Methods : Patients with hypothyroidism were selected in a cross-sectional study, - PowerPoint Presentation

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Methods

: Patients with hypothyroidism were selected in a cross-sectional study,

followed

prospectively

for 12 months

, and

classified as subclinical or overt hypothyroidism.

The

patients were divided into two groups: with and without HAH.

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34%

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Conclusion

Patients

with HAH may present with

unilateral

,

pulsatile

,

episodic pattern

, and

nausea/vomiting

, which is at

odds with the criteria for HAH established by ICHD 3 beta. Not all individuals responded to levothyroxine, and patients with the subclinical form of hypothyroidism benefit from this treatment.The question remains as to whether migraineurs with hypothyroidism have a ‘‘true’’ HAH or whether theirmigraine attacks worsened with this new hormonal dysfunction.

Fronto-orbital : 49%Temporal : 37%Posterior part of the head : 15%

involving

areas

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A 45-year-old woman presented with a

6 month

history of intermittent episodes of

diarrhea,

vomiting and abdominal pain, each followed by persistent nausea

.

She also reported general malaise, and lost approximately 3 kg in weight

.

Routine blood tests including full blood count, urea and electrolytes, glucose, liver function and bone profile were normal.

Gastroscopy

was normal, and gastric and duodenal biopsies were histologically normal.

An

abdominal computed tomography (CT) scan showed no intra-abdominal pathology.Subsequently, repeat blood tests were performed. Thyroid function tests then revealed a raised TSH >75 mU/ml (normal range (NR) 0.5–5.0

mU/ml), a low free T4 at 6.06 pmol/L (NR 10.0–25.0 pmol/l), and low T3 1.04 nmol/l (NR 1.1–2.8 pmol/L). A raised prolactin concentration of 1052 mU

/l (NR 64–420

mU

/l) was also noted. The plasma cortisol concentration was normal. The raised prolactin was thought to be due to the hypothyroidism.

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Treatment

Initially

, she was given levothyroxine 25

μg

daily for 2 weeks, increasing to 50

μg

for a further 2 weeks and then to 75

μg

as a maintenance dose.

Outcome

and follow-up

At

a 5 week review appointment the patient reported that all of her symptoms had gone. Pituitary, parathyroid and adrenal profiles were not carried out. In addition, the colonoscopy was cancelled. She continues on thyroxine replacement therapy and to date her symptoms have not returned.A literature review revealed no similar cases in adults. No reports were found of abdominal pain, vomiting and diarrhea being associated with hypothyroidism.

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Case 1

The patient was a 35-week-gestation

boy . When

feedings were initiated with breast milk on

day 5

,

bilious emesis

developed.

An abdominal

radiograph was normal. A barium

enema study

showed no evidence of malrotation or obstruction

. When feedings were resumed, initially with clear fluids and then with breast milk, he had recurrence of bilious emesis. Feedings were again discontinued, and a barium follow-through study was performed the next morningthat confirmed that there was no obstruction or malrotation.However, the results suggested a marked decrease in gastrointestinal motility, and the patient did not

pass the contrast per rectum for several days.On day 12, Laboratory reported abnormally elevated TSH (greater than 50 micIU/mL) . Confirmatory tests showed thyroxine (T4) less than

2.5

micg

/dL

(normal: 3.0–18.0

micg

/dL

), and TSH more

than 1000

micIU

/mL

(normal: 9.0–18.0

micIU

/mL

).

Treatment with

25

micg

L-thyroxine once a day was begun.

Feedings were

begun again and proceeded uneventfully. No

further episodes

of emesis occurred. He was

discharged home

on day 21 receiving full feedings.

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Case

2

The patient was a full-term

girl with

thyroid

aplasia

.

At her visit to the

endocrinology clinic

, her parents reported continuing

abdominal distension

and dry skin on the extremities. She was

feeding normally and was not constipated.Results of thyroid function tests showed T4 of 1.5 micg/dL and TSH of 306 micU/mL

.Treatment with 25 micg L-thyroxine once a day was begun. At the follow-up visit at 4 weeks of age she was alert and interactive. The posterior fontanel was closed. The

abdomen was

minimally distended

and soft.

At

follow-up she was thriving.

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In adults with myxedema, abnormal

physiologic findings

include a

decrease in electrical and motor activity

of the gastrointestinal tract

, a decrease in the

number and

frequency of muscle contractions in the sigmoid

colon and rectum, and

prolonged gastric emptying

time

.

Bassotti et al. reported decreased lower esophageal sphincter pressure and contractility, scarce gastric activity during fasting, and sporadic non propagated bursts of contractions in the small intestines in an adult patient with intestinal pseudo-obstruction

secondary to hypothyroidism.Duret R, Bastenie P. Intestinal disorders in hypothyroidism: clinical and manometric study. Am J Dig Dis 1971;16:145–50.

Holdsworth

D,

Besser

G. Influence of gastric emptying rates and

of insulin

response on glucose tolerance in thyroid disease.

