Why might levothyroxine be a problem for some people?

[helvella]

Before reading further, please be aware that these reports are few in number and spread extremely thinly around the world and in time.

We see a steady stream of people who appear intolerant of levothyroxine. Quite often they are desperate to stop taking levothyroxine - but the hypothyroid state that results of course takes its own toll. Some of these people feel that changing to a regime of liothyronine (T3) has been beneficial.

The mention of antibodies to T4 in the second paper is interesting. These (and also antibodies to T3 and to TSH) have been mentioned in the literature but we never see anyone being tested for them.

(Note: The first paper appears to have a bit of a problem in the underlined bit. I *think* it means that the powder form does not have any Fe2O3 but the tablet form does.)

Fe2O3 is Iron(III) oxide also known as ferric oxide.

Endocr J. 2015 May 19. [Epub ahead of print]

Occurrence of thyroxine tablet (Thyradin S®) - induced liver dysfunction in a patient with subclinical hypothyroidism.

Kang S1, Amino N, Kudo T, Nishihara E, Ito M, Hirokawa M, Miyauchi A, Tamada D, Yasuda T.

Author information

1Department of Internal Medicine, Kuma Hospital, Kobe, Japan.

Abstract

A 54-year-old woman with subclinical hypothyroidism developed liver dysfunction after increasing dose of levothyroxine (L-T4) in tablet form (Thyradin S®) from 25μg to 50μg. Viral hepatitis, autoimmune hepatitis and NASH were ruled out with examinations. After cessation of levothyroxine in 50μg tablet form, liver enzymes gradually returned to normal. She was diagnosed levothyroxine-induced liver injury, based on criteria proposed in DDW-J 2004 workshop. Thyradin S® powder 0.01% (here in after referred to as L-T4 in powder form) was tried as an alternative, and liver enzymes have remained within normal range. As for Thyradin S® tablet, additives are different for each type of levothyroxine sodium content. The difference of additive is whether Fe2O3 is contained or not: it is not included in Thyradin S® 50μg tablet and powder form. Although there are two case reports in the Japanese literature and three case reports in the English literature of liver dysfunction suspected due to L-T4, we cannot find past reports about cases of drug induced liver dysfunction due to Fe2O3 free levothyroxine tablet form. This is a rare case report of drug induced liver injury due to Fe2O3 free levothyroxine tablet form, and administration of L-T4 in powder form may be useful for treatment of cases similar to this one.

PMID: 25994001 [PubMed - as supplied by publisher]

ncbi.nlm.nih.gov/pubmed/259...

Endocr J. 1999 Aug;46(4):579-83.

Levothyroxine-induced liver dysfunction in a primary hypothyroid patient.

Ohmori M1, Harada K, Tsuruoka S, Sugimoto K, Kobayashi E, Fujimura A.

Author information

Abstract

Here we report a case of levothyroxine-induced liver dysfunction. T4 (levothyroxine) has been more commonly used for the treatment of hypothyroidism than T3 active hormone (triiodothyronine), because with the former drug a stabler plasma concentration is obtained after oral administration. Although there are few reports on levothyroxine-induced liver dysfunction, we treated a primary hypothyroid patient with high serum aminotransferase after administration of levothyroxine. Liver dysfunction was improved after cessation of the drug administration. Antibody to T4 was found in the serum of the patient after this event. From clinical course and laboratory data of the patient, the episode of liver damage was considered to be induced by levothyroxine. We then administrated triiodothyronine, and it did not induce liver dysfunction. Changing levothyroxine to triiodothyronine resulted in a successful clinical course in this case, as re-administration of the doubtful drug is strictly limited.

PMID: 10580751 [PubMed - indexed for MEDLINE]

ncbi.nlm.nih.gov/pubmed/105...

Free full text:

jstage.jst.go.jp/article/en...

Intern Med. 2007;46(14):1105-8. Epub 2007 Jul 17.

Liver injury induced by levothyroxine in a patient with primary hypothyroidism.

Kawakami T1, Tanaka A, Negoro S, Morisawa Y, Mikami M, Hojo M, Yamamoto T, Uegaki S, Aiso M, Kawasaki T, Ishii T, Kuyama Y, Fukusato T, Takikawa H.

Author information

Abstract

We report a patient with primary hypothyroidism, who developed hepatocellular injury due to levothyroxine, synthetic thyroxine. A 63-year-old male was admitted to our hospital due to elevation of liver enzymes. The patient was diagnosed as having hypothyroidism and had been treated with levothyroxine for almost two months until admission. Drug-induced liver injury induced due to levothyroxine was suspected and liver enzymes were rapidly decreased after discontinuation of levothyroxine and dried thyroid powder, also containing thyroxine. Synthetic triiodothyronine, the deiodinated form of levothyroxine was administered instead, and was well tolerated by the patient. The drug-induced lymphocyte stimulation test (DLST) using levothyroxine was negative. Since triiodothyronine which structurally resembles levothyroxine did not cause liver injury, and DLST using levothyroxine was negative, it is unlikely that levothyroxine itself was targeted by the immune system. Rather, we assume that the complex of levothyroxine as the hapten and liver-related macromolecules in the body as the carrier might have acquired antigenicity in this patient and subsequently resulted in liver injury.

PMID: 17634708 [PubMed - indexed for MEDLINE]

ncbi.nlm.nih.gov/pubmed/176...

Free full text:

jstage.jst.go.jp/article/in...

[Clutter]

Helvella, it's so infuriating that my endo insisted Levothyroxine could not cause adverse effects and to then read quite old research which is demonstrating significant adverse effects. My sister's gastroenterologist intimated that Levothyroxine may be causing her bowel inflammation.

[helvella Administrator Thyroid UK in reply to Clutter]

In the huge archive of thyroid-related papers there are so many observations. Diligent research will often find papers that back the stories and descriptions of real patients. All too often, the same stories that are ignored or rubbished by real medics.

Of course, finding a paper is far short of proof, but given a suggestion and a patient, cannot medics take on board the possibility that the presentation is real? That they need to look further and investigate appropriately?

[Clutter in reply to helvella]

Helvella, you'd certainly think that multiple patients presenting unrelieved symptoms, and worse, acquiring more symptoms, after starting Levothyroxine would ring bells somewhere.

[helvella Administrator Thyroid UK in reply to Clutter]

Trouble is, if such patients are evenly spread so that each GP has one of them, the GPs are flummoxed as the rest of their patients are doing reasonably well. These odd cases do not get reported, yet the total in the country could be many tens of thousands.

(Of course, this is a gross unrealistic over-simplification.)

[Clutter in reply to helvella]

Helvella, I was thinking about Endos. I forget most people are under the care of their GPs.

[helvella Administrator Thyroid UK in reply to Clutter]

And I was forgetting about endos...

(Sometimes forgetting about endos has appeared to be a good idea. )

[gabkad in reply to Clutter]

Clutter, these people became extremely ill and needed to be hospitalized in a relatively short time after being put on thyroxine. Much worse than just unrelieved symptoms. Are the Japanese better at diagnosing problems or is there something wrong with Japanese thyroxine?

Rod, in your searches through published reports, did you ever find anything like these for UK, USA or any European country?

[helvella Administrator Thyroid UK in reply to gabkad]

Not yet. At least, not in recent searches though I have a vague memory that I have in the past. Maybe I am using terms which tend to pick up Japanese papers?

I'd certainly not point my finger at Japanese levothyroxine, though the question has to be asked.

Arch Intern Med. 1986 Aug;146(8):1624-5.

Hypersensitivity caused by synthetic thyroid hormones in a hypothyroid patient with Hashimoto's thyroiditis.

Shibata H, Hayakawa H, Hirukawa M, Tadokoro K, Ogata E.

Abstract

A 63-year-old hypothyroid woman with Hashimoto's thyroiditis developed fever, eosinophilia, and liver dysfunction in response to replacement doses of triiodothyronine, or L-thyroxine. The symptoms disappeared on cessation of the replacement therapy. Lymphocyte stimulation tests showed high stimulation indexes for both hormones. After an interval of four months, when the patient became severely hypothyroid, treatment with triiodothyronine on a slowly increasing dose program was tried and resulted in a good control without ill response at this time. This observation indicates that, under certain pathologic conditions, hypersensitivity may be induced to thyroid hormones administered exogenously.

PMID: 3755319 [PubMed - indexed for MEDLINE]

ncbi.nlm.nih.gov/pubmed/375...

Endocrinol Jpn. 1978 Jun;25(3):275-9.

Low serum thyroxine due to anti-thyroxine antibody.

Ikekubo K, Konishi J, Nakajima K, Endo K, Mori T, Torizuka K.

Department of Radiology, Kyoto Uninersity Sohool of Medide 2) Department of Internal Medicine, Kobe Central Municipal Hospital

Abstract

In one case of untreated Hashimoto's thyroiditis, the serum thyroxine (T4) value, obtained by radioimmunoassay (RIA) employing resin to separate bound and free T4, was significantly lower than that obtained by competitive protein binding analysis (CPBA). The discrepancy was found to be due to the presence of anti-thyroxine autoantibody in the serum. This phenomenon is considered to be of practical importance in interpreting the T4 value by RIA in cases with autoimmune thyroid diseases.

PMID: 581194 [PubMed - indexed for MEDLINE]

ncbi.nlm.nih.gov/pubmed/581194

Free full text:

jstage.jst.go.jp/article/en...

[HIFL]

Graves' patients often have elevated liver enzymes because high levels of thyroid hormone stress/damage the liver. The last article said: "Thus, the diagnosis of primary hypothyroidism was made, and oral replacement therapy with 25 mg/day of levothyroxine was initiated on December 15, 2005, and the dosage was increased

to 50 mg/day on January 5, 2006, 22 days later."

If that is not a typo, isn't 50 mg a day = 50,000 mcg? Average human dose is 100 mcg, so what they gave him was 500 times normal.

[helvella Administrator Thyroid UK in reply to HIFL]

I am sure that is a typo.

Have seen doses a little over 3 milligrams but, as you say, 500 milligrams is ridiculous.

[Glynisrose]

Maybe because levo is T4 alone and naturally your thyroid produces T1, T2, T3,T4 and calcitonin?

[helvella Administrator Thyroid UK in reply to Glynisrose]

Do you have any reference as to how much T2 and T1 is produced by a human thyroid?

By far the majority of T2 and T1 seems to come from deiodination of T3 to T2, then T2 to T1, which takes place extrathyroidally. The odd molecule might be produced in the thyroid.

[Glynisrose]

I still think "Why do doctors give you T4 when your own thyroid produces other hormones"?