Transcript Objectives - London Health Sciences Centre

Post Partum Shakes:
A Case of PPT With a Twist
Sanam Shorey M.D.
Endocrinology Fellow
March 5, 2003
OUTLINE
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Case Presentation
Definition, Prevalence
Pathophysiology
Predisposing Factors
Diagnosis and Treatment, Follow-up, Morbidities?
Current Screening Recommendations?
PPTD and Depression Linked??
Revisit the Case
CASE
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28yo G1P1A0L1
2 months post partum
C/O fatigue, irritability, sweats, heat intolerance
No hx preceding illness, neck pain, or eye
changes
No Personal hx Thyroid or Diabetes
No Family hx Thyroid or Diabetes
Medns: Nil
Allergies: Nil
CASE (cont’d)
 BP 100/62, HR: 72bpm regular
 TG: palpable, firm at 25 grams, no nodularity
or audible bruits
 Mild infraorbital puffiness without proptosis
or lid lag
 Brisk reflexes
CASE (cont’d)
 TFTS: FT4 20, TSH <0.05
 A-MC 1:25600
 TBII negative
 Thyroid Scan and Uptake: Low RAIU
CASE (cont’d)
 Dx: Post partum thyrotoxicosis
 Not symptomatic enough to warrant
propranolol
 TFTs q monthly  euthyroid in 2-3 months
 Warned about impending hypothyroidism
CASE (cont’d)
 Presented 6 months post partum
 C/O intermittent fatigue, occasional
confusion, moderate weight gain
O/E:
 BP 110/70, HR 72
 TG normal size with no nodularity
 Achilles reflex delayed relaxation
CASE (cont’d)
 TSH 18
 FT4 (low)
 A-MC: positive 1:6400
 Confirmed resolution of thyrotoxicosis and
development of hypothyroidism (typical or
biphasic PPT)
 L-T4 commenced and pt restored to
euthyroidism 9 months postpartum
 L-T4 d/c 14 months after delivery
 F/U TFTs q 6 months
POST PARTUM THYROIDITIS
Definition:
 Silent thyroiditis of the Postpartum period
 Flare up of a chronic autoimmune process
occurring in the first year after delivery
Table 1 -Possible types of postpartum thyroid dysfunctIon
Prevalence
Hyperthyroidism then hypothyroidism
Commonest (70%)
Hypothyroidism alone
Hyperthyroidism alone
Common (20%)
Less common (5%)
Hypothyroidism then hyperthyroidism
Rare
.
Table 2- Possible causes of postpartum hyperthyroidIsm
Common (> 95%)
Prevalence*
Painless thyroiditis: first attack vs. recurrence
70-80%
Graves' disease: first attack vs. recurrence
10-15%
Rare {< 3-5%)
·
·
·
·
Toxic nodular goitre (single vs. multiple nodules)
Painful (typical) subacute thyroiditis
lodine-induced (Jodbasedow)
Thyrotoxicosis factitia
*Author's estimates based upon a summary of personal observations in Toronto, Canada, and those of others in Canada,
Japan, & the United States and Sweden.
.
Survey Toronto, Canada
AIMS:
1) Prevalence of PPTD
2) Characteristics of PPTD seen

1376 randomly selected mothers enrolled
immediately postpartum followed prospectively
for two yrs

495 (36%) completed at least 3 mos f/u

300(22%) completed 1yr f/u
(Walfish et. al. 1992)J
Endocrinol Invest
Type PPTD
#
Minimal
Prevalence
rate
PPT (typical)
44
3.2%
Transient hyperthyroidism
17
1.25%
Hypothyroidism only
17
1.25%
Graves’ Hyperthyroidism
3
0.2%
TMNG
1
0.07%
TOTAL
82
6.0%
PREVALENCE
 Ranges 5-10%
 Probably much more common
PATHOPHYSIOLOGY
Acute phase of Autoimmune thyroid dysfunction
1)
Relationship between presence of TPO antibodies
and occurrence of PPT
2)
Histology of PPT (focal organized and diffuse
destructive lymphocytic thyroiditis)
3)
Presence in the circulation of activated T-cells in
postpartum patients
4)
Associations between the genetic inheritance of
MHC molecules and the occurrence of PPT
5)
PPT frequently leads to permanent autoimmune
thyroid failure
PATHOPHYSIOLOGY
ROLE OF TPO ANTIBODIES
Is there a real association???
