Post Partum Shakes: A Case of PPT With a Twist

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Post Partum Shakes A Case of PPT With a Twist

• Sanam Shorey M.D.
• Endocrinology Fellow
• March 5, 2003

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OUTLINE

• Case Presentation
• Definition, Prevalence
• Pathophysiology
• Predisposing Factors
• Diagnosis and Treatment, Follow-up, Morbidities?
  
• Current Screening Recommendations?
• PPTD and Depression Linked??
• Revisit the Case

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CASE

• 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

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CASE (contd)

• 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

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CASE (contd)

• TFTS FT4 20, TSH lt0.05
• A-MC 125600
• TBII negative
• Thyroid Scan and Uptake Low RAIU

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CASE (contd)

• Dx Post partum thyrotoxicosis
• Not symptomatic enough to warrant propranolol
• TFTs q monthly ? euthyroid in 2-3 months
• Warned about impending hypothyroidism

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CASE (contd)

• 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

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CASE (contd)

• TSH 18
• FT4 (low)
• A-MC positive 16400
• 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

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POST PARTUM THYROIDITIS

• Definition
• Silent thyroiditis of the Postpartum period
• Flare up of a chronic autoimmune process
  occurring in the first year after delivery

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Survey Toronto, Canada

• AIMS
• Prevalence of PPTD
• 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
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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
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PREVALENCE

• Ranges 5-10
• Probably much more common

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PATHOPHYSIOLOGY

• Acute phase of Autoimmune thyroid dysfunction
• Relationship between presence of TPO antibodies
  and occurrence of PPT
• Histology of PPT (focal organized and diffuse
  destructive lymphocytic thyroiditis)
• Presence in the circulation of activated T-cells
  in postpartum patients
• Associations between the genetic inheritance of
  MHC molecules and the occurrence of PPT
• PPT frequently leads to permanent autoimmune
  thyroid failure

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PATHOPHYSIOLOGY
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ROLE OF TPO ANTIBODIES

• Is there a real association???
• TPO is only expressed at the apical border of
  thyroid follicular cells hardly accessible to
  circulating antibodies
• Circulating TPO antibodies found in a number of
  euthyroid elderly women

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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

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PATHOPHYSIOLOGY
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CD4 HELPER T-CELLS

• TH2
• Stimulate B-lymphocytes to produce antibodies
  (TPO, TG) through cytokines
• TH1
• Stimulate cell destruction
• Activate macrophages and natural killer cells via
  cytokines such as gamma interferon to kill target
  cells

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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

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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.

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PREDISPOSING FACTORS

1. Personal or Family hx of Thyroid disease
   (Primarily Hashimotos)
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)

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PREDISPOSING FACTORS

• White and Asian women as opposed to blacks
• 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

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DIAGNOSIS AND TREATMENT

• Thyrotoxicosis
• RULE OUT
• GH High RAIU, TBII , Opthalmopathy, more
  symptomatic and persists
• Subacute thyroiditis neck pain, increase ESR,
  low RAIU
• TMNG high RAIU, scan lights up in spots

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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

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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

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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

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WHAT TO WARN PATIENTS ABOUT?

• 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

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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
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STUDY (contd)

• Hypothyroid form of PPTD
• High TPO Ab levels
• 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

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WHAT TO WARN PATIENTS ABOUT?

• Recurrent PPT
• 70 recurrence rate

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WHAT TO WARN PATIENTS ABOUT?

• Conception and Pregnancy
• 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
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WHAT TO WARN PATIENTS ABOUT?

• Offspring
• Pop et al.1999 Clinical Endocrinology 50149-155
• FT4 levels less than the 10th percentile
  (irrespective of TSH or TPO status) at 12 wks
  gestation significant risk factor for impaired
  psychomotor development

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OFFSPRING (contd)

• Haddow et al. 1999 (NEJM 341549-555)
• 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.

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SHOULD WE SCREEN FOR PPT?

• Must satisfy 4 questions
• Is PPT prevalent?
• Yes 5-10

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• 2. 3. COMORBIDITIES AND TREATMENT?
• 25 develop primary hypothyroidism within 5 yrs
  of delivery
• No known interventions can decrease high rate of
  permanent hypothyroidism
• 70 chance of recurrent PPT
• Does T4 prevent recurrence?

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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
• No change in the incidence or time course of PPT
• degree of hypothyroidism was significantly
  reduced compared with 20 untreated Ab women

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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.

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• Increased rate of spontaneous abortion
• Vaquero et al (2000)Am J Reprod Immunology
  43204-208
• Data suggested recurrent miscarraige in women
  with thyroid antibodies can be prevented by T4

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• Offspring psychomotor development
• Unknown if T4 replacement will effectively
  prevent neuropsychological abnormalities in the
  offspring

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CURRENT SCREENING RECOMMENDATIONS

• Two specific populations would clearly benefit
  from screening
• Women with previous hx of PPT (prevalence of
  recurrent PPT 70)
• Women with Type 1 diabetes (prevalence of PPT
  25)
• Measure TSH at 3 and 6 months post partum
• Women with increased of decreased TSH require
  further investigations.

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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

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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
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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 180327-330
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RESULTS

• Rates of depression and major depression at each
  visit were similar in both groups
• Overall rate of major depression was 18.5

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OVERALL RESULTS

• Rates of depression here were similar to study by
  Harris et. al. 1992
• Positive TPO Ab associated with PPD
• 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

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FINAL CONCLUSIONS

• High Prevalence
• Pathogenesis unknown
• Significant morbidities
• Some prevented by L-T4
• Screening effective with TSH in certain groups

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• What happened to my patient???
• 2 yrs later
• C/o chronic fatigue, wt loss, irritability and
  palpitations

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• 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

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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

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MECHANISM (contd)

• 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

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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

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