosis.

Both the medial and lateral circumflex arteries arise from the deep femoral

artery, a direct branch of the femoral artery. The lateral epiphyseal artery

arises from the circumflex arteries, specifically from the intracapsular ring,

and penetrates the head and neck of the femur. The superior and inferior

metaphyseal arteries, named according to the portion of the femur where

they enter the bone, also arise from the circumflex arteries.

The medial epiphyseal artery arises instead from the artery of the

ligamentum teres, which is in turn a branch of the obturator artery, and

supplies the head of the femur, even though its contribution to the viability

of the tissue is negligible. (Figure 3)

Figure 3: proximal femur vascular supply

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1.2: Femoral fractures

1.2.1: Epidemiology and risk factors

As the population ages, the number of femoral fractures increases

accordingly, representing one of the most common fractures in older adults.

Femoral fractures can be divided into open/closed, depending on whether

or not the broken bone punctures the skin, displaced/non-displaced,

depending on the alignment of the two segments involved, and can be

comminuted, when the bone shatters in multiple pieces. Impacted fractures

occur when the broken ends of a bone are pushed into each other by the

force of trauma or injury.

We can classify them into proximal, diaphyseal and distal, according to the

portion of the femur involved.

Hip fractures are usually a result of falling directly onto the lateral hip,

twisting of the joint with a planted foot or the completion of an insufficiency

fracture. In younger adults, this kind of injury tends to occur as a result of

high energy traumas such as motor vehicle accidents.

Risk factors for hip fracture are numerous, the main ones being age, sex,

low bone mass, low BMI and estrogen deficiency. Other risk factors are

tendency to fall, disability and immobilization, use of psychotropic or

hypnotic drugs, low calcium intake, osteomalacia, thyrortoxicosis, smoking,

alcoholism and diabetes mellitus.1 Localized osteoarthritis (OA) of the hip

poses a challenge to patients as pain influences balance and coordination,

10
also reducing the amount of physical activity the subject can perform,

leading to muscular weakness and increased risk of falling. Interestingly, hip

OA was found to affect the site of fracture, showing a higher prevalence

among subjects with extracapsular than those with intracapsular fracture,

meaning OA of the hip could be a protective factor for intracapsular fractures

and a risk factor for extracapsular ones.2

Incidence of proximal femur fractures is particularly high in the over 75

population group, where both the prevalence of osteoporosis (more than

45% for women and 18% for men) and the risk of falling are much higher.

In the population group over 65, women’s risk to incur into a proximal femur

fracture is more than doubled with respect to men.3

Mortality in proximal femur fractures ranges between 30 and 35 % in

literature4, moreover, older adults with hip fractures are 3-4 times more likely

to die within one-year after surgery than the general population.5

1.2.2: Clinical and radiological evaluation

Patients with hip fractures usually cannot walk or bear weight on the

affected leg, moreover they can present limb deformity.6 Impacted fractures

represent an exception as patients, even though in pain, might be able to

weight bare and walk until the fracture displaces.

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When the fracture is associated to hip dislocation, the affected limb will be

shorter than the contralateral one, flexed and extra-rotated.7 When the

fracture is intracapsular, the bruising on the skin is minimal.

Anamnesis is paramount: history of loss of consciousness, syncope, chest

pain, hip pain and tumors suggesting a pathological fracture all need to be

evaluated in order to choose the most suitable treatment, especially in

elderly patients with comorbidities.6

Blood typing should be performed on all hip fracture patients, as they tend

to be anemic in postoperative days. In particular, patients at higher risk of

hemorrhage have at least two of the following89

- Hemoglobin at presentation < 12 g/dL

- Peritrochanteric fracture

- > 75 years of age

When suspecting a hip fracture, radiographic imaging should be obtained,

specifically an anterior-posterior (AP) view (Figure 4), a lateral view (Figure

5) and an AP projection of the pelvis (Figure 6) to compare the contralateral

joint.

Plain radiographs, most of the time, are enough to diagnose a hip fracture.

Evaluation of the images should focus on identifying bone discontinuity,

12
cortical deficiencies, changes in the angle and length of the neck and

alterations in the physiologic trabecular organization. When X-rays are not

enough for the evaluation of the fracture, the patient should undergo further

imaging studies as a CT scan or MRI.

Figure 4: AP projection of fractured femur. Case courtesy of Andrew Murphy, Radiopaedia.org, rID: 55944

Figure 5: Lateral hip view. Case courtesy of Dr Matthew Lukies, Radiopaedia.org, rID: 51246

13
Figure 6: normal AP pelvis view of a male. Case courtesy of Dr Benoudina Samir, Radiopaedia.org, rID: 43111

1.2.3: Hip fracture classification

Hip fracture classifications are numerous. Anatomically, we can divide

proximal femur fractures into medial (subcapital and transcervical) and

lateral (basicervical and pertrochanteric).

The most used classification in literature is the Garden classification, which

is easily applied to all patients and predicts the occurrence of avascular

necrosis of the femoral head. Garden’s classification focuses on fractures

of the neck, classifying subcapital and transcervical fractures depending of

the position of medial compressive trabeculae and predicting the

development of AVN.

The most valuable predictive factor for AVN of the head of the femur after

hip fracture is the distance of the trochanteric region, the most important

part of the proximal femur for what concerns blood supply, from the line of

bone discontinuity. If the fracture were to damage the retinacular vessels,

the risk of AVN of the hip and pseudarthrosis would increase proportionally

to the grade of displacement, which can be evaluated via imaging.

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Garden classification is divided into 4 stages (Figure 7):

1. Garden I: non-displaced incomplete or valgus impacted fractures.

Medial trabeculae may show a green stick fracture.

2. Garden II: non-displaced complete fractures. No alteration of

medial trabeculae.

3. Garden III: complete fractures, incompletely displaced. The varus

tilt of the head causes the medial trabeculae to be out of line with

the pelvic ones.

4. Garden IV: complete fractures, completely displaced. The head is

in alignment, so the medial trabeculae are in line with the pelvic

ones.

For non-displaced fractures (Garden Types I and II) internal fixation with

preservation of the femoral head is generally preferred. Displaced fractures

(Garden Types III and IV) need careful analysis of each single case to

choose the most suitable method of fixation: the tendency is to perform

hemiarthroplasty or total hip replacement (THA) in all patients, but internal

fixation should be at least considered in younger subjects, even with the

high risk of AVN this kind of fractures carry.

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 Figure 7: Visual representation of Garden's classification

The AO/OTA Foundation Classification allows to precisely characterize the

type of fracture, facilitating the process of choosing the best therapeutic

option.

