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Liver injury induced by levothyroxine tablets in a patient with hypothyroidism

helvella profile image
helvellaAdministrator
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We see all too many individuals who have difficulty tolerating one or more formulations of levothyroxine but, eventually, find at least one which they can tolerate.

Rarely written up in medical literature - this is a very welcome exception.

Recommend you view the actual document.

Liver injury induced by levothyroxine tablets in a patient with hypothyroidism

Wu, Bo1; Xie, Cheng2

Editor(s): Cui, Yi

Author Information

Chinese Medical Journal 132(16) : p 2015-2016, August 20, 2019. | DOI: 10.1097/CM9.0000000000000340

To the Editor: On March 9, 2018, a 31-year-old woman presented with liver dysfunction after thyroid cancer surgery. She was physically healthy; had no chronic diseases, such as hypertension and diabetes; had no history of infectious diseases, such as hepatitis and tuberculosis; had no history of drugs, food allergies, smoking, and alcohol consumption; and presented no obvious complaints during the disease course. B-ultrasound in the physical examination 3 years prior showed “left thyroid-occupying position.” On February 5, 2018, she had undergone surgery at our hospital. Laboratory findings on February 6, 2018 revealed white blood cells (WBCs) 9.06 × 109/L (3.50–9.50 × 109/L); neutrophils (NEs) 5.66 × 109/L (1.80–6.30 × 109/L); triiodothyronine (T3) 0.94 (0.80–2.00) ng/mL; thyroxine (T4) 6.4 (5.1–14.1) μg/dL; free T3 (FT3) 3.95 (3.10–6.80) pmol/L; free T4 (FT4) 15.57 (12.00–22.00) pmol/L; thyroid-stimulating hormone (TSH) 2.56 (0.27–4.20) mU/L; thyroid peroxidase antibody (TPOAb) 8.2 (0–34.0) IU/mL; thyroglobulin antibody (TgAb) <10 (≤115) IU/mL; total bilirubin (T-BIL) 21.5 (5.0–22.0) μmol/L; direct bilirubin (D-BIL) 6.3 (0–10.2) μmol/L; alanine transaminase (ALT) 27.5 (7.0–40.0) U/L; aspartate transaminase (AST) 22.7 (13.0–35.0) U/L; and alkaline phosphatase (ALP), 48.9 (35.0–100.0) U/L. Hepatitis C antibody, hepatitis B surface antigen, and hepatitis B core antibody immunoglobulin M tested negative. On February 7, 2018, intra-operative pathology during left thyroidectomy indicated micro-papillary carcinoma. On February 11, 2018, she was discharged and prescribed levothyroxine tablets A (LTA; Merck KGaA, Darmstadt, Germany) 100 μg and calcium carbonate D3 tablets (CC-D3; Pfizer, China) 600 mg once daily.

On March 9, 2018, outpatient review laboratory findings revealed T3 1.11 ng/mL; T4 8.7 μg/dL; FT3 5.50 pmol/L; FT4 20.13 pmol/L; TSH 0.035 mU/L; thyroid-stimulating receptor antibody <0.3 IU/L; T-BIL 16.2 μmol/L; D-BIL 4.10 μmol/L; ALT 325.2 U/L; AST 144.9 U/L; and ALP 60.6 U/L. Anti-nuclear antibody (ANA), anti-mitochondrial antibody M2 sub-type (AMA-M2), anti-smooth muscle antibody (ASMA), anti-liver kidney microsomal antibody (LKM-1), anti-soluble liver antigen/liver-pancreatic antigen antibody (SLA/LP), and hepatocyte solute antigen (LC-1) tested negative. We suspected liver injury induced by LTA. The R value [R = (ALTmeasured_value/ALTnormal_upper_limit)/(ALPmeasured_value/ALTnormal_upper_limit)] was 13.42.[1] Therefore, the admission diagnosis was drug-induced liver injury (hepatocyte injury type, acute, Roussel Uclaf causal relationship assessment method [RUCAM] 6 points, severity grade 1) and thyroid papillary cancer.

Admission examinations revealed body temperature 36.4°C; pulse 74 times/min; and blood pressure 120/65 mmHg. No yellow staining of the skin and mucous membranes and no liver area pain were noted. After admission, LTA was reduced to 75 μg once daily, and she continued to take CC-D3 tablets 600 mg once daily. Considering her hepatocyte injury type, magnesium isoglycyrrhizinate injection 100 mg with reduced glutathione for injection 2.4 g were intra-venously dripped once daily for liver protection. Laboratory examinations on March 12, 2018 revealed the following: WBCs 5.46 × 109/L; NEs 2.60 × 109/L; and ANA, AMA-M2, ASMA, LKM-1, SLA/LP and LC-1, negative. Abdominal B-ultrasound presented no obvious abnormalities. Laboratory examinations on March 14, 2018 revealed the following: T-BIL 22.6 μmol/L; D-BIL 6.0 μmol/L; ALT 126.2 U/L; AST 43.3 U/L; and ALP, 52.9 U/L. The patient was discharged with the following prescriptions: LTA 75 μg and CC-D3 tablet 600 mg once daily, and glycyrrhizic acid diamine (GAD) capsules 100 mg and polyene phosphatidylcholine (PPC) capsules 456 mg 3 times/day.

Figure 1 presents the clinical course. On March 25, 2018, she presented with T-BIL 15.60 μmol/L; D-BIL 4.20 μmol. LTA was discontinued and switched to levothyroxine tablets B 75 μg (LTB; Berlin Chemie AG, Germany) once daily. GAD capsules, PPC capsules, and CC-D3 tablets were continued. On April 6, 2018, she presented with T-BIL 10.70 μmol/L; D-BIL 3.00 μmol/L. LTB was increased to 87.5 μg once daily, GAD capsules were reduced to 50 mg 3 times/day, PPC capsules were reduced to 228 mg 3 times/day, and CC-D3 tablets were continued. On May 10, 2018, she presented with T-BIL 15.30 μmol/L; D-BIL 3.90 μmol. LTB was increased to 87.5 μg and 100 μg, once daily alternately; GAD capsules and PPC capsules were discontinued. On June 19, 2018, she presented with T-BIL 16.00 μmol/L; D-BIL 4.60 μmol/L. LTB was increased to 100 μg once daily. On August 7, 2018, she presented with T-BIL 13.00 μmol/L; D-BIL 3.30 μmol/L. Abdominal B-ultrasound showed no obvious abnormalities.

The patient's liver function indicators before taking LTA were within normal ranges before treatment and were impaired after 26 days of treatment; transaminases decreased after 16 days of reduction and liver protection treatments. However, her liver function did not return to the pre-dose level, and we switched LTA to LTB. Transaminases decreased further after 12 days. She had no obvious abdominal B-ultrasound or autoimmune liver group abnormalities, liver dysfunction caused by liver parenchymal lesions were excluded, and TPOAb and TgAