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VKP 2018
20. 4. 2018
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THE SYSTEMIC inflammatory
response syndrome (SIRS)
 a clinical expression of nonspecific inflammation,
is a major cause of morbidity and mortality and is
a leading cause of death in intensive care units.
 SIRS can be initiated by a variety of causes,
including infection, and may vary in severity from
mild to life threatening.
 Few reliable serum markers exist that can provide
useful clinical information regarding the severity of
illness or the prognosis for the many SIRS-related
conditions.
Sérový pre-CT jako klinický
marker sepse
 Serum pre-CT is a clinically important serum
marker for systemic inflammation and sepsis.
Maximal levels were consistently elevated,
and the highest values were seen in the most
severely ill patients or fatalities. The elevated
serum pre-CT not only identifies patients with
these conditions, but also reflects their clinical
course. To be most useful for prognosis, daily
determinations should be made, because it is
the peak value that is the most informative.
Posttranslational processing of
CT precursors
 Mature CT is produced in the form of a preprohormone that
undergoes extensive posttranslational processing. Initially, the
signal sequence is cleaved, producing pro-CT. The molecular
moieties that exist at low levels in the peripheral circulation of
normal persons are pro-CT, aminopro-CT, mature CT, CCP-I,
and free conjoined CT:CCP-I. The mature, free CT molecule
has 32 amino acids, lacks a glycine at its carboxyl-terminus, and
is amidated. This amidation confers much of the biological
activity to this hormone. There is also a CCP-II peptide that is
present mostly in neural tissue. K, Lysine; G, glycine; R,
arginine. Enzymatic cleavage occurs at the basic amino acid
pairs or triplets.
Prokalcitonin (PCT)
 116 AK , produkován C buňkami štítné
žlázy.
 Zvýšené hladiny: hyperkalcémie,
glukokortikoidy,
 Preprokalcitonin je v ER štěpen na
prokalcitonin , pak katakalcinem na
kalcitonin. Všechen produkovaný PCT v
C-buňkách je štěpen na kalcitonin.
PCT jako biomarker sepse
 Za fyziologických okolností jsou proto
hladiny PCT v krvi stopové.
 Pokud se prokalcitonin octne v krvi, je
problém ho odbourat (poločas 25-30 hod
oproti kalcitoninu s 4-5min!!!)
 PCT jako modulátor syntézy NO?
 Nejvyšší hladiny u bakteriální sepse
 Korelace s hladinami prozánětlivých
cytokinů-protein akutní fáze.

Determination of the sensitivity, specificity, positive predictive value, and
negative predictive value of a diagnostic test. The positive likelihood ratio is
calculated as the sensitivity/1-specificity, and the negative likelihood ratio as 1sensitivity/specificity.
Positive likelihood ratios over the range of values of the
diagnostic test is represented by the receiver operating characteristics curve,
the area under the curve being a reflection of the accuracy of the test across
a range of values.
Representative time course of pre-CT peptides in systemic
inflammation and sepsis. The time-course curves for both serum preCT
and APACHE II scores followed similar patterns, peaking
simultaneously in those select patients who had discrete peaks in their
serum levels. The serum levels of pre-CT, determined by the two-site
assay in this figure, reflect the daily clinical progress of these patients,
indicating improvement or deterioration.
Typ infekce
 Most of the patients had bacterial
infections.
 Patients with viral infection commonly,
but not always, have considerably lower
serum pre-CT values. This probably is
related to the lower incidence of
associated severe systemic
inflammation in viral infection.
Sérové hladiny pre-CT v čase
 The serum pre-CT levels often reflected the
patient’s daily clinical progress, suggesting
improvement or deterioration in select
patients who demonstrated discrete peaks in
the serum levels. This relationship was based
on a close parallelism with the APACHE II
score. However, this could not be
demonstrated in patients who had only
modest elevations of serum pre-CTs without
distinguishable peaks.
Calcitonin gene-related petide
(CGRP)
 Rodina -6 členů:
 Kalcitonin, amylin, intermedin
(adrenomedulin-2), adrenomedulin a
CGRP (- 37 AK-NS a -enterické nervy a
hypofýza).
 Funkce: modulace NS, KVC, RS, GIT,
endokrinního systému, imunitního systému,
muskuloskeletálního systému
 Terapie migrény?
Klinický případ 85 letá paní osaměle
žijící, po patologické fraktuře kyčle
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Stav kosti u PMP ženy
 Osteoporóza ?
 Osteodystrofie?
 Osteomalácie?
 Kombinace?
Stav kosti u postmenopauzálních
žen
 Patologická fraktura
 Bolest (opioidy!)