The femur, in this classification, is represented by the number 3, and its

proximal part by the number 1.

Therefore, proximal femur fractures are all under the category “31”, followed

by a letter (Figure 8):

1. 31.A: fractures involving the trochanteric region, further divided

into:

a. 31.A1: simple pertrochanteric fracture

b. 31.A2: multifragmentary pertrochanteric fracture

c. 31.A3: intertrochanteric (reverse oblique) fracture

2. 31.B: Fractures of the neck of the femur, further divided into:

a. 31.B1: subcapital fracture

b. 31.B2: transcervical fracture

c. 31.B3: basicervical fracture

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 3. 31.C: All fractures of the femoral head, further divided into:

a. 31.C1: slips fracture

b. 31.C2: depression fracture

Figure 8: Visual representation of the AO/OTA classification

The Garden and AO classifications are the most used in order to make a

therapeutic choice, but we also have older classifications.

Pauwels classification needs mentioning. It characterizes lesions

depending on the angle of the fracture line: type I (0-30°), type 2 (30°-70°)

and type III (70° or more) (Figure 9). This system is still frequently used to

determine appropriate treatment, but its low reproducibility, the absence of

a standard for measuring the angle, makes it less reliable than other

classifications.10

17
 Figure 9: Visual representation of Pauwels classification

Pipkin classification is also worth mentioning: it deals primarily with femoral

head fractures. Garrett Pipkin subclassified injuries that were already

defined as grade IV by Stewart and Milford, providing a management

protocol for these fractures.

The Pipkin classification has 4 different types, focusing on the relationship

of the injury with the fovea capitis femoris (Figure 10):

1. Type 1: hip dislocation with a femoral head fracture caudal to the

fovea

2. Type 2: hip dislocation with a femoral head fracture cephalic to

the fovea

3. Type 3: Type 1 or 2 with an associated femoral neck fracture

4. Type 4: Type 1 or 2 with and associated acetabular rim fracture

18
 Figure 10: Visual representation of Pipkin's classification

The rationale behind this classification stems from the ligamentum teres: if

it remains attached to the inferior segment in a type 2 injury, it will likely

rotate it making it difficult to correct the lesion by closed means.

Even though there are no studies on the inter- and intra-observer reliability

of this classification system, several showed better outcomes in patients

with Pipkin Types 1 and 2 compared to ones with Pipkin Types 3 and 4.11

For what concerns intertrochanteric fractures, there are some specific

classifications that can be used: Evan’s Classification, AO classification,

Jenson’s classification and others. All of these divide the lesion into stable

and unstable (reverse oblique and coronal split fractures). 12

1.2.4: Hip fracture treatment

The treatment of hip fractures is almost exclusively surgical. Some patients

with contraindications to surgery can be treated with a cast or an orthopedic

brace, but the mortality in patients undergoing conservative treatment is

19
much higher than in those undergoing surgical repair.13 Timing of surgery

has a considerable impact on patients’ outcome, in particular Simunovic et

al. found that early treatment of hip fracture (<24, <48, <72 hours) is

associated to a risk reduction in mortality, pneumonia and pressure sores

14
. Surgery should be performed within 24 hours in stable patients, as it is

associated with better pain management and decreased length of stay with

respect to delayed treatment (>24 hours)15, and as soon as feasible in

patients with comorbidities who need extensive preoperative evaluation.

Delaying surgery more than 72 hours should be avoided in all patients.

Many conditions need to be prevented or evaluated in hip fracture patients:

• Analgesia has to be adequate and pain should not be

underestimated: acute pain in hospitalized elderlies increases risk of

functional decline, atelectasis, nosocomial pneumonia,

thromboembolism, delirium and depressed immune function 16;

• Thromboembolic prophylaxis should be administered to all patients

waiting for hip surgery, though each case needs to be evaluated for

risk of bleeding;

• Antimicrobial prophylaxis should be initiated in all patients

undergoing surgery for hip fracture to prevent the occurrence of

surgical site infection (SSI);

• Delirium needs to be evaluated and preventive measures should be

initiated for patients at risk;

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 • Osteoporosis can manifest through hip fractures, which in the

elderlies are mostly due to fragility. Daily oral dietary

supplementation should be implemented in patients with femoral

neck fractures as it improves clinical outcomes (6-months mortality

and complications) and reduces length of hospital stay 17.

Intracapsular non-displaced (or minimally displaced) fractures have a very

low risk of AVN, hence they can be treated with internal fixation and

osteosynthesis. This surgical procedure consists in inserting a metal

(usually titanium) nail through the medullary canal of the femur and fixating

it with screws in order to keep the proper alignment during the healing

process. New systems of plate and screw which enhance fixation, provide

more stability and diminish surgical trauma are being implemented in

everyday practice. (Figure 11)

Figure 11: New system for internal fixation.

21
Fractures presenting high risk of AVN as displaced fractures (Garden III and

IV), require a more radical treatment. The indicated surgical procedures are

hemiarthroplasty, in which case the prosthesis only replaces the femoral

portion of the hip, and total hip arthroplasty (THA), where also the

acetabular surface is replaced. Hemiarthroplasties are usually preferred in

elderly subjects who don’t live independently and patients with debilitating

comorbidities or cognitive impairment, as they allow earlier standing and the

surgical trauma is less pronounces than with THA.

Impacted fractures can be overlooked as pain might be minimal and patients

can usually lift their leg from the bed (some may even be able to walk).

Unfortunately, the risk of a secondary displacement is quite high, making

surgery the most common therapeutic choice. Nevertheless, some

physicians recommend bed rest and passive light mobilization of the limb

by a physiotherapist. Others, instead, prefer the use of a cast while slowly

progressing to weightbearing and walking. The latter approach definitely

has some advantages to the former one, as light weightbearing can favor

consolidation and reduce the incidence of complications such as VTE and

pressure ulcers. Both strategies require a tight radiological surveillance

schedule.

Surgical procedures can be split into three broad categories: internal

fixation, hemiarthroplasty and total hip replacement.

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INTERNAL FIXATION:

Internal fixation is mostly indicated in young patients, in fractures without

marked displacement and per-subtrochanteric fractures.

After reducing the fracture on the traction table, a nail or a plate is used for

the synthesis: a cephalic screw stabilizes the fracture and, using an

intramedullary nail or a plate, the femoral epiphysis is anchored to the

proximal portion of the diaphysis. The choice between the nail and the plate

is driven by the kind of fracture and its orientation. (Figure 12)

As these injuries don’t pose a high risk of AVN, weightbearing is allowed

very early: in a matter of days when the surgeon manages to reach a stable

synthesis and in a month for comminuted fractures where synthesis does

not guarantee immediate stability.