Lancet 1968;2:700–2

.

Vassilopoulou

–

Sellin

R,

Sellin

JH. The gastrointestinal tract

and liver

in hypothyroidism. In:

Braverman

LE,

Utiger

RD, eds.

The Thyroid

. 6th ed. Philadelphia: J. B. Lippincott; 1991:1017–21

.

Bassotti

G,

Pagliacci

M,

Nicoletti

I, et al. Intestinal

pseudoobstruction

secondary

to hypothyroidism: importance of small bowel

manometry

. J

Clin

Gastroenterol

1992;14:56–8.

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Factors

may significantly influence the

absorption of

LT4

:

Interval

between the ingestion of the drug

and the

last

meal

Eating habits

Different

functional and organic pathologies of the gastro-intestinal tract

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Patients who

require

more

than 2

μg

/kg

of LT4 per day, with constantly increased

TSH

level, should be diagnosed with the suspicion

of

pseudomalabsorption or real absorption disorderLT4 absorption test

After excluding non-compliance :Lactose intolerance (lactose-free LT4 preparation and a lactose-free diet)Coeliac diseaseAtrophic gastritisHelicobacter pylori

infection

Bowel resection

Inflammatory

bowel

disease

Parasite infection

mainly in the jejunum and ileum and,

to

a lesser degree, in the duodenum

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Persistently

abnormal serum TSH levels despite adequate

titration of

l­T4 substitution therapy, requires biochemical and instrumental investigation, but

no definite

etiology is found in up to 15% of cases

.

Design

:

Patients on l­T4 substitution therapy referred to three Italian outpatient

Clinics of

Endocrinology between 2013 and 2015 for refractory hypothyroidism were investigated for levothyroxine tablet exposure to humidity, light, and high temperature

.Results: We report 8 patients, accounting for approximately 1% of all hypothyroid patients and 5% of those with refractory hypothyroidism in our series. Conclusion

:

Refractory hypothyroidism linked to improper storage of l­T4 tablets

does exist

and might be an

under recognized

entity.

In

addition to proper modalities of

ingestion of

l­T4 tablets, patients need to be instructed on

proper modalities of storage, as well.

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The common approach to managing

patients with

unusual thyroxine needs is

to escalate the dose

of levothyroxine

until targeted TSH levels are achieved.

Problems

:

Increase

the risk for prolonged exposure

to supratherapeutic

doses of levothyroxineEscalate the costs of treatment, as frequent office visits and laboratory tests

systematic approachApproximately 10 – 20% of patients requiring greater than standard replacement doses of levothyroxine despite an extensive diagnostic work-up

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The most common cause of failure of oral

replacement therapy

is non-compliance

Muñoz-Torres M,

Varsavsky

M, Alonso G

: Lactose

intolerance revealed by severe

resistance to

treatment with levothyroxine.

Thyroid 2006

; 16: 1171–1173.

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Once weekly administration of

levothyroxine is

safe and efficient and therefore a

possible alternative

to customary daily therapy

Using the absorption test, serum

fT

4 and TSH

measurements are

assessed before and after 1, 2, 4, and 6 h

using supervised

intake. An increase in

fT 4 is observed with a maximum level within the first 120 min, known to be a normal time interval for absorption by the small intestine.In order to diagnose ‘‘pseudomalabsorption,’’ a 1,000-

μg levothyroxine absorption/challenge test can be used to demonstrate an appropriate increase in fT 4 levels (two- to threefold increase) and a decrease in TSH by 40% of the initial values after 2 h. [2, 5, 17, 18, 24–26] .

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Objectives

:

We present the successful completion of

2-hour

levothyroxine absorption testing

in 3 patients as a retrospective case series

.

Patients and Methods

:

Serum levels of thyroid stimulating hormone (TSH), FT4, and free

triiodothyronine (FT3) were drawn at 0, 60, and 120 minutes after 1000 mcg of oral levothyroxine.Patients were instructed to skip their usual dose of levothyroxine on the day of the test. They were asked arrive by 8:00 AM for the test after at least an 8 hour fast. Serum levels of TSH, FT4, and FT3 were drawn at 0, 60, and 120 minutes after administration of 1000 mcg of levothyroxine orally as 5 tablets of 200 mcg each.

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Results:

In all 3 cases, baseline thyroid function indicated the patients had taken their prescribed doses of levothyroxine prior to the absorption test. Despite high baseline levels both FT3 and FT4 increased during each absorption test, providing more evidence of adequate levothyroxine absorption. Subsequently, patients achieved normal TSH levels on lower doses of levothyroxine.

Conclusions

:

Levothyroxine absorption testing over 2 hours may offer a more rapid alternative to the commonly used longer protocols to rule out malabsorption. Scheduling a levothyroxine absorption test may induce some patients to start adhering to levothyroxine therapy.