 Rizikové faktory:
 Faktory životního stylu
 Faktory genetické
 Endokrinopatie
Příčiny osteoporózy
 Nedostatek estrogenů
 Nadbytek glukokortikoidů
 Nedostatek vitaminu K2
 Nedostatečná pohybová aktivita
Faktory životního stylu se zvýšeným
rizikem fraktur u PMP žen
 Vyšší spotřeba alkoholu
 Léčba některými antacidy
 Vysoká spotřeba kávy
 Anamnéza dlouhodobé imobilizace
 Nízký BMI
 Nízké hladiny kalcia a deficit vitaminu D
(nedostatek slunečního záření, chronické renální
selhání)
Osteoporóza
Etiopatogeneza: chronicky zvýšený podíl mezi osteoklastickou a
osteoblastickou aktivitou v kosti
Incidence
radiologických
fraktur páteře,
kyčle a distálního
předloktí v závislosti
na věku a pohlaví.
Data derived from
European
Prospective
Osteoporosis Study
and General
Practice Research
Database.
Předpokládaná reciproká endokrinní regulace funkcí kosti a tukové tkáně: Karboxylovaný
osteoKalcin (OCN) je produkován osteoblasty a je následně vázán na hydroxyapatitový minerál
vyzrálé kosti.
Během resorbce kosti řízené osteoklasty se uvolňuje do cirkulace nekarboxylovaný osteokalcin
(ucOCN), odkud významně podporuje produkci inzulínu pankreatem. Inzulín zvyšuje expresi OCN
osteoblasty a zároveň podporuje jeho dekarboxylaci působenou osteoklasty. Inzulín má také
pozitivní vliv na sekreci leptinu adipocyty, což vede k inhibici kostní produkce i resorbce
hypotalamickým vlivem leptinu. Produkce ucOCN je tak snížena a dochází k modulaci
orexigenních efektů ucOCN na produkci inzulínu pankreatem.
Glukokortikoidy
obecně působí
jako antagonisté
inzulínu …
Doporučená léčba osteoporózy
99m-Technetium-
hydroxymethylene
diphosphonate bone
scintigraphy.
The scan is typical for a
bone metabolic disease,
even though, in theory, any
foci could correspond to a
primary bone tumor.
Osteodystrofie
 Sekundární hyperparathyreoidismusis –
obvykle u chronického onemocnění ledvin s
tendencí k rozviji chronického ledvinného
selhání v důsledku neschopnosti ledvin
resorbovat kalcium- renální osteodystrofie
jako projev excesivní kostní remodelace. .
 Jiné příčiny-obvykle nutriční: deficit kalcia a
fosfátů ve stravě, nadbytek fosfátů ve stravě.
Onkogenní osteomalácie nebo tumorem
indukovaná osteomalácie (TIO)
 Dosud publikováno jen asi 160 případů.
Často poddiagnostikována
 Projevy
 Vážná hypofosfatémie, hyperfosfaturie,
velmi nízké hladiny 1,25-(OH)2 D3
 Závažná osteomalácie
Stav kosti u postmenopauzální
ženy
Women with a history of anorexia nervosa,
panhypopituitarism, androgen insensitivity or other causes of
premature ovarian failure are at an exquisitely increased risk
of pathological fractures.
Diabetes, hyperparathyroidism, hyperthyroidism and adrenal
gland diseases can also put the woman at an increased risk of
pathological bone changes, especially during the
perimenopausal period.
Absorption disorders, such as celiac disease, gastric bypass,
inflammatory bowel disease, or pancreatic disease are
associated with impaired vitamin D absorption and possibly a
higher risk of osteomalacia.
Stav kosti u postmenopauzální
ženy
U žen po patologické fraktuře je potřeba vynechat:
 Heparin
 Antiepileptika
 Inhibitory aromatázy
 Chemoterapii
 Steroidy
 Litium
Screening for Osteoporosis in Women
 Dual-energy X-ray absorptiometry (DEXA) is
the method of choice for assessing the bone
mass density in postmenopausal women and
in the prediction of the risk of pathological
fractures.
 The result of DEXA is usually reported as a Tscore
that represents the difference between
the patient’s bone density from the mean of
the population’s normal bone mass density in
standard deviations.
Screening for Osteoporosis in Women
 Normal bone mass density should have a T-score less than 1
SD below the mean.
 Bone mass density between 1 to 2.5 SD indicates osteopenia.
 Osteoporosis is defined as a bone mass density below 2.5 SD
below the mean.
 Z-score might be more appropriate for the interpretation of a
DEXA study result than a T-score. Z-scores consider the
patient’s age. A Z-score that is below -2.0 is indicative of
clinically significant osteoporosis.
 Note: The measurement of hip bone mass density using DEXA
has the strongest correlation and predictive power of
pathological fractures.
