Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2745_Библиотеки_им_академика_М_И_Перельмана
.pdf
the body has prompted dedicated research in the last 2 decades
exploring vitamin D’s role in the disease process that leads to
and perpetuates MS. Several observational studies have shown
a higher MS risk in individuals with low serum 25dihydroxyvitamin D [25(OH)D].
2,3
Others, such as Mokry et
al, used Mendelian randomization to show that individuals
with genetically lower 25(OH)D had a twofold greater odds of
MS. 4 It appears that vitamin D status not only is associated
with risk of MS but also plays a role in modulating the degree
of disease activity.
5-7
Other studies have demonstrated an
effect of vitamin D supplementation on MS disease activity. A
randomized, double-blind, placebo-controlled study conducted
in Finland found that vitamin D3 supplementation at
20,000 IU weekly had no adverse effects, but the vitamin D3
(add-on treatment to interferon [IFN]-b) group had a
significantly lower number of gadolinium-enhancing lesions
on brain magnetic resonance imaging (MRI). 8 The double-
blind, multicenter, 48-week SOLAR (double blind placebo
controlled study of high dose cholecalciferol oil add on
treatment to subcutaneous interferon beta 1a) study is the
largest study to date. 9 The authors found no statistical
significant differences in disease-free activity between the
placebo group and the vitamin D group. However, there was a
nonsignificant trend toward lower relapse rates in the vitamin
D-treated group as well as a statistically significant reduction
in new lesions at 48 weeks. Several other randomized
controlled studies are currently underway to further elucidate
the role of vitamin D in MS.
It is recommended that all patients with MS or MS risk factors
be screened for vitamin D deficiency. 25(OH)D should be the
assay used to evaluate vitamin D status. Vitamin D deficiency
is defined as a 25(OH)D below 20 ng/mL, and vitamin D
insufficiency as a 25(OH)D of 21 to 29 ng/mL. 10 Vitamin D
comes in multiple forms. Vitamin D2 (ergocalciferol) is the
plant form of vitamin D and is primarily manufactured.
Vitamin D3 (cholecalciferol) is found in animal-based foods
and synthesized in humans in the skin by a photolytic process.
11
https://t.me/medicina_free
Foods rich in vitamin D include fatty fish (e.g., salmon,
mackerel), cod liver oil, egg yolk, and shiitake mushrooms.
Cholecalciferol and ergocalciferol are also available from
fortified foods (e.g., milk, cereal, orange juice, and cheeses).
In general, diet by itself is often a poor source of vitamin D,
providing only 40 to 400 IU per food serving. It is also
important to note that sunlight (ultraviolet B) exposure and
vitamin D production in the skin is highly variable. Factors
such skin pigmentation, age, use of sunscreen, and
environmental factors such as winter season, high latitude,
pollution, cloud cover, and ozone levels will alter an
individual’s vitamin D production through the skin.
12
Vitamin D supplementation through food and production
through sunlight will often be inadequate and unpredictable.
Therefore, in the setting of vitamin D deficiency or
insufficiency, it is not recommended for individuals to use
food or sunlight as their main source of repletion. Vitamin D
supplementation can be administered daily, weekly, or
monthly. Vitamin D3 (cholecalciferol) is widely preferred over
vitamin D2 (ergocalciferol), as it has been proved to be the
more potent form of vitamin D in humans. 13 The Endocrine
Society recommends a daily supplement dose of 600 to 800 IU
to satisfy the requirements for optimal bone health, but a
higher intake (1500-2000 IU) may be needed to achieve and
maintain 25(OH)D levels at 30 ng/mL. 10 Considering current
evidence, many clinicians who treat patients with MS may
choose to empirically supplement to a higher vitamin D level
goal, such as 40 to 60 ng/mL, until more conclusive data are
found. To obtain such levels, patients may need to take
between 2000 and 5000 IU/d of vitamin D.
