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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2745_Библиотеки_им_академика_М_И_Перельмана
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should undergo serial glucose monitoring during treatment.
37
If indicated, consider treatment with metformin to help
decrease overall insulin resistance and insulin therapy in
conjunction with steroid or Acthar Gel doses.
Case Study
Case: A 40-year-old man with a history of MS presents to
you for new-onset hyperglycemia. He has no prior history of
diabetes mellitus. Three days ago, administration of
methylprednisone 500 mg daily was started for symptoms of
an acute MS. He takes methylprednisone every morning and
is to complete 4 days of steroids for a total of 7 days. He
reports symptoms of polyuria and polydipsia that started
yesterday. You do a fingerstick glucose test, and the result is
389. He weighs 95 kg. What is the best way to manage this
patient’s hyperglycemia?
This patient has no prior history of diabetes but now has
steroid-induced hyperglycemia. NPH insulin can often be
used safely in patients with steroid-induced hyperglycemia,
as its duration of action matches steroids with an
intermediate half-life (methylprednisone, prednisone). The
total daily insulin dose can be calculated by multiplying
0.2 U/kg. Half of this would be the patient’s basal
requirement. NPH insulin has a duration of action of
12 hours; thus, taking half of the basal requirement would be
an appropriate starting NPH dose. Therefore, this patient
should be given NPH 10 U daily to be administered with the
steroid dose. Also, metformin can be used with the insulin to
optimize glucose control. Although insulin promotes weight
gain, metformin may help attenuate weight changes and
often helps with weight loss.
38
Thyroid Disorders
Autoimmune Thyroid Disorder
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In the general population, autoimmune thyroid disorder
(AITD) has an estimated prevalence of 5% and is higher in
females as well as patients with other autoimmune disorders.
In one meta-analysis, a summary estimate of prevalence of
AITD in patients with MS was 6.44%. 39 AITD presents as
three clinical phenotypes: autoimmune hypothyroidism
(Hashimoto), autoimmune hyperthyroidism (Graves disease
[GD]), and silent thyroiditis.
Autoimmune hypothyroidism, characterized by elevated
thyroid peroxidase (TPO) antibodies, is the most common. It is
a painless, chronic lymphocytic thyroiditis that develops over
years, eventually resulting in hypothyroidism. Treatment
involves thyroid replacement hormone and is routinely
managed in primary care. Autoimmune hyperthyroidism is the
second most common phenotype, caused by uncontrolled
stimulation of the TSH or thyrotropin receptor by thyroid
receptor antibodies (TRAbs), resulting in thyroid hormone
overproduction. Clinically, patients present like GD and can
even develop orbitopathy. Treatment is a bit more
complicated, involving months of antithyroid medications
(i.e., methimazole) or definitive treatment with radioactive
iodine or thyroidectomy. Symptomatic treatment with a betablocker (i.e., propranolol) is often used. Finally, AITD can be
exhibited as silent thyroiditis, a painless, self-limited subacute
lymphocytic thyroiditis. There are often positive TPO
antibodies, similar to hypothyroidism, but the clinical course is
different. It starts with hyperthyroid symptoms due to
inflammation and leakage of thyroid hormone and then leads
to transient hypothyroidism, with gradual return of normal
thyroid function over weeks to months. Ultrasound uptake and
scan of the thyroid during the hyperthyroid state often shows
decreased uptake (as opposed to increased uptake in Graves).
Treatment is primarily supportive care and close monitoring.
Screening for AITD would entail evaluating clinical symptoms
for hypothyroidism or hyperthyroidism and checking serum
TSH and free T4. Diagnosis of AITD is made via clinical
symptoms and laboratory studies: serum TSH, free T4, and
antibodies (TPO antibodies for hypothyroidism, TRAbs for
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hyperthyroidism). Treatment depends on diagnosis, and close
follow-up with endocrinology is recommended.