Stav kosti u postmenopauzální
ženy - léčba
Low dose estradiol (0.14mg) as a skin path that doesn’t
require progesterone for endometrial protection is the
method of choice in hormonal replacement therapy for the
prevention of osteoporotic fractures.
Weight-bearing and non-weight-bearing exercises, especially
of the lower limbs, definitely lower the risk of osteoporotic
fractures in postmenopausal women and are recommended.
Postmenopausal women should be encouraged to limit their
alcohol intake to less than 2 drinks per day and to quit
cigarette smoking for women.
Treatment of Osteoporosis in Women
Treatment for osteoporosis should be started in any
postmenopausal woman:
 Who is older than 50 years.
 Who sustained a fragility fracture before or who has a
DEXA t-score below 2.5.
 When loss of bone mass is associated with an
elevated 10-year fracture risk using the FRAX online
risk calculator.
Treatment of Osteoporosis in Women
This is especially true when the woman is at an increased risk of osteoporotic
fractures due to the presence of multiple risk factors.
Bisphosphonates are the mainstay of the treatment of osteoporosis in
postmenopausal women and are very important in the secondary prevention
of osteoporotic fractures. They decrease the risk of vertebral and nonvertebral
fractures, but do not have any effect on the bone mass density.
Unfortunately, bisphosphonates are associated with a significantly increased
risk of gastrointestinal tract side effects such as esophagitis.
Selective estrogen-receptor modulators are very effective in the prevention of
vertebral and non-vertebral fractures in osteoporotic women, but not in the
prevention of hip fractures. They increase bone mass density which is
another added advantage over bisphosphonates. Unfortunately, they are
associated with an increased risk of venous thromboembolism disease.
Treatment of Osteoporosis in Women
Hormone replacement therapy is known to lower the risk of
osteoporosis, especially in women with premature ovarian failure and
the risk of osteoporotic-related fractures. They decrease the rate of
bone mass density loss and are effective in lowering the rates of hip,
vertebral and non-vertebral fractures in postmenopausal women.
They also ameliorate the vasomotor symptoms, urogenital symptoms
and mood symptoms of menopause. Hormone replacement therapy
use after more than 10 years of menopause is not recommended due
to the increased risk of cardiovascular disease.
Parathyroid hormone and calcitonin can be also used for the
secondary prevention of osteoporotic fractures in postmenopausal
women. Their efficacy is inferior compared to the previous
interventions, but they can be used as adjunctive therapy.
Treatment of Osteoporosis in Women
Denosumab was recently approved for the prevention of
osteoporotic-related fractures and the treatment of osteoporosis. It
reduces the risk of vertebral and non-vertebral fractures in addition to
lowering the risk of hip fractures. Denosumab also increases the
bone mass density at the lumbar spine and hip.
The main side effects of denosumab are gastrointestinal irritation,
dermatitis, limb and back pain, headache and hypercholesterolemia.
Because bisphosphonates are very efficacious and considerably
cheaper than this option, they remain the first-line therapy for
osteoporosis in postmenopausal women. Denosumab has the
advantage of being administered only once every six months, but the
cost-effectiveness of the drug and the similar efficacy to
bisphosphonates makes it a second-line therapy that should be used
only in very high-risk patients.
Denosumab
 Denosumab je nový biologický lék určený k léčbě stavů
charakterizovaných patologicky zvýšenou kostní resorpcí s
následnou ztrátou kostní hmoty a zvýšeným rizikem vzniku
fraktur. V současné době je v České republice registrován pro
terapii postmenopauzální osteoporózy a pro léčbu úbytku kostní
hmoty v souvislosti s androgen deprivační terapií u mužů s
nemetastazujícím karcinomem prostaty. Denosumab je unikátní
svým složením i cíleným mechanismem účinku. Jde o plně
humánní monoklonální protilátku proti cytokinu RANKL (ligand
pro receptor aktivátoru nukleárního faktoru kB). RANKL je
klíčovým faktorem potřebným k diferenciaci a aktivaci nových
generací osteoklastů.
Denosumab
Denosumab se v místech, kde je kost metabolicky aktivní, váže na
RANKL a jeho blokádou inhibuje osteoklastogenezi. Ve škále
antiporotických léčiv je denosumab řazen mezi inhibitory kostní
resorpce. U nemocných léčených denosumabem byl ve srovnání s
placebem prokázán významný pokles rizika vzniku
osteoporotických fraktur všech typů (vertebrálních i nevertebrálních
včetně zlomenin kyčle). Pacienti v klinických hodnoceních léčbu
denosumabem dobře tolerovali. Režim podávání v jednorázové
subkutánní injekci jednou za 6 měsíců příznivě ovlivňuje
compliance nemocných s léčbou.
Díky za pozornost