11
Vitamin D toxicity is a rare event caused by inadvertent or
intentional ingestion of excessively high amounts of vitamin
D. 10 The Endocrine Practice Guidelines Committee expressed
concerns in individuals with 25(OH)D levels of 150 ng/mL or
higher, when daily doses of vitamin D exceed 10,000 IU or
when high intake of vitamin D is combined with high intake of
calcium (>1200 mg daily). 10 Although the study was of
limited duration, Kimball et al showed that large doses of
vitamin D supplementation ranging from 28,000 to
https://t.me/medicina_free
280,000 IU/wk was well tolerated and had no significant
adverse effects such as hypercalcemia or hypercalciuria.
14
Other studies performed in pregnant patients demonstrate
safety with giving doses of 50,000 IU weekly for up to
12 weeks or a dose as high as two doses of 300,000 IU
intramuscularly. 15 Additionally, there have been several
studies conducted specifically in patients with MS that showed
safety using doses of vitamin D above 10,000 IU/d.
14,16,17
Follow-up in these studies ranged from 12 weeks to 1 year. To
date, there is a paucity of evidence supporting the use of
higher doses of vitamin D over a prolonged time; therefore,
regardless of the dose of supplementation initiated, we
recommend that 25(OH)D levels are checked 3 months after
initiating supplementation and trended over time to ensure
levels are within goal and to adjust vitamin D dose. Caution
should be taken in patients with impairment of renal function
or other disease states such as sarcoidosis or lymphoma that
could compound the effects of vitamin D supplementation and
lead to hypercalcemia. Additionally, there is some evidence to
suggest that higher doses of vitamin D is associated with an
increased risk of falls in the elderly.
18
Case Study
Case: A 55-year-old woman with history of MS is referred
to you for a low 25(OH)D level. Three months ago, she was
found to have a 25(OH)D of 15. She was administered
vitamin D3 400 IU twice a day by her primary care
physician. Repeat laboratory tests today show a 25(OH)D of
16. What should you recommend to treat this patient’s
vitamin D deficiency?
She should be given ergocalciferol (D2) 50,000 IU weekly
for 8 weeks. Following that, she should be maintained on
vitamin D3 2000 to 5000 IU daily. 25(OH)D levels should
be determined again in 3 months for further dose
adjustments for a goal 25(OH)D level of 40 to 60 ng/mL.
https://t.me/medicina_free
Management of Glucocorticoid-Induced
Osteoporosis
GCs have a particularly large impact on bone loss and
fractures. 19 The highest rate of bone loss occurs within the
first 3 to 6 months of GC treatment followed by a slower
decline with continued GC use. 20 Both high daily and high
cumulative GC doses increase the risk of fracture, particularly
vertebral fracture, because of the greater effects of GCs on
trabecular bone than on cortical bone. However, this effect is
largely reversible. Once GC treatment is terminated, bone
mineral density increases and fracture risk declines.
20
Physicians should take a thorough history evaluating the
details of GC use (dose, duration, pattern of use) and assess for
risk factors for osteoporosis and fractures (falls, history of
fractures, frailty, low body weight, hypogonadism, secondary
hyperparathyroidism, thyroid disease, family history of hip
fracture, history of alcohol use or smoking). In patients older
than 40 years, it is recommended that the FRAX calculator
(https://www.sheffield.ac.uk/FRAX/) be used to assess fracture
risk if the patient does not have osteoporosis. When GC use is
included as a risk factor in FRAX, the risk generated is
associated with a prednisone dose of ≤7.5 mg/d; therefore,
fracture risk should be increased if patients are on a dose
above 7.5 mg/d (15% for major osteoporotic fracture and 20%
for hip fracture risk). 21 Patients treated with long-term or
high-dose GC who have concomitant osteoporosis risk factors
are the individuals at the highest risk of GC-induced
osteoporosis. These patients should undergo bone mineral
density testing within 6 months of beginning GC treatment.