Figure 12: Different kinds of internal fixation devices. (A) shows a plate fixation, whether (B) and (C) show
and intramedullary nail.

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HEMIARTHROPLASTY:

Hemiarthroplasty is mostly indicated in the elderlies or those patients in poor

general condition, in order to have a reduced surgical trauma compared to

THA. The procedure consists in removing the femoral head and most of the

neck and replacing them with a metal prosthesis (usually, but other

materials can be employed), anchoring it in the diaphysis via a metal shaft

inserted in the medullary canal.

Two kinds of prosthesis can be employed (Figure 13):

1. Cephalic prostheses have been used since 1952. In Moore’s

prosthesis the femoral head is replaced by a metal head, attached

to a long shaft which goes inside the femoral diaphysis. The

surgical trauma is minimal. Moore’s prostheses have two major

inconveniences: they can sometimes damage the cartilage in the

cotyle, even if the caliber of the metal head suits the acetabulum

perfectly; the shaft doesn’t always anchor properly to the bone,

leading to a progressive sinking of the prosthesis. Nonetheless,

long-term results are favorable. Thompson’s prosthesis is

identical to Moore’s one, but it is cemented.

2. Intermediate prostheses (or bi-articular prostheses) have been

introduced to reduce the wear of the cotyle cartilage by minimizing

stress on the acetabulum: The cephalic portion of the prosthesis

has two components (the head and the acetabular cup) which can

articulate with each other.

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 3. Weightbearing is usually allowed on the same day of the

operation and, not much later, the patient is allowed to walk in

crutches.

Figure 13: Thompson's prosthesis (on the left) and Moore's prosthesis (on the right)

TOTAL HIP ARTHROPLASTY (THA)

THA is mostly indicated in patients who are between 65 and 80 years of

age: younger patients tend to be treated with internal fixation and older

patients with hemiarthroplasty.

It is employed when the cotyle surface is not optimal, often due to

osteoarthritis, in order to have a total prosthesis where both components of

the joint (the ball and the socket) are replaced.

This operation maintains close-to-normal joint mobility in the hip and is

performed utilizing one of many models of prostheses made by a femoral

shaft and an acetabular component (Figure 14).

The acetabular portion is made by a titanium alloy cup which is provided

with a polyethylene, metal or ceramic component meant to accommodate

25
the cephalic extremity (which is either ceramic, metal alloy or stainless

steel).

All the components can either be cemented into the bone or covered by

hydroxyapatite which, favoring bone growth around the prosthesis, should

give a more durable result in the anchoring process.

Different prostheses and anchoring systems have been developed

throughout the years in order to reduce the wear of prosthetic components

and the incidence of their detachment from the bone. The occurrence of the

latter requires a prompt surgical intervention to replace the prosthesis with

a new one.

As of today, prosthetic models and anchoring techniques are not

standardized and single cases should be evaluated taking into

consideration patients’ age, osteoporosis, amount of mechanical stress the

prosthesis needs to endure etc.

Figure 14: THA schematic representation

26
1.2.5: Complications

Complications can be divided into general and local ones. General

complications must be avoided in the perioperative period, as they tend to

frequently progress and deteriorate the patient’s condition until exitus. The

most common are:

1. Postoperative infections: They are defined as any infection that

occurs within 30 days of operation and may or may not be directly

related to the procedure itself. Infections after surgical procedures

have a terrible impact on the patient’s outcome, causing longer

hospital stay, surgical complications and even death. Risk factors for

postoperative infections are diabetes, obesity, older age, emergency

operations and obvious contamination of the injury or surgical area.

Prevention of postoperative infections consists in the right choice of

antimicrobial prophylaxis, adequate timing and duration of antibiotic

therapy and glycemic control in diabetic patients.18

Antibiotics are paramount in the treatment of infections, but cultures

need to be taken in order to check for bacterial susceptibility to the

chosen agent. If orthopedic devices are involved in the infection, they

need to be removed and eventually replaced.

The most common postoperative infections are surgical site

infections (SSIs), accounting for 38 percent of all nosocomial

infections in surgical patients and developing in 2 to 5 percent of

27
 them.19 Pneumonia and catheter associated UTIs are also common

in the postoperative setting.

2. Pressure sores: these injuries are typical of bedridden patients and

pose a risk for infection. Using pressure-reducing devices (e.g.

Mattresses) and positioning patients properly are the two most

important measures to be taken for preventing pressure ulcers;20

3. Phlebothrombosis: hip procedures, being major orthopedics

surgeries, carry a high risk of venous thromboembolism (VTE).

Prophylaxis should be administered to all patients after assessing the

risk of bleeding and should consist of LMWH or DOACs. Prophylaxis

should be initiated also in those patients with a fractured hip who do

not undergo surgery, as the fracture in itself poses an increased risk

for VTE;

4. Postoperative anemia: Anemia is defined by the WHO as Hb level <

13 g/dL in men and < 12 g/dL in women. The prevalence of anemia

on admission in hip surgical patients in literature is 45.6 percent and

its presence correlates with higher 6-months and 12-months

mortality21. As the older patients frequently display multimorbidity, it

is common for them to develop anemia of chronic disease.

Postoperative anemia is multifactorial, it can both result from a pre-

existing anemia or from blood loos due to the trauma or the surgical

procedure. Anemia has a negative impact on patients’ outcome and

quality of life. A postoperative hematocrit of < 30 percent, as well as

a greater intraoperative blood loss and more postoperative

28
 transfusions, are predictors of development of delirium, with all the

negative implications it carries in itself.22 Specifically regarding hip

arthroplasty, a positive correlation has been found between Hb levels

on discharge and changes in QoL two months after surgery.23 Blood

transfusion has no clear-cut indication and its employment needs to

be carefully tailored to the single patient, as allogenic red cell

transfusion is itself correlated with increased postoperative infections

in hip fracture patients, adding to the already present literature

showing adverse clinical outcomes in patients receiving blood

transfusions.24 Evidence is emerging in support of the use of

“transfusion sparing” interventions for perioperative blood

management. [Anemia in the older surgical patient: a review of

prevalence, causes, implications and management] Factors

influencing the choice to transfuse a patient are numerous, but

laboratory values are inadequate to define the appropriateness of

therapy. When caring for elderly patients a target Hb of 9-10 g/dL is

recommended.25

The development of VTE and pressure sores is strongly facilitated by

immobilization, prolonged bed rest and spica casts, which are used in

conservative management of hip fractures.