1) TPO is only expressed at the apical border of
thyroid follicular cells hardly accessible to
circulating antibodies
2) Circulating TPO antibodies found in a number of
euthyroid elderly women
ROLE OF TPO ANTIBODIES
1) TPO Ab does not seem to be the primary
disruptive event in the pathogenesis of
PPT
2) Serves as a marker of disease activity for
PPT
PATHOPHYSIOLOGY
CD4 HELPER T-CELLS
1) TH2:
• Stimulate B-lymphocytes to produce
antibodies (TPO, TG) through cytokines
2) TH1:
• Stimulate cell destruction
• Activate macrophages and natural killer
cells via cytokines such as gamma
interferon to kill target cells
CD8 T-CELLS
• Destroy target cells
• Recognize autoags directly on target cells
when in the context of MHC class I
molecules
• Kill via perforin and other cytokine
molecules
APOPTOSIS
• Proapoptotic and antapoptotic factors also
act in target cells under attack.
• Balance of CD95 receptor signalling death
with bcl-2 and CFLIP antiapoptotic family
• Interferon also promotes apoptosis through
caspase and CD95 upregulation.
PREDISPOSING FACTORS
1) Personal or Family hx of Thyroid disease
(Primarily Hashimoto’s)
2) Previous PPT
3) TPO Ab titres in 1st trimester ( assoc with 30-35%
incidence PPT)
4) Other endocrine autoimmune disorders (esp
Type 1 DM)
PREDISPOSING FACTORS
5) White and Asian women as opposed to blacks
6) Cigarette smoking
altered production proinflammatory cytokines in
lung ???
•
No effect maternal age, parity, presence of
goiter, breast feeding, infant birthweight, on the
incidence of PPT
DIAGNOSIS AND TREATMENT
Thyrotoxicosis:
•
RULE OUT
1) GH : High RAIU, TBII +, Opthalmopathy, more
symptomatic and persists
2) Subacute thyroiditis: neck pain, increase ESR,
low RAIU
3) TMNG: high RAIU, scan lights up in spots
DIAGNOSIS AND TREATMENT
Other parameters studied:
 Serum TG elevated in both GH and PPT
 US echogenicity correlates well with thyroid
dysfunction but can also be seen in GH
 High TPO Ab titres assoc with PPT
TREATMENT
• Usually unnecessary
• Symptomatic treatment with b-blockers
which must soon be tapered and
discontinued as the thyrotoxic phase quickly
resolves
• Monitor TSH, FT4 q monthlyrisk of
hypothyroidism
HYPOTHYROID PHASE
Dx:
 TSH, FT4
Tx:
 T4 (50-75ug) if clinically symptomatic for 6-12
months or at least 1 yr postpartum as 80% will be
euthyroid by yr 1
 Subsequently follow TFTs q 6 months since risk
hypothyroidism
WHAT TO WARN PATIENTS
ABOUT?
1. Risk of hypothyroidism
•
Jansson et al: 30% prevalence end yr 5
•
Othman et al: followed 43 pts with PPT
during 2-4 yr period 23% women
developed permanent hypothyroidism
compared to none of the 173 controls
STUDY: PPT AND LONG TERM
THYROID STATUS
• Followed 98 TPO Ab + and 70 TPO Ab –
women over 66-140 months
• 24.5% TPO Ab + developed subclinical
hypothyroidism c/w 1.4% of the TPO ab –
controls.
Premawardhana et al. 2000
JCEM 85: 71-75
STUDY (cont’d)
A. Hypothyroid form of PPTD
B. High TPO Ab levels
C. Hypoechogenic ultrasound pattern
•
Led to a high relative risk of 32 of long
term thyroid dysfunction in TPO Ab+ PPT
+ c/w TPO Ab- PPT – controls
•
Long term surveillence of TPO Ab + and
PPTD positive women is required
WHAT TO WARN PATIENTS
ABOUT?
2. Recurrent PPT
•
70 % recurrence rate
WHAT TO WARN PATIENTS
ABOUT?
3. Conception and Pregnancy
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•
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Positive TPO +/- Tg antibodies in 1st trimester
pregnancy is a RF for spontaneous fetal loss
Studied 552 consecutive women in 1st trimester
of pregnancy and found that the spontaneous
abortion rate in thyroid Ab positive women was
significantly higher than in Ab negative women
(17 vs 8.4%)
Mechanism: defective immune system failing to
become tolerant to the fetus or mild thryoid
insufficiency remains uncertain
Stagnara-Green et al 1990 JAMA 264
WHAT TO WARN PATIENTS
ABOUT?
4. Offspring
• Pop et al.1999 Clinical Endocrinology
50:149-155
• FT4 levels less than the 10th percentile
(irrespective of TSH or TPO status) at 12
wks gestation significant risk factor for
impaired psychomotor development
OFFSPRING (cont’d)
• Haddow et al. 1999 (NEJM 341;549-555)
• Children born to mothers with hypothyroidism
during the 2nd trimester pregnancy as determined
by an elevated TSH have lower IQ scores and
more educational difficulties at age 7-9 yrs than
children born to mothers with normal TSH during
pregnancy
• Chronic autoimmune thyroiditis is the most
frequent cause of low normal FT4 and raised TSH
in women.
SHOULD WE SCREEN FOR PPT?