40,41
Thyroid Nodules
Thyroid nodules are often found incidentally, either on clinical
examination or on imaging done for another purpose. They are
very common, occurring in up to 50% of the general
population by age 60 years. They are most often benign (over
90%), but all nodules should be further evaluated for
hyperactivity or malignancy. A formal thyroid ultrasound scan
should be ordered, as well as serum TSH and free T4 to assess
if the nodule is producing any excessive thyroid hormone.
Most thyroid nodules are nonfunctioning and do not cause any
symptoms. Rarely, if a nodule is large enough, it can cause
compressive symptoms, such as dysphagia or hoarseness. If on
ultrasound scan the nodule has suspicious features, such as
size >2 cm, calcifications, irregular margins, taller than wide,
or evidence of extrathyroidal extension, patients should be
referred to endocrinology for a fine-needle biopsy and further
evaluation.
42
Alemtuzumab (Lemtrada)-Related Thyroid
Dysfunction
Alemtuzumab is a monoclonal anti-CD52 used to treat
relapsing forms of MS. The precise mechanism is not fully
understood, but it appears to be depletion then repopulation of
T and B lymphocytes in an attempt to shift the immunologic
balance. This immune reconstitution phase may result in the
formation of autoantibodies, including those targeting the
thyroid.
40,43
Autoimmune thyroid disease (AITD) is the most
common autoimmune disorder after treatment, followed by
immune thrombocytopenia and glomerular nephropathies. In
phase 3 clinical trials, there was a 40.7% chance of thyroidrelated adverse events within 5 years, with a peak at 3 years
post treatment (16% in the CARE-MS trials [phase 3
comparison of alemtuzumab vs interferon beta 1a in relapsing
remitting MS]).
40,43,44
Hyperthyroidism was four times more
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prevalent than hypothyroidism and more common than
subacute thyroiditis.
41,43
Thyroid dysfunction was typically
mild to moderate, its incidence peaked at year 3, and it either
self-resolved (one in three cases of hyperthyroidism) or was
treatable along current guidelines. In the 10-year phase 2
CAMMS223 (phase 2 study of alemtuzumab vs interferon beta
1 a in early relapsing remitting MS) study as well as the phase
3 CARE-MS (phase 3 comparison of alemtuzumab and
interferon beta 1a efficacy in RRMS) study, no deaths
occurred as a result of thyroid events.
40,43,44
A 2016 Belgian task force proposed a clinical management
algorithm to address alemtuzumab treatment-related thyroid
adverse events (Figure 10.1). 40 The clinical management
algorithm and recommendations are similar to those proposed
by Devonshire et al, in the Journal of Neurology, 2018.
44
Before starting alemtuzumab, patients should be evaluated for
risk factors for thyroid disease (family history, prior head/neck
irradiation, or smoking), current or prior treatment for thyroid
disease, and baseline thyroid function tests, including TPO
antibodies. It is also important to ask female patients about
contraception or pregnancy plans, as thyroid dysfunction and
its treatment can lead to pregnancy-related complications.
After starting alemtuzumab, patients should have routine
clinical screening for symptoms of hyperthyroidism or
hypothyroidism, along with biochemical monitoring. Thyroid
function tests (TSH and free T4) should be checked every
3 months during therapy, until up to 48 months after the last
dose. Patients with TPO antibodies or prior thyroid history
should be watched closely, because of an increased risk of
AITD. Women of childbearing potential should use effective
contraceptive methods during and up to 4 months after
alemtuzumab treatment.
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FIGURE 10.1 Thyroid management algorithm before
alemtuzumab. Ab, antibody; ATD, antithyroid drug; fT4, free
T4; GD, Graves disease; LT4, levothyroxine; neg, negative; nl,
normal; pos, positive; TAE, thyroid adverse event; TPO,
thyroperoxidase; TR, thyrotropin receptor; TSH, thyroid
stimulating hormone; ULN, upper limit of normal.
*Symptoms/signs of hypothyroidism or TSH > 10 mU/L favor
initiation of LT4; $LT4 ± 0.5 µg/kg/d; #LT4 ± 1 µg/kg/d.