Local complications, specific for internal fixation, are:

29
1. AVN of the femoral head: it is a typical late onset complication of

medial proximal femoral fractures and it becomes more likely as the

line of fractures shifts medially (it is more likely in Garden Type IV

injuries than Garden Type I). This condition is vascular in origin, as it

is due to the interruption of blood supply to the femoral head by

circumflex arteries. AVN is an insidious condition which starts with

persistent hip pain, even if the fracture has consolidated. On X-ray

imaging, the head shows radiopaque areas, representing necrosis of

cancellous bone, and alteration of the femoral profile, representing

the flattening of the trabeculae (Figure 15) . Treatment of AVN of the

femoral head consists in THA.

Figure 15: Normal AP x Ray of a hip (left); AP x Ray of a hip with AVN of the femoral head.

2. Pseudarthrosis of the femoral neck: This condition is exclusive of

medial fractures, due to the scarce blood supply of the proximal

fragment. It can also happen in well vascularized heads, without

progression to necrosis. On X-rays the fracture line remains apparent

and the neck is reduced in length or, rarely, is completely radiolucent

30
 due to reabsorption phenomena. Treatment depends on patient’s

age and elderlies most often undergo THA, allowing early

weightbearing and walking.

3. Varus/Valgus consolidation: it is a late complication of lateral

fractures, especially if the treatment was not surgical. Varus

consolidation is responsible for the origin of hip osteoarthrosis,

secondary to the alteration of the articular and mechanical

relationship of the femur and acetabulum. Valgus consolidation is

better tolerated.

4. Fracture of intramedullary nail: it is a rare complication of patients

treated with internal fixation, leading to the necessity of complex

revision surgeries (Figure 16). Factors increasing likelihood of

intramedullary nail fracture are low ASA score at time of injury,

pathological fractures and subtrochanteric fractures.26

Figure 16: X ray of a fractured intramedullary nail.

31
1.3: The thyroid gland

The thyroid is a butterfly-shaped gland located anteriorly to the trachea.

(Figure 17)

Figure 17: A visual representation of the thyroid gland both isolated and in relation to surrounding
structures.

Functionally, it is composed by thyroid follicles which are made of colloid

surrounded by follicular (thyrocytes) and parafollicular (C cells) cells.

Follicular cells are responsible for the production of thyroxine (T4) and

triiodothyronine (T3), whether parafollicular cells produce calcitonin. (Figure

18)

Figure 18: Thyroid section representation on the left, thyroid slice histology on the right.

32
Thyroid hormones have a critical role in growth and development in children

while primarily influencing the basal metabolic rate in adults. T3 and T4 are

the sole hormones that need an essential element, iodine, for the production

of their active form. They are stored in the colloid, a highly proteinaceous

material composed mainly of thyroglobulin to which they are bound. Thyroid

hormones act at nuclear level influencing protein synthesis like steroid

hormones.

Calcitonin, produced by C cells, plays a role in Ca2+ and phosphate

homeostasis.

T3 is much more important than T4: even though circulating T4 is 50 times

more than T3, only 0.02% of T4 is free (against 0.50% of T3), part of T4 is

converted into T3 when it enters the cell (T3 and T4 concentration inside

the cells is similar) and thyroid hormone receptors (TR) in the nucleus have

a 10 times higher affinity for T3 than T4. These are the reasons why T3 is

responsible for 90% of TR’s occupancy in the euthyroid state.

Reverse triiodothyronine (rT3) is mostly made outside of the thyroid by

removing an iodine atom from T4 and is an isomer of T3. Functionally, it is

the inactive metabolite of T4.

Thyroid hormones act on the whole body increasing the metabolic rate and

affecting protein synthesis. Specifically, they influence protein, fat and

carbohydrate metabolism having a role in cellular energy consumption. T3

and T4 stimulate futile cycles of catabolism/anabolism increasing energy

33
expenditure and thermogenesis, they stimulate both lipogenesis and

lipolysis, protein synthesis and protein breakdown, gluconeogenesis and

glycogenolysis.

Regulation of thyroid hormone synthesis and secretion is carried out by the

anterior pituitary gland, which in turn is controlled by the hypothalamus.

Neurons in the arcuate nucleus and median eminence of the hypothalamus

secret Thyroid-Releasing Hormone (TRH), which reaches thyrotropes in the

anterior pituitary. TRH stimulates thyrotropes to synthetize and secrete

Thyroid-Stimulating Hormone (TSH or thyrotropin) which, ones in the

thyroid, binds to follicular cells.

TSH, lastly, stimulates T3 and T4 synthesis and secretion.

The regulation of the hypothalamic-pituitary-thyroid axis is carried out by a

negative feedback mechanism: a monodeiodinase in the anterior pituitary

converts T4 into T3, which negatively feeds back on thyrotropes and TRH-

releasing neurons in the hypothalamus. Furthermore, somatostatin and

dopamine released by the hypothalamus inhibit TSH secretion, influencing

the amount of TSH released in response to specific levels of T3. (Figure 19)

34
 Figure 19: Thyroid hormones physiology.

Thyroid disease can be categorized under typical patterns of hormone

imbalance (Figure 20):

• Primary hypothyroidism: high TSH, low FT3 and FT4

• Secondary hypothyroidism: low TSH, low FT3 and FT4

• Hyperthyroidism: Low TSH, high FT3 and FT4

Figure 20: Thyroid imbalances

35
1.4: The parathyroid glands

Parathyroid glands are usually 4 and they are located behind the thyroid.

They are made by chief cells, which synthesize and release parathyroid

hormone (PTH), and oxyphil cells, the function of which is unknown. The

glands monitor calcium levels in the blood and react by changing the

amount of PTH produced and released. (Figure 21)

Figure 21: A visual representation of the parathyroid glands.

PTH acts at the level of the bone, intestine and kidney influencing calcium

and vitamin D metabolism.

PTH causes, through osteoclasts, the release of calcium into the

bloodstream to fine tune the amount of circulating calcium. It also induces

differentiation of osteoblasts into osteoclasts. Osteoclasts have bone

remodeling abilities, thus they degrade hydroxyapatite and other organic

material to release calcium. Under normal circumstances this process does

not influence the structural integrity of the bone. Too much PTH as in

hyperparathyroidism cause osteopenia and osteoporosis, making bones

much more susceptible to fractures.

36
At the level of the kidney, PTH acts in three different ways:

1. It targets the most distal part of the nephron (distal convoluted

tubule and collecting duct) increasing calcium resorption;

2. It decreases phosphate resorption at the proximal convoluted

tubule. As phosphate ions form salt with calcium ions, their

reduction increases plasma calcium;

3. It stimulates the production of 1alpha-hydroxylase in the proximal

convoluted tubule, required for the synthesis of 1,25-

dihydroxycolecalciferol (1,25(OH)2D), the active form of vitamin

D, which in turn has a role in calcium resorption in the distal

convoluted tubule.