Must satisfy 4 questions:
1. Is PPT prevalent?
Yes 5-10%
2. & 3. COMORBIDITIES AND TREATMENT?
i.
25% develop primary hypothyroidism within 5 yrs
of delivery
•
ii.
No known interventions can decrease high
rate of permanent hypothyroidism
70% chance of recurrent PPT
•
Does T4 prevent recurrence?
LT4 & RECURRENCE
•Kampe et al 1990 JCEM 70: 1014-1018
• T4 0.1mg daily from wk 4-38 and 0.05 mg
from 39-42 wks postpartum in 18 TPO+
women
Results
1. No change in the incidence or time course of
PPT
2. degree of hypothyroidism was significantly
reduced compared with 20 untreated Ab +
women
LT4 & RECURRENCE
 TSH in vitro increases the expression of
thyroid microsomal antigen and in the
presence of gamma interferon increases
HLA class 2 expression on thyrocytes
 Believed that thyroid doses given were not
as high as anticipated since 9 of the 18
women still had TSH values above 5 mU/L
despite treatment.
iii. Increased rate of spontaneous abortion
•
Vaquero et al (2000)Am J Reprod
Immunology 43:204-208
•
Data suggested recurrent miscarraige in
women with thyroid antibodies can be
prevented by T4
iv. Offspring psychomotor development
•
Unknown if T4 replacement will
effectively prevent neuropsychological
abnormalities in the offspring
CURRENT SCREENING
RECOMMENDATIONS
Two specific populations would clearly benefit from
screening:
1. Women with previous hx of PPT (prevalence of
recurrent PPT =70%)
2. Women with Type 1 diabetes (prevalence of PPT
=25%)
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Measure TSH at 3 and 6 months post partum
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Women with increased of decreased TSH require
further investigations.
PP DEPRESSION AND PPTD
LINKED?
Postulated mechanism:
• Hypothyroidism can reduce central
hydroxytryptamine neurotransmission
• Some believe cytokines released during
autoimmune eg IL-6 and IL-1 interact with
neurotransmission cause problems
PP DEPRESSION AND PPTD
LINKED?
• Recent studies Oretti et al (2002) show
excess of depression in general related to
positive thyroid antibody status rather than
to PPTD
• They believe it is due to subtle changes in
thyroid hormone levels
International Journal of Social Psychiatry, in
press
DOES L-T4 PREVENT DEPRESSION
IN TPO AB POSITIVE WOMEN??
 AIM : to test that stabilising thyroid function pp by
administrating daily T4 reduces the rate of
occurrence and severity of associated depression.
 METHOD:
 randomised double blind placebo controlled trail
 100ug of T4 or placebo were given daily to 446
TPO AB + (342 were compliant) for 6 wks to 6
months pp
 Psychiatric and thyroid status checked q 4 wkly
 RDC for depressive disorder and Asberg
depression Rating scale
Harris et. al. 2002 British Journal of Psychiatry 180:327-330
RESULTS
1) Rates of depression and major
depression at each visit were similar in
both groups
2) Overall rate of major depression was
18.5%
OVERALL RESULTS
1. Rates of depression here were similar to study
by Harris et. al. 1992
2. Positive TPO Ab associated with PPD
3. T4 administration does not reduce post natal
depression
•
Abnormal biochemical thyroid function has no
effect rather TPO Ab status and number of
negative events has impact
FINAL CONCLUSIONS
• High Prevalence
• Pathogenesis unknown
• Significant morbidities
• Some prevented by L-T4
• Screening effective with TSH in certain
groups
What happened to my patient???
• 2 yrs later
• C/o chronic fatigue, wt loss, irritability and
palpitations
• High Ft4, Suppressed TSH, serum A-TG
and A-Mc weakly positive
• 24 hr uptake 40% , TBII positive 51%,
diffuse uptake on scan
• RX: PTU than ablation
• HLA haplotyping revealed susceptibility
alleles associated with GH and PPT
PROPOSED MECHANISM
• Immunological activation of a destructive
thyroiditis releases thyroid antigen
• Inflammatory response accompanied by a
lymphocytic infiltrate : APC, CD8 cytotoxic T
cells
• Activate TH1 cells of destruction and
reciprocally suppress the TH2 pathway
MECHANISM (cont’d)
 In genetically predisposed mothers
 Released thyroid Ag triggers
 immune cascade
 activates TH2 pathway
 B-cells
 TSH Receptor Ab
 When Ab sufficient levels  GH clinically and
biochemically evident
PRIMARY LESION THEORY OF
AUTOIMMUNITY
• Preexisting injury plays an important role: In development
of persistent autoimmune endocrine dysfunction in those
individuals with an underlying genetic susceptibility
Other Examples:
• Post parathyroidectomy painless thyroiditis with underlying
autoimmune thyroiditis
• Post Subacute thyroiditis
• Post I131 for TMNG
• External head and neck irradiation