(Reprinted with permission from Decallonne B, Bartholomé E,
Delvaux V, et al. Thyroid disorders in alemtuzumab-treated
multiple sclerosis patients: a Belgian consensus on diagnosis and
management. Acta Neurol Belg. 2018;118(2):153-159.)
Thyroid dysfunction is not an absolute contraindication to
alemtuzumab therapy, as most associated AITDs are mild/selfresolve. It is important for the clinician to be aware of them
and perform appropriate clinical and biochemical screening
before, during, and after treatment.
Interferon-Related Thyroid Dysfunction
IFN-β therapy is also used in the treatment of MS, and AITD
can be a side effect of therapy, occurring in up to 6.2% of
patients. The mechanism of action is unknown but is proposed
to be due to the result of autoantibodies or immune system
dysregulation. Preexisting thyroid antibodies (TPO or TRAbs)
are a risk factor, with 70% of the cases with IFN-β-associated
AITD occurring in patients with MS with TPO antibodies.
Hypothyroidism in general occurred more frequently than
hyperthyroidism in treated patients (3.9% vs. 2.3%,
respectively). Patients can present with a destructive
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thyroiditis picture, with early transient hyperthyroidism
followed by hypothyroidism. Most thyroid dysfunction was
subclinical and found on screening laboratory work.
Spontaneous resolution occurred in almost 60% of patients
regardless of IFN therapy.
45
Similar to alemtuzumab, thyroid dysfunction is not an absolute
contraindication to therapy, as AITD is usually subclinical or
mild and 60% self-resolve. There also does not appear to be a
dose-dependent or time-dependent relationship with IFN-β.
Nevertheless, it is important for the prescribing clinician to be
aware and perform appropriate clinical and biochemical
screening during therapy.
45
Biotin-Associated Thyroid Laboratory
Abnormalities
Biotin is a water-soluble vitamin (B7) that is being studied for
use in high doses (300-600 mg/d) for the treatment of primary
progressive MS. It has been known to interfere with laboratory
thyroid assays that use biotin as a test reagent. In competitive
binding immunoassays (used for free and total T4 and T3),
biotin interference causes a falsely high result. In sandwich
immunoassays (used for TSH), excessive biotin can give a
falsely low result. This can lead to an inaccurate diagnosis of
hyperthyroidism (more common) or hypothyroidism.
46-49
Studies have shown persistent biotin interference even after
16 hours after the last dose. 47 Therefore, it is recommended
that patients stop biotin treatment for at least 2 days before
having laboratory tests done. 46 In addition, any abnormal
laboratory results should be correlated with clinical signs and
symptoms. Of note, biotin has been found to also interfere
with assays for parathyroid hormone, dehydroepiandrosterone
sulfate, testosterone, thyroglobulin, estradiol, and ferritin. This
results in abnormal laboratory data because of assay
interference, but the data do not correlate with clinical
findings.
46,47,50
Conclusion
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MS is a complex disorder with various treatment modalities.
There are endocrine-related complications of both the disease
itself as well as side effects from therapy. Patients with MS
have a higher rate of osteopenia and osteoporosis, both as a
function of the musculoskeletal changes in MS as well as
prolonged steroid exposure. Vitamin D deficiency has been
reported at higher rates. GC therapy is associated with a
multitude of endocrine adverse effects, such as osteoporosis,
iatrogenic Cushing syndrome, and secondary adrenal
insufficiency. Hyperglycemia can result from T1D, T2D, GCs,
or Acthar Gel. Patients are at risk for metabolic syndrome and
associated cardiovascular disease. Autoimmune thyroid
disorders occur at a higher rate in patients with MS even
before taking into account treatment. Alemtuzumab
immunotherapy can result in thyroid dysfunction, especially
hyperthyroidism. Biotin can interfere with thyroid laboratory
assays, resulting in false results. One should be aware of these
endocrinopathies when caring for patients with MS.
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