At the level of the small intestine, vitamin D plays a role in increasing the

absorption of dietary calcium.27 (Figure 22)

Figure 22: Schematic representation of PTH function

37
Parathyroid disease can cause either a hyper or hypo production of PTH,

giving rise to hyper and hypoparathyroidism.

Hyperparathyroidism is much more common and can be primary, secondary

or tertiary. Primary one is usually due to an adenoma or hyperplasia,

secondary one is caused by PTH hypersecretion in response to abnormally

low calcium levels, usually due to renal insufficiency, malabsorption or

vitamin D deficiency. Tertiary hyperparathyroidism is not common and it is

present when, after the resolution of a condition causing low calcium levels,

PTH hypersecretion continues.

Symptoms of hyperparathyroidism are related to hypercalcemia: thirst,

constipation, bone pain and kidney stones.

Hypoparathyroidism is mostly transient and occurs after a person has

surgical removal of a parathyroid gland. Autoimmune diseases targeting

parathyroid glands are also a common cause of hypoparathyroidism.

Its symptoms are mainly related to hypocalcemia, the symptoms of which

are: ECG abnormalities, Chvosteck’s and Trousseau’s signs (Figure 23),

abdominal pain, muscle cramping and numbness and tingling.

Figure 23: Trousseau and Chvosteck's signs.

38
1.5: Calcium metabolism

Over 99 percent of total body calcium is stored as hydroxyapatite in bones

and teeth. The amount that is circulating and in the extracellular fluid is

fundamental for mediation of vascular contraction and vasodilation, muscle

function, nerve transmission, intracellular signaling and hormonal

secretion.28

Circulating ionized calcium is kept within a narrow range (8.5 and 10.5

mg/dL) and, when it deviates, PTH, calcitriol and calcitonin quickly bring

calcium levels back to their physiologic values.

When calcium drifts below physiologic range, PTH acts at the level of the

bone, kidney and intestine increasing circulating calcium and restoring

homeostasis. PTH also acts at the level of the kidney and intestine to

increase serum phosphorus, which in high concentrations suppresses

calcitriol formation providing a negative feedback.

On the contrary, when calcium goes above physiologic range, thyroid C

cells secrete calcitonin, which inhibits bone resorption and helps lower

circulating calcium levels.28 (Figure 24)

Figure 24: Visual summary of calcium metabolism.

39
1.6: Vitamin D

Vitamin D receptors (VDRs) are found in nearly every tissue and VDR

binding sites are found in hundreds of genes, implying vitamin D participates

in numerous processes throughout the body.29

For what concerns its production, vitamin D is produced in the skin by UV

radiations. Vitamin D is metabolized to 25OHD, its principal circulating form,

in the liver and other tissues. 25OHD is in turn metabolized in the kidney to

1,25(OH)2D, the hormonal form which is responsible for most of vitamin D

biologic action.30

In the topic of femoral fractures and parathyroid glands (PTG) vitamin D has

a pivotal role, acting both on the skeleton and on the PTG itself. Bishop-

Ferrari et al. found that there is a dose dependent correlation between

vitamin D and fracture prevention.31 PTH levels are inversely related to

circulating 25OHD levels, even though this relationship’s interpersonal

variability is large, and maintaining proper levels of 25OHD in the blood

reduces the risk of PTG hyperplasia and increased PTH secretion, in turn

reducing PTH potential negative effect on bone.29 Vitamin D has a role in

many other pathologies as diabetes mellitus, cardiovascular diseases,

metabolic syndrome etc.

40
1.7: Euthyroid sick syndrome (ESS)

Euthyroid sick syndrome (ESS), also known as nonthyroidal illness

syndrome or low-T3 syndrome, is a condition in which thyroid hormones

parameters are abnormal in patients with acute illness but without prior

history of thyroid disease. The most common pattern of presentation of this

condition includes low T3, decreased T4, normal TSH and increased

reversed T3 (rT3), highlighting what is a profound alteration of negative

feedback mechanisms.32 These changes are rarely isolated and usually

correlate with decreased serum gonadotropin and sex hormones and

increased ACTH and cortisol levels.33 (Figure 25)

Figure 25: ESS evolution related to time/severity of disease.

TSH levels are usually within normal range at the beginning of acute illness,

while they tend to decrease with disease progression.

41
The reasons for these changes in thyroid hormone homeostasis when

facing acute illness are not well established. ESS can be seen as

counteracting the excessive catabolism present during illness or as part of

the acute response mediate by cytokines. A variety of mechanisms are

known to take part in the development of ESS, even though no clear and

fully comprehensive mechanism has been described. Even though reduced

T3 and T4 are poor predictors in severely ill patients, treatment aimed at

restoring physiologic levels of thyroid hormones has shown to be even

detrimental in some cases.32

NTIS represents a clear change in thyroid hormone metabolism both at the

level of the hypothalamus-pituitary-thyroid (HPT) axis and at the organ

level.34

42
2: Materials and methods

This is a prospective observational study conducted on all patients older

than 65 arriving to the emergency room (ER) of the Policlinico Agostino

Gemelli Hospital with a hip fracture from September 2018 to May 2019.

Exclusion criteria were admission to the ER >72 hours after injury; ongoing

neoplastic diseases; thyroidal illness; acute cardio-pulmonary events and

therapy with drugs that interact with thyroidal function (calcium carbonates,

cholestirammine, dopamine-agonists, estrogens, growth hormone,

spironolactone, sulfunilurea, octreotide). (Figure 26)

Figure 26: Drugs influencing thyroid function

43
All recruited patients underwent blood sampling for routine blood analysis

and thyroid profiling on arrival, first and third postoperative days and they all

underwent surgery within 48 hours from injury.

Diagnosis of proximal femoral fracture was made radiologically and only

patients with AO fractures 31A and 31B requiring surgical interventions

were included in the study.

Treatment choices have always been made by an experienced orthopedic

surgeon based on patient’s peculiar characteristics and fracture type.

All included patients signed an informed consent to participate in the study

on arrival.

All included patients signed an informed consent giving permission to blood

transfusions if needed.

Anemic symptomatic patients were transfused when below cutoff

hemoglobin values:

• Hb < 7 g/dL in otherwise healthy patients

• Hb < 8 g/dL in subjects suffering from cardio-pulmonary pathologies

Thyroid profiling and vitamin D measurements were performed by

immunoassay method, reference values were:

• TSH: 0.34-3.20 microIU/mL;

• fT3: 2.3-4.2 pg/mL;

44
 • fT4: 8.5/16.5 pg/mL

• vit D: 31-100 ng/mL

According to these values, the diagnosis of ESS was made when fT3 was

< 2.3 pg/mL and fT4 and TSH were within the aforementioned ranges.

PTH measurements were performed via chemiluminescence method,

reference value was 14-72 pg/mL.

Patients anamnestic and anthropometric data were collected in order to

obtain BMI, Charlson Comorbidity Index (CCI), Short Form Health

Questionnaire (SF-12), Activities of Daily Living scale (ADL) and

Instrumental Activities of Daily Living scale (IADL).

Infections were evaluated taking into consideration signs and symptoms of

local and systemic inflammation and documented when positive cultures

were associated with typical signs and symptoms.

Outcomes considered in patients with and without ESS were:

1. Changes in Vit D values

2. Changes in PTH values

3. Number of transfusions

4. Type of fracture

5. Infection incidence

45
2.1: Statistical analysis

Data collected were inserted into an Excel (Microsoft, Redmond, USA)

document and analyzed with SPSS v. 25.0 (IBM, Armonk, New York).

Differences between groups were evaluated with T-student test, Mann-

Whitney U test and Chi Square test.

An additional linear regression analysis was performed on variables which

could represent confounding factors.

46
3: Results

In this study 781 patients were enrolled in the time span of 9 months. Of

these 79 patients, 20 were males (25.3 %) and 59 were females (74.7 %),

highlighting the higher prevalence of hip fractures in elderly women with

respect to men.3

30 patients had a normal thyroid profile on admission (9 males and 21

females), while 49 were diagnosed with ESS (11 males and 38 females).

The group of non-syndromic patients had an average age of 83.5 years (SD

7.2), an average BMI of 24.5 (SD 3.3) and prevalence of arthrosis was 2.47

(SD 0.7).

The group of syndromic patients had an average age of 84.9 years (SD 6.6),

an average BMI of 23.5 (SD 4.4) and prevalence of arthrosis was 2.57 (SD

0.7) in this population.

Average concentrations of fT3, fT4, and calcium on admission were 2

pg/mL, 11.2 pg/mL and 9.2 mg/dL respectively in the ESS group. The

control group showed instead an average of 2.8 pg/mL, 12.4 pg/mL and 9.4

mg/dL respectively. (Figure 27)

47
 Admission values
14
12
10
8
6 11,2
12,4

9,2 9,4
4
2 2,8
2
0
fT3 (pg/mL) fT4 (pg/mL) Ca (mg/dL)

ESS Non-ESS

Figure 27: fT3, fT4 and Ca on admission divided by group

There was no statistically significant difference in age and prevalence of

arthrosis between the two groups, proving how homogeneous they are in

composition.

3.1: Changes in Vitamin D values

Vitamin D changes between admission and first postoperative day were

evaluated using a T-test for dependent means and a T-test for independent

ones.

The control group had a decrease in Vit D value of 2.18 ng/mL (p = 0.001,

CI 1.33 to 3.05).

48
The syndromic group had a more significant decrease in Vit D, 3.96 ng/mL

(p = 0.001, CI 2.81 to 5.10).

After carefully evaluating different factors involved in Vit D changes (BMI,

gender, PTH variation), ESS proved to be a statistically significant predictor

of Vit D concentration decrease when comparing it to controls with a normal

thyroid function (-2.5 ng/mL, p = 0.005, CI -4.225 to 0.826). (Figure 28)

Vit D changes
24
22
20
18
16 22,3
20,1
18,9
14
14,9
12
10
Vit D on admission (pg/mL) Vit D on first post-op day
(pg/mL)
ESS Non-ESS

Figure 28: Vit D values on admission and first post-operative day divided by group.

3.2: Changes in PTH values

After noticing the difference in Vit D concentration between the two groups,

also PTH was evaluated to see if it showed a similar pattern.

49
On admission, the PTH value in the control group was, on average, 68.6

pg/mL and increased to an average value of 98.7 pg/mL on the first

postoperative day.

The syndromic group had an initial average value of 104.6 pg/mL and

showed an opposite trend decreasing to 98.1 pg/mL on the first

postoperative day.

These differences were first evaluated with a T-test for dependent means,

then with a T-test for independent ones. (Figure 29)

PTH changes
110

100

90
104,6
80 98,1 98,7

70
68,6
60
PTH on admission (pg/mL) PTH on first post-op day
(pg/mL)

ESS Non-ESS

Figure 29: PTH values on admission and first post-operative day divided by groups.

Controls thus had an increase of 30 pg/mL of PTH (p = 0.004, CI -49.4 to

10.86), whereas syndromic patients had a decrease of 6.45 pg/mL (p =

0.382, CI -8.5 to 21.4).

50
T-test for independent means thus showed that the difference between the

two groups averages was 36.6 pg/mL (p = 0.003, CI -60.0 to -13.2).

A multiple regression model which took into consideration BMI, gender and

Vit D differences unveiled a statistically significant difference between the

two groups, which corresponded to PTH values 44.29 pg/mL lower in

syndromic patients with respect to controls.

3.3 Number of transfusions

The difference in transfusion need between the two groups has been

evaluated and demonstrated. The T-student test revealed an average

number of transfusions 1.06 higher in ESS patients with respect to controls

(t = 2.75; df = 25.07). (Figure 30)

This result is statistically significant (p = 0.01, CI -1.9 to -0.3), allowing for

the rejection of the null hypothesis (that there was no difference in

transfusion necessity between the two groups).

Even though the number of participants did not allow us to make a normal

distribution, we used the Mann-Whitney U test which was statistically

significant (p = 0.02) highlighting the differences in number of blood

transfusions in the two groups of patients.

51
 Transfusions
1,8
1,6
1,4
1,2
1
0,8
0,6
0,4
0,2
0
ESS Non-ESS

Figure 30: Average number of transfusions divided by groups.

We proceeded employing a linear regression model which could rule our

confounding factors influencing blood loss.

Only one patient was on anticoagulants and 30 % of patients were on

cardioaspirin.

In a linear regression model, after checking for variations due to gender and

cardio-aspirin therapy, ESS was a statistically significant predictor of an

increased need of blood transfusions showing a 1 unit-increase in blood loss

with respect to controls.

52
3.4 Type of fracture

When dividing patients according to the type of fracture, there is no

statistically significant difference in age (p = 0.06).

The degree of arthritis in patients affected by peritrochanteric fractures is

0.46 points lower than in those affected by neck fractures (p = 0.002; CI

0.11 to 0.53).

Despite the larger age span among those affected by the syndrome, no

statistically significant difference could be noted for this variable among

those affected by ESS compared to controls (p = 0.7).

The presence of the syndrome is not a significant predictor of

peritrochanteric fracture when adjusting for the aforementioned variables.

The participants affected by ESS have an OR of getting a peritrochanteric

fracture 91% higher than the non-affected counterpart. This result is,

however, not significant (p = 0.204). (Figure 31)

Figure 31: Type of fracture in relation to fT3.

53
3.5 Infection incidence

Our sample size is not large enough to have a clear-cut result regarding the

relationship between ESS and infection incidence, but a preliminary

statistical analysis points towards a causal relationship between the two.

Further analysis should shed light on the impact thyroid imbalances have

on the immune system and the development of post-operative infections,

possibly opening an important chapter of infection prevention in surgical

patients.

54
4: Discussion

4.1 ESS

ESS is a clinical entity which is very common amongst hospitalized patients

and has been described in a great variety of acute and chronic conditions,

especially in the elderlies in long-term care.35

The presence of ESS correlates with an increase in postoperative

complications, infections, low levels of albumin and selenium and

malnutrition.35 36

Recent evidence seems to indicate that the initial adaptive response to an

acute condition consists mainly in an increased peripheral inactivation of

thyroid hormones and, reducing energy expenditure and activating the

immune response, this would prove to be beneficial to the organism.

In contrast, a prolonged illness seems to provoke a central suppression of

the thyroid axis, aggravating the syndrome and proving to be maladaptive.37

At the molecular level, ESS appears to be caused by an alteration of

deiodinases activity (decreasing transformation of T4 into T3), by

inflammatory cytokines and by a reduction in sensitivity of the hypothalamus

to thyroid hormones.38

IL-6 in particular correlates with the presence of ESS and is subject to wide

variations in patients with hip fractures.39

Maia et al40 demonstrated that most circulating T3 derives from muscle D2-

deiodinase. Hip fractures cause muscle tissue damage and immobility,

55
possibly giving rise to ESS in this context and justifying the high percentage

of patients with a proximal femur fracture having the syndrome.

T3 has a stimulating role in muscle tissue, increasing the rate of contraction-

relaxation.41 The role of mitochondria in muscle pathologies is well known

and could shed light on a relationship between sarcopenia and the

consequences of its presence in patients affected by ESS.

The correlation between trauma and ESS has already been described in

literature but never had it been studied specifically in proximal femur

fractures. Our study also evaluates how the presence of ESS in hip fracture

patients has an impact on the Vitamin D-PTH axis, causing alterations in

calcium metabolism.

4.2 Calcium metabolism

An increase in PTH is a risk factor for pertrochanteric fractures and the risk

of falling strictly correlates with functional recovery.42,43

The presence of low vit D in patients with proximal femur fracture is well

described in literature.44 In our study, low vit D (< 20 pg/mL) was present in

57.7 % of participants.

In response to hypovitaminosis D an increase in PTH is to be expected, but

in our sample PTH had a peculiar trend: it increased in response to low vit

D in controls and instead decreased in syndromic participants.

56
Johansen et al.45 found that PTH levels in femoral fracture patients are

important in the evaluation of the metabolic state of the subject in the

postoperative period.

Moreover, PTH is linked to IL-646, which has a pivotal role in the

development of ESS.

PTH’s role in calcium homeostasis is to move calcium from bone to the

bloodstream. When PTH is elevated it inevitably causes bone to lose its

calcium storage making it less resistant to stress and trauma, a condition

called osteopenia or osteoporosis, depending on the degree of bone

weakening.

After a fracture, the physiologic response is for PTH to increase, causing a

mobilization of calcium storages which helps in the process of fixation of the

fracture. When comparing the two groups of participants (syndromic and

controls), there is a significant difference in PTH’s response: PTH increased

by 30 pg/mL (p = 0.004, CI -49.4 to 10.86) in controls, whereas it decreased

by 6.45 pg/mL (p = 0.382, CI -8.5 to 21.4) in the syndromic group.

PTH in participants with ESS showed an opposite trend compared to

controls, suggesting a maladaptive and non-physiologic response to trauma

and injury in syndromic patients.

Vitamin D trends also differed in the two groups: syndromic participants had

a bigger decrease in vit D values on the first postoperative day (-2.5 ng/mL,

p = 0.005, CI -4.225 to 0.826) with respect to controls.

57
Vit D has been linked to a wide variety of pathologies and more specifically

to thyroid pathologies47, justifying our results, even though a causal

relationship is yet to be defined.

Vit D’s effects go beyond calcium homeostasis, being implicated in the

activity of the immune and cardiovascular systems.48

Our results seem to point towards a link between ESS and hypovitaminosis

D, specifically to the latter exacerbating the syndrome (and all its

consequences), and not merely to these subjects being more susceptible to

hypovitaminosis D.

It’s possible that these abnormal responses to acute stress in ESS patients

are also present as a result of minor stressors, which do not require

hospitalization, but have a significant impact in long-term prognosis of

syndromic patients.

The elderlies are very susceptible to dietary deficiencies and ESS can

exacerbate this predisposition. Moreover, the altered bone metabolism

derived from the impaired calcium homeostasis could impact bone’s

structural integrity causing secondary fractures and other complications.47

58
4.3 Type of fracture

In our population, patients experiencing a peritrochanteric fracture had a

degree of arthritis 0.46 lower than those experiencing a neck fracture (p =

0.007, CI 0.12 to 0.89). The relation between hip osteoarthritis (OA) and hip

fractures has been widely studied and described in literature: some authors

have found OA to be a risk factor for extracapsular fractures (i.e. neck

fractures) and a protective factor for intracapsular ones (i.e. peritrochanteric

fractures).49 The rationale behind this relationship stems from the increased

bone density of the femoral neck which is associated with hip OA.50

Other studies instead found no relationship between type of hip fracture and

OA prevalence, leaving the topic still up for debate.51

According to Fisher et al., PTH plays a pivotal role in the type of fracture

patients suffer: they found that a marked PTH response to hypovitaminosis

D correlates positively with peritrochanteric fractures, whereas a weak or

absent response correlates positively with cervical ones.52 This is explained

by micro-foci of bone weakness in the trochanteric region that these poor

responder to hypovitaminosis develop. Our study seemingly identified the

possible cause of this relationship: syndromic patients show higher PTH

levels on admission when compared to controls, together with the inability

to raise PTH after the fracture. A pre-existing Non-thyroidal Illness

Syndrome (NTIS) would explain the initially raised PTH and could be the

reason why peritrochanteric fractures are more represented in the

syndromic group.

59
Controls instead have lower PTH values on admission and respond

appropriately to the trauma and surgical insult raising PTH levels to mobilize

calcium.

Unfortunately we do not have data regarding the baseline thyroid profile of

our participants, and a population study is needed in order to define the

causative relationship between ESS, PTH and the type of fracture, but our

results seem to point in that direction as participants experiencing a

peritrochanteric fracture showed levels of fT3 0.35 points lower than those

having a cervical one (p = 0.002, CI 0.11 to 0.53).

4.4 Number of transfusions

Anemia plays an important role in patients with chronic pathologies.

Anemia of chronic disease is a well-defined clinical entity and is mostly

related to shortened red blood cell (RBC) survival, impaired erythropoiesis

and altered iron metabolism. More specifically, an increase in hepcidin

inhibits iron absorption and recycling leading to sequestration.47

Hepcidin production is stimulated by inflammatory cytokines as TNF, IL-1

and IL-6, which increase iron sequestration and its reduction in

reticuloendothelial cells, also decreasing ferroportin absorption.53

60
Iron deficiency has consequences both on thyroid hormone secretion and

on T4 conversion into T354, just like pro-inflammatory cytokines in ESS

contribute to the decrease of circulating T3. It’s also plausible that

alterations in iron homeostasis, being due to inflammatory cytokines (mostly

IL-6), contribute to reduction of T3 in ESS more than in other

circumstances.47

Some authors found a direct relationship between T3 and T4 values and

some erythrocyte parameters (Hb, hematocrit, erythrocyte count) and some

hormonal changes correlate with alterations of these parameters to the point

where clinically significant anemia develops.55

Fractures and surgical operations both cause hemorrhages and subsequent

anemia.

Post-operative anemia is very common in surgical patients and is clearly

associated to a great variety of adverse outcomes, as it has also been found

to significantly increase risk of death in fragile patients.56 57

Scientific evidence clearly highlights the clinical benefits blood transfusions

carry, but their use is still controversial due to their association to adverse

outcomes.

Some studies found perioperative blood transfusions to be correlated to an

increase in infection incidence but a decrease in postoperative delirium58,

which is a good predictor of post-operative mortality.

Blood transfusions significantly improved the prognosis of elderly patients

with hip fracture.

61
Other authors found that perioperative transfusions are an independent and

important risk factor for post-operative mortality.59

Halm et al. demonstrated that correcting anemia correlates with a better

quality of life in relation to the global health status of the subject.60 They also

found that anemia causes prolonged hospital stays, increases post-

operative re-admission and slows functional recovery after the operation.60

4.5 Infections

The relationship between ESS and infection incidence was extensively

evaluated in this study. Even though when comparing the two groups there

was not a statistically significant relationship between ESS and infection

incidence, syndromic patients showed a higher incidence of infections on

average.

Even though our sample is not numerous enough for this result to acquire

statistical significance, the relationship between ESS and postoperative

infections in surgical patients has already been evaluated and proved to be

significant in other kinds of surgery.61

The immune system’s function is influenced by a great variety of hormones

and stimuli, including thyroid hormones and vitamin D. Syndromic patients

do not have a physiological hormonal profile so it is understandable how

they would be more prone to suffering post-operative infections with respect

to controls.

62
Further investigation should be carried out increasing the number of

participants in order to shed light on the relationship between ESS and

infection in hip fracture patients.

63
5: Conclusions

This study highlighted the prevalence of ESS in patients with proximal

femoral fracture.

ESS had already been studied both in acutely and chronically ill subjects,

but to our knowledge it had never been specifically studied in the context of

hip fractures.

When comparing the two groups, it is clear how ESS affects patients’ global

health status and how it can impact disease progression and functional

recovery. If the relationship between hip fracture and ESS was to be

confirmed in a larger study, it would be paramount to take into consideration

the presence of the syndrome and its consequences.

It is clear how ESS is a positive predictive factor for the necessity of

transfusions.

We think results related to postoperative anemia indicate the need for

thyroid profiling in order to identify the patients at increased risk, so that

preventive measures can be implemented.

Syndromic patients also showed abnormal levels of PTH and vit D, linking

the syndrome to a wider concept of patients’ well-being.

Continuing recruitment and analyzing the differences between the two

groups in further studies, it will be possible to understand all the implications

and the pathogenesis of ESS in hip fracture patients. A deeper

understanding of the subject would also allow us to find links between the

64
syndrome and mortality or postoperative complications, focusing on

functional recovery in further follow-ups.

The incidence of postoperative infections in the two groups needs further

investigation in order to clarify how the syndrome influences its

development. A direct relationship between the two could call for the

implementation of more serious preventive measures in patients with an

altered thyroid profile on admission, positively impacting the surgical

outcome.

65
 Tables

Table 1: Anamnestic data, routine blood analysis and CCI of our sample population.

ESS Non-ESS p-value

Gender 11 M - 38 F 9 M - 21 F

Age 84,9 83,5 0,8

BMI 23,5 24,5 0,02

Hb 11,9 12,4 0,2

Na 138,7 139,1 0,6

K 4,3 4,3 0,8

Albumine 28,6 29,8 0,2

Creatinine 0,89 0,96 0,3

ALT 14,5 17 0,3

CCI 0,7 1,1 0,2

66
 Table 2: fT3, fT4, Ca, PTH and Vit D values throughout illnes divided by group.

ESS Non-ESS p-value

fT3 2 2,8

fT4 11,2 12,4 0,03

Ca on admission 9,2 9,4 0,1

Ca on first post-op day 8,3 8,7 0,01

PTH variation -6,4 30,1 0,001

Vit D variation -4 -2,2 0,01

67
 Table 3: Number of transfusions, INR, anticouagulation therapy and duration of surgery divided by group.

ESS Non-ESS p-value

Transfusions 1,56 0,5 0,01

INR 1,07 1,23 0,34

NAO 0 0 1

TAO 0 2 1

ASA 16 13 0,72

Duration of surgery (min) 67 86 0,1

Table 4: Infection and diabetes in the two groups.

ESS Non-ESS p-value

Infection 11 4 0,1

Diabetes 11 7 0,6

68
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6 years of struggle, of success and failures, of blue

and yellow, of dreams and plans.

Thanks to my parents who guided me through it all;

Thanks to Chiara who never let me doubt myself;

Thanks to Lorenzo who never left my side;

And thanks to all those who gave a meaning to this

(almost) never-ending journey.

77