Clinical Endocrinology (2009)

70

, 671–673 doi: 10.1111/j.1365-2265.2009.03536.x

© 2009 Blackwell Publishing Ltd

671

C L I N I C A L Q U E S T I O N

Blackwell Publishing Ltd

How do you approach the problem of TSH elevation in a patient on high-dose thyroid hormone replacement?

John C. Morris

Division of Endocrinology, Mayo Clinic, Rochester, MN, USA

Summary

Persistent elevation of TSH levels in patients under treatment for

hypothyroidism is a relatively common clinical problem in endo-

crinology practice. The most common cause for this phenomenon

is poor patient compliance with their thyroid hormone tablets. In

the compliant patient, however, multiple aetiologies are possible and

a methodological and stepwise approach to the patient’s problem

will uniformly identify a cause, or at least a resolution.

(Received 12 December 2008; returned for revision 26 December

2008; finally revised 19 January 2009; accepted 20 January 2009)

Thyroid hormone therapy is generally one of the most gratifying and

effective hormone replacements within the clinician’s armamentarium.

Most patients are satisfactorily managed with a single tablet of

synthetically derived levothyroxine daily. To make that possible, a

wide variety of tablet sizes are available from a number of manufacturers

and feature both brand-name products and several generic

preparations. Although the average dose for effective and optimal

replacement varies somewhat from patient to patient, most hypo-

thyroid patients are managed within a fairly narrow dose window that

varies according to body weight, the average being near 1·6–1·8

μ

g/kg.

1

Although total body weight is a convenient measurement upon

which to base initial dosing, correct replacement dosing correlates

better with lean body mass than total body weight.

2

In most patients

the circulating concentration of TSH serves as a reflection of thyroid

hormone effect upon the pituitary and thereby as an effective marker

of the adequacy of the replacement dose. However, one of the

common clinical problems that I am asked to review is that of the

patient who requires higher doses of levothyroxine for normalization

of their TSH or whose TSH level remains persistently elevated despite

these high doses.

For example, a recent patient I was referred was a 40-year-old

woman from a neighbouring community who was diagnosed with

hypothyroidism 1 year prior to her visit. In brief, at that time she

expressed symptoms compatible with hypothyroidism, such as

severe constipation, fatigue and a modest amount of weight gain,

and her thyroid gland was firm, moderately diffusely enlarged but

without nodularity, suggestive of autoimmune thyroid disease.

Laboratory investigation demonstrated marked TSH elevation

(145 mIU/l, normal 0·3–5·0 mIU/l) and low free thyroxine

(3·9 pmol/l, normal 10·3–23·2 pmol/l). Her primary care physician

started thyroxine replacement at standard doses and adjusted the

dosage upwards on three occasions because of persistently elevated

TSH levels. After taking 300

μ

g of levothyroxine for 6 weeks, she was

referred for further evaluation when her TSH remained elevated

(77 mIU/l) and free thyroxine remained low at 7·7 pmol/l.

My approach to this patient and those with persistently elevated

TSH levels despite doses of thyroid hormone that should be adequate

is outlined below. I recommend following these steps, although the

order of them and the number that may need further pursuit may

vary from one patient to the next, based upon the individual patient’s

circumstances.

(1)

Confirm the diagnosis and laboratory results.

Frank primary

hypothyroidism by laboratory definition requires low levels of

thyroid hormones (total and free T4 and T3) and elevated TSH. The

finding of a persistently elevated TSH level is not enough to confirm

the diagnosis here, it is also crucial to measure thyroid hormone

levels (T4 and T3). Markedly elevated TSH levels without low or at

least low-normal thyroid hormones suggests other diagnoses or

reasons for the discrepant dose requirements such as heterophilic

antibody interference with TSH measurements, TSH secreting

pituitary tumours, or thyroid hormone resistance syndromes. If the

thyroid hormone levels are not low, more investigation and

establishing the correct diagnosis are essential. Elevated thyroid

hormone levels that indicate the patient is taking and absorbing the

thyroxine tablets appropriately suggest that investigations including

more careful quenching of the serum samples for heterophilic

antibody interference by the laboratory, serial dilution of the TSH

sample, screening of the family members or genetic testing for

thyroid hormone resistance, and pituitary imaging for evidence of

pituitary tumours may be helpful. Measurement of free T4 and/or

free T3 by equilibrium dialysis may at times be helpful as these more

direct methods of assay are less susceptible to the effects of thyroxine

binding proteins.

(2)

Ask about compliance.

The most common reason for unusually

high thyroid hormone dose requirements in my practice is poor

compliance with the daily dosing of levothyroxine. One day’s tablet

accounts for 14% of the total weekly dose and because of the long

Correspondence: John C. Morris, Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA. E-mail: Morris.John@Mayo.edu

672

J. C. Morris

© 2009 Blackwell Publishing Ltd,

Clinical Endocrinology

,

70

, 671–673

half-life of levothyroxine, missing a day will have an influence on

thyroid hormone and TSH levels that is manifest over several days.

Thus, having a discussion with the patient about compliance should

always be the first step in the process. Many patients will acknowledge

forgetting their tablets occasionally if asked in a nonaccusatory,

nonjudgemental manner. What is sometimes difficult here is

determining how often ‘occasionally’ occurs.

(3)

Check the patient’s medication bottles and tablets.

At times the

patient’s reported dose may differ from that prescribed and of course

errors by the pharmacist also occur, resulting in tablets inside the

bottle that differ from those reported on the label. The colour coding

of thyroxine tablets is helpful for determining the dose the patient

is taking, but many patients, and occasionally their physicians, have

colour vision deficiencies making actual inspection of the tablets an

important step in understanding exactly what the patient is currently

ingesting. Confirming records of prescriptions and refill records with

the pharmacy may also be helpful in documenting compliance, or

lack thereof.

(4)

Review the thyroxine ingestion history.

The most efficient and

reproducible way of taking levothyroxine is to ingest the tablets on

an empty stomach and avoid ingesting other medications or food

for 30–60 min afterwards. A fairly large and still growing number

of medications, supplements and even food items can alter the

fraction of an ingested dose that is absorbed.

3,4

The ingestion of one

or more of these items at or near the time of dosing with thyroxine

can substantially change the dose requirement in an individual

patient, especially when practised as routine. The most common

offenders that I see are calcium and iron supplements. Some multi-

vitamin preparations may also influence thyroxine absorption but

the effect does not seem as clear or commonly problematic as that

for calcium and iron supplements. A list of medications that may

interfere is included in Table 1, but this list is certainly incomplete

as new offending medications are reported frequently.

(5)

Investigate for malabsorption.

Unfortunately, levothyroxine is not

fully absorbed after oral ingestion. On average, only about 70–80%

of the available tablet dose is absorbed in euthyroid individuals.

5

Interindividual variability in the efficiency of gastrointestinal (GI)

absorption is fairly large and this variability accounts for most of the

range of requirement seen between compliant patients after

adjustment for body size. Malabsorption syndromes increase the

requirement for levothyroxine by further reducing the fraction of the

ingested dose that is absorbed. Patients with short bowel from prior

small bowel bypass or resection commonly require higher than

expected T4 doses. If the patient has frequent, voluminous stools, a

malabsorption disorder may be evident and measurements of stool

fat can confirm this diagnosis. However, thyroxine malabsorption

has been reported as the initial finding in patients with otherwise

asymptomatic malabsorptive syndromes, especially coeliac disease.

6

I screen patients that get this far along the diagnostic pathway with

measurement of tissue transglutaminase antibodies and, if positive,

send them for GI evaluation, usually including small bowel biopsy

and stool fat measurements. Correction of the malabsorption will

normalize or at least improve thyroxine absorption in these patients.

Helicobacter pylori

infection, especially when accompanied by

atrophic gastritis and achlorhydria, has been reported to impair

thyroxine absorption by up to 37% in patients with multinodular

goitre. Antibiotic treatment of the

H. pylori

infection was also

demonstrated to improve absorption and reduce thyroxine require-

ment in those patients.

7

(6)

Consider increased turnover or excretion.

A number of drugs or

clinical conditions may increase the turnover or excretion of thyroid

hormone and thereby increase considerably the requirement in

individuals that are thyroid hormone dependent. Some examples are

phenytoin, carbamazapine and rifampin. Several of the new kinase

inhibitors, such as imatinib and sunitinib, that are entering the clinic

for various malignancies appear to influence thyroxine requirements

in this manner and this may be a class effect, although reports to

date are few.

8–10

In addition, patients with nephrotic syndrome who

excrete large quantities of albumin may have increased thyroxine

requirements due to binding of T4 to the excreted albumin.