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Case

:

We present a 32-year-old female patient with severe

hypothyroidism despite

the daily use of 250

μg

of LT4. She was submitted to the rapid absorption

test of

thyroid hormones, with supervised intake of 1000μg of LT4 and serial

measurement of

serum TSH and FT4, confirming the status of

pseudomalabsorption

. The patient underwent a psychiatric evaluation and was diagnosed as having a bipolar affective disorder with a current episode of severe depression, and a personality disorder with emotional instability.

The patient was treated with mood stabilizers and supervised daily doses of LT4, and a significant improvement in clinical and laboratory was achieved. We analyzed 19 patients with LT4 malabsorption published in the literature and, compared to baseline, the minimum increase in FT4 was 2.5 times.

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The

most common psychiatric disorders include

depression

,

Munchausen

syndrome, and

factitious

disorder

We

emphasize that the benefit of using LT4 absorption test is clear in these cases and, although clinical studies are needed to determine a standard protocol with appropriate cutoffs,

we suggest that an increase of at least of 2.5

The authors found a strong correlation between measures of total T4 and FT4 (r = 0.88, p<0.001), suggesting that FT4 may be used instead of total T4

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Thyroid hormone uptake has different characteristics across

cell types

, with regard to ligand specificity, energy (ATP) dependence

, Na

+-dependence and interaction with various compounds (20

). Several

thyroid hormone transporters

have become known

over the

years, including

Na+/

taurocholate

cotransporting polypeptide(19), fatty acid translocase (21), multidrug resistance-associated proteins (22), L-type amino acid transporters (23), and members of the organic anion-transporting polypeptide (OATP) family (24) and monocarboxylate

transporter (MCT) family (25). Some of the known thyroid hormone transporters have been localized in the small intestine, including OATP1A2 (26), OATP2B1(27), MCT10, LAT1 and LAT2 (28).

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The apparent pH dependence of intestinal T4 absorption in vivo

as well

as of T4 uptake in Caco2 cells in vitro may be explained by

the involvement

of a pH dependent transporter, or by the effect of pH on the

T4 molecule. The

pK

value of the phenolic hydroxyl group of T4 is ~6.5

, which

implies that this part of the T4 molecule is largely neutral at

lower (

acidic) pH values, whereas it largely exists as the

phenolate anion at pH 7.3. In contrast, the phenolic hydroxyl group of T3 (pK ~8.5) does not dissociate if the pH rises to pH 7.3 and thus remains largely neutral.

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TH uptake takes place in the small intestine

, but

the mechanism of uptake remains to be elucidated. Therefore,

we characterized intestinal TH transport, using the human

colorectal adenocarcinoma

cell line Caco2 as a model.

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T4 uptake

by Caco2 was

Na+ independent

, but

highly dependent on

pH

.

T4

uptake was markedly higher at pH 5.3 than at pH 7.3. At acidic pH

, T4

uptake was inhibited by leucine and 2-aminobicyclo-(2,2,1)-heptane-

2-carboxylic acid (BCH), prototypic ligands for the L-type amino acid transporters, suggesting that T4 is transported in Caco2 cells by an L-type amino acid transporter at low pH. LAT1-transfected COS1-cellsshowed the same characteristics of T4 uptake as Caco2 cells and RT-qPCR analysis showed abundant mRNA expression of LAT1 in our cell line

T3 uptake by Caco2 cells was both Na+ and pH independent. T3 uptake was inhibited by tryptophan and verapamil but not by leucine and BCH. This suggests the involvement of a T-type amino acid transporter,most likely MCT10. RT-qPCR demonstrated abundant MCT10

mRNA expression

in our Caco2 cells. Remarkably, the addition of BSP, which

is a

prototypic ligand for organic anion transporting polypeptides as well as

for multidrug resistance-related efflux transporters, resulted in a

marked increase

in uptake of T3 and in particular T4.

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Our data provide evidence that amino acid transporters are important

for uptake

of T4 and T3 by Caco2 cells.

T3 uptake appears to be

mediated largely

by MCT10

, and

T4 uptake by LAT1, in particular at low

pH.

At neutral pH, MCT10 seems

important in

the transport of T3, and to a lesser extent T4

. At acidic pH LAT1 seems to be important for T4 transport.

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A single high dose of LT4

1000-2000

μg

should be ingested by the patient under supervision of a nurse, to

check proper ingestion and prevent surreptitious regurgitation

.

TSH

and FT4 levels

should then be monitored over time (

0, 2, 4 and

6 hours

after ingestion

).No well-established standard is available to which individual patient results can be compared. However, from previous case reports and data on pharmacokinetics of LT4, it is known that peak absorption takes place 2-4 hours after ingestion and FT4 levels should rise 50-100% above basal level

Pseudo-malabsorption

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Summary

Psychiatric consult (

Pseudo-malabsorption

)

Gastritis/HP

infection treatment

Increasing LT4

dosage / + Vit C

Intravenous ,intramuscular or

single weekly oral dosing of

levothyroxine

Liothyronine (?)