22
In addition to causing bone loss and fractures, steroid use puts
individuals at risk for avascular bone necrosis (AVN). Steroids
are now the second most common cause of AVN after trauma,
and the prevalence of AVN varies between 3% and 38%.
23
The pathogenesis of GC-induced AVN is not fully understood,
but it has been hypothesized to involve progressive destruction
of bone vasculature and death of osteocytes, ultimately leading
to alteration of bone architecture. 23 The duration of steroid
treatment, the total cumulative dose, and the highest daily dose
https://t.me/medicina_free
of steroids have been implicated as important factors in the
development of avascular necrosis. AVN is typically
characterized by pain that is gradual in onset, worsens with
activity, relieved by rest, and radiates from the joint down the
affected limb. It is important for clinicians to be mindful of
these symptoms in their patients taking steroids, as early
diagnosis is crucial to prognosis. Conventional radiography is
generally the first-line test, with MRI being the most sensitive
modality in diagnosing AVN.
23
The American College of Rheumatology 2017 Guidelines
recommend that all patients taking prednisone ≥2.5 mg/d for
≥3 months should have a calcium intake of 1000 to 1200 mg/d
and 600 to 800 IU/d of vitamin D in addition to lifestyle
modifications of smoking cessation, limiting alcohol intake,
and incorporating resistance exercises into daily routine.
22
Those with moderate to high risk of fracture should be treated
with oral bisphosphonates (BPs) such as alendronate 70 mg
weekly, ibandronate 150 mg monthly, or risedronate 35 mg
once weekly. Oral BPs are preferred for safety, cost, as well as
the lack of evidence of superior antifracture benefits from
other osteoporosis medications. An advantage of oral BPs is
that they can be stopped if GCs are discontinued; however,
because they are poorly absorbed in the gastrointestinal tract,
they should be used with caution in patients with upper
gastrointestinal disease because of the potential for worsening
of gastrointestinal symptoms. For those who do not tolerate
oral BPs because of gastrointestinal side effects, intravenous
BPs (zoledronic acid 5 mg intravenously per year) can be
used. All BPs are contraindicated in patients with
hypocalcemia and renal impairment (creatinine clearance
below 30 mL/min) and in those who are pregnant or lactating.
Rare but recognized side effects of long-term BP use include
osteonecrosis of the jaw and atypical subtrochanteric or
diaphyseal femoral fractures. Given these concerns, patients
on BPS should discuss the medications with their dentist/oral
health care provider. Additionally, the need to continue
treatment should be reviewed at regular intervals. After
5 years of oral alendronate, risedronate, or ibandronate or after
3 years of intravenous zoledronic acid, fracture risk should be
reassessed and a drug holiday should be strongly considered.
https://t.me/medicina_free
Lastly, if oral or intravenous BPs are contraindicated, other
options include recombinant parathyroid hormone (teriparatide
20 µg subcutaneous daily) and monoclonal antibody RANK
ligand inhibitors (denosumab 60 mg subcutaneous every
6 mo).
Adrenal Gland
Evaluation and Management of Adrenal
Insufficiency
Another major complication that comes with GC use for
longer durations is the suppression of the HPA axis. 24 With
exogenous steroid use, the adrenocorticotropic hormone
(ACTH)-secreting cells of the pituitary atrophy so that when
steroids are withdrawn, the pituitary fails to respond
appropriately and low ACTH with subsequently low cortisol
levels are observed. The longer an individual takes exogenous
steroids, the more likely the adrenal gland itself also atrophies
leading to an impairment of the adrenals to respond to ACTH.
Depending on the duration and dose of GC use, the degree of
HPA axis suppression can vary. In general, patients who are
more likely to develop HPA axis suppression are those who
receive high doses (>20-30 mg prednisone or equivalent) of
systemic GCs for long periods (>3 wk) and those who appear
to have Cushingoid features. 25 Individuals with adrenal
insufficiency typically exhibit nonspecific symptoms such as
fatigue, decreased appetite, and abdominal discomfort;
however, when they are exposed to any stressor, these same
individuals can become critically ill with nausea, vomiting,
orthostatic hypotension, and even hemodynamic instability.
The full recovery of the HPA axis varies from 1 week to
several months after discontinuation of GCs.
26
Before starting any course of GC, clinicians should educate
their patients about the risk and symptoms of adrenal
insufficiency. It is important for clinicians treating patients
with MS to have a high suspicion for adrenal insufficiency
particularly in patients after discontinuation of high-dose or
https://t.me/medicina_free
long-term treatment of GC or patients with nonspecific
symptoms after discontinuing steroids of any dose or duration.
To identify patients with suppressed endogenous cortisol
production, the standard high-dose cosyntropin stimulation test
should be performed. This test consists of measuring serum
cortisol immediately before and 30 and 60 minutes after
administration of 250 µg of cosyntropin, a synthetic derivative
of ACTH. Normal adrenal function is indicated by a serum
cortisol concentration ≥18. Those patients with cortisol
concentration ≤18 need to be considered for GC replacement
therapy under the guidance of an endocrinologist. The
stimulation test should be performed once the patient has
stopped taking steroids or is given a physiologic dose of
steroids (hydrocortisone 10 mg in the morning and 5 mg in the
evening or prednisone 5 mg daily). If a patient continues to
take steroids at physiologic dosing, then he or she must not
take the steroid on the morning of the stimulation test and
instead must wait until completing the stimulation test.
Management of Iatrogenic Cushing
Syndrome
Development of iatrogenic Cushing syndrome (CS) is another
potential complication seen in patients receiving long-term
high-dose steroids. Although patients taking steroids of higher
doses and longer durations are at higher risk of developing CS,
it is difficult to predict exact doses and the time course at
which CS will develop owing to factors such as varying GC
potency, formulations, and administration method, in addition
to other medications that the patient may be taking that can
influence steroid metabolism. 27 Exogenous CS presents with
the same signs and symptoms as spontaneous CS. The CS
stigmata includes central obesity, dorsocervical and
supraclavicular fat pads, moon facies, thin skin, straie, and
proximal muscle weakness.
The diagnosis of iatrogenic CS requires clinical suspicion.
These individuals will have surprisingly very low morning
serum cortisol particular for their degree of Cushingoid
features. 28 ACTH levels will also be low because of
https://t.me/medicina_free
suppressed pituitary production. The treatment for iatrogenic
CS is dose reduction or discontinuation of steroid therapy.
However, this often poses a clinical challenge because of
concern of HPA-axis suppression (as discussed earlier) or
exacerbation of underlying MS symptoms for which steroids
were initiated. For this reason, clinicians should always initiate
GC therapy judiciously; using the minimum dose for the
shortest duration possible along with frequent follow-up to
reassess for MS-related symptoms.
Glycemic Control and Metabolic
Syndrome
Type 1 Diabetes Mellitus and Multiple
Sclerosis
Type 1 diabetes mellitus (T1D) is caused by autoimmune
destruction of pancreatic islet cells, resulting in irreversible
insulin deficiency. Similarly in MS, there is an autoimmune
destruction of myelin in the central nervous system. Both
diseases have been noted to occur at a higher rate in patients
with one of the diagnoses. The similarity in epidemiology,
clinical, and immunologic features suggest a possible common
mechanism of development or genetic predisposition.
29-31
In a cohort study done in Sardinia, the prevalence of T1D in
patients with MS was five times greater than that of the
general population sample. The prevalence was three times
greater when compared with healthy siblings. Healthy patients
with a first- or second-degree relative with MS also had an
increased risk of developing T1D. 29 Other studies analyzing
the reverse (development of MS in patients with T1D) have
resulted in similar rates of concurrence.