11,12

Women experience increased thyroxine requirements during normal

pregnancy, that may reach as much as 50% at its peak.

13

(7)

Perform a thyroxine absorption test.

A clinical test to estimate

thyroxine absorption has been proposed that may have utility in

patients who have unexpectedly high T4 requirements. This test

involves administration of a single large dose of levothyroxine,

usually in the range of 1000

μ

g, then monitoring T4 levels in blood

over time.

4

Although I have occasionally performed this test, I do

not find it to be generally helpful unless it demonstrates completely

‘normal’ results, thereby supporting patient noncompliance. Unfor-

tunately, there is no well-established standard to which individual

patient results can be compared, especially one done in hypothyroid

patients with normal absorption. In the few circumstances when

I have asked a patient to perform the test, the results indicate that

the patient does absorb thyroxine when exposed to a large dose, but

leaves me wondering if it is a normal amount or not, because of the

lack of adequate normal standards. Furthermore, severe hypo-

thyroidism itself may impair absorption, presumably due to oedema

of the small bowel mucosa and this cannot be quantified by the test.

Table 1. Drugs that increase thyroxine requirements

Reduced absorption

Ferrous sulphate

Calcium carbonate (? other calcium salts)

Aluminium hydroxide

Multivitamins

Sucralfate

Sodium polystyrene sulfonate (Kayexalate)

Cholestyramine

Cholestipol

Sevelamer HCl

Chromium picolinate

Proton pump inhibitors

Increased metabolism

Carbamazepine

Rifampin

Phenytoin

Imatanib

Motesanib

(? Sunitinib and sorafenib)

Oestrogen

? indicates reports and/or data are suggestive but inconclusive.

Difficult hypothyroidism

673

© 2009 Blackwell Publishing Ltd,

Clinical Endocrinology

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, 671–673

Thus, I have not found that this test helps me very much in the

decision-making process in individual patients.

(8)

Treat the patient.

If an error by the pharmacy or patient, or a

compliance-related cause, is identified, correction of these underlying

factors will help to resolve the situation. In some circumstances

compliance issues are best treated by increasing the tablet size,

assuming that compliance will continue at a similar rate. As a ‘last

resort’ in patients with continued poor compliance, evidence

supports successful use of thyroxine administered once weekly. This

quantity is roughly equivalent to the entire weekly total as calculated

above, but given as a single oral dose,

14

and administration can be

monitored if needed. Removing interfering drugs or changing

ingestion patterns when present can also be helpful when possible.

In many patients the best course is to increase the patient’s T4 dose

and titrate upwards until the TSH and T4 levels normalize. Except

in patients with surgical small bowel syndromes, I have not yet seen

a patient who required parenteral administration of thyroid

hormone for maintenance. Even relatively large doses of levothyroxine

administered orally are less expensive and better tolerated that

intravenous or intramuscular injections.

The patient described at the beginning of this article was very con-

vincing in her description of faithfully ingesting her thyroxine tablets

and had for several months been doing so in the absence of other,

potentially interfering medications or supplements after advice from

her primary care provider. Although she still described symptoms

of hypothyroidism, I could not elicit symptoms suggestive of

malabsorption. Her thyroid function tests confirmed inadequately

replaced primary hypothyroidism in that her TSH remained elevated

at 29·4 mIU/l and her free and total thyroxine levels were at the lower

end of the normal range, this after ingesting 300

μ

g of thyroxine for

approximately 8 weeks. The screens for malabsorption and coeliac

disease (transglutaminase antibodies and stool fat measurement)

were negative and urinalysis was normal. I elected to increase her

levothyroxine dose to 400

μ

g daily and 6 weeks later her TSH was

below normal (0·2 mIU/l) and free thyroxine was elevated

(25·7 pmol/l). We reduced the thyroxine dose to 350

μ

g daily and

after 8 weeks found that her TSH and free thyroxine levels had

returned to normal. Her fatigue and constipation also improved and

she stated that she felt much better than before.

I have seen a small number of patients (unreported) that appear

to have selective malabsorption of thyroxine. These patients clearly

absorb levothyroxine poorly but do not have evidence of generalized

malabsorption or of coeliac disease and respond well to increasing

the levothyroxine to levels well above those considered usual, in the

range of 400–600

μ

g per day. At present I am not aware of a

physiological explanation for these findings but I suspect one will

be forthcoming with further investigation into thyroxine transport

and absorption. The patient described above may be a representative.

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