30,31
The etiology of
the association is unclear. There may be a shared HLA-DR,DQ
genetic locus, although the haplotype is unclear. In a genomewide linkage scan, there were two specific regions at 10q21.1
and 20p12.3 that coincided. 32 Currently, the precise genetic or
environmental link between the two conditions is yet to be
fully understood.
https://t.me/medicina_free
Microvascular and Macrovascular
Complications of Diabetes Mellitus and
Multiple Sclerosis
In addition to the diagnosis of diabetes itself, microvascular
and macrovascular complications of T1D affect the overall
health of patients with MS. Diabetic neuropathy damages the
peripheral nervous system, resulting in paresthesias, sensory
loss, neuropathic pain, and autonomic dysfunction.
Uncontrolled hyperglycemia can result in increased risk of
cerebrovascular accidents. Recurrent severe hypoglycemia can
result in cerebral ischemia, cognitive dysfunction, or
impairment of coordination and executive function. 31 Macular
edema is a prominent adverse event in patients treated with
fingolimod (a sphingosine-1-phosphate receptor modulator)
for relapsing forms of MS. Diabetes itself is a risk factor for
macular edema, by weakening the retinal vasculature, and
approximately 10% of patients with diabetes develop macular
edema. Therefore, patients with diabetes being treated with
fingolimod may have a higher predisposition to developing
fingolimod-associated macular edema (FAME) and should be
screened at baseline as well as 3 to 4 months into treatment. It
is not an absolute contraindication to therapy. FAME does
appear to be dose dependent and typically resolves with
cessation of therapy. 33 Therefore, appropriate diagnosis and
timely treatment of patients with T1D is essential.
Metabolic Syndrome and Multiple
Sclerosis
Patients with MS often have reduced exercise capacity,
increased immobility, and a sedentary lifestyle, which may
lead to metabolic syndrome and cardiovascular disease. In a
study of 130 patients with MS, 30% had metabolic syndrome,
56% had central obesity, 28% had hypertension, and 10% had
type 2 diabetes mellitus (T2D). 34 Other studies have shown
greater body fat mass and fat percentage, higher blood
pressure, resting heart rates, triglyceride levels, and impaired
glucose tolerance. 35 The likelihood for cardiovascular
https://t.me/medicina_free
mortality is significantly greater than in the general population
(up to 2.4-fold increased rate).
34,36
Metformin is often used as
a first-line therapy to decrease insulin resistance in patients
with metabolic syndrome, especially if patients are taking
steroids. Therefore, it is important for patients to maintain
regular follow-up with their primary care doctor to prevent and
manage metabolic syndrome. Of note, the body mass index is
not an accurate measurement for patients with MS, as the
lower ratio of muscle to fat leads to an underestimation of the
amount of adipose tissue.
34
Treatment-Associated Glucose Intolerance
In addition to having increased risk of metabolic syndrome,
patients are frequently on courses of GC therapy.
Approximately 44% of patients with MS have at least one
acute exacerbation a year, the primary treatment of which is
high-dose corticosteroids. Repeated exposure to steroids has
been known to result in steroid-induced hyperglycemia, and
even T2D. Some patients respond well to lifestyle changes,
including limited processed carbohydrates and increase
activity. Patients with preexisting diabetes require adjustments
to their antihyperglycemic regimens. Insulin resistance
associated with steroids profoundly affects postprandial
hyperglycemia. Insulin may be needed depending on when
patients are taking or have stopped taking steroid therapy. It is
essential to work with an endocrinologist to determine the best
regimen to counter the hyperglycemia associated with steroids.
Fluctuations in glycemic control may lead to complications.
Therefore, checking and maintaining steady glucose control
during an MS exacerbation is important.
37
H.P. Acthar Gel (ACTH hormone) is a cosyntropin injection
that is occasionally used in lieu of high-dose steroids for MS
relapses. ACTH acts by stimulating the adrenal cortex to
produce endogenous corticosteroids rather than using
solumedrol, an exogenous synthetic steroid. There have been
reports of hyperglycemia after Acthar Gel administration.
Therefore, it should be used with caution in patients with
known diabetes or prior hyperglycemia, and these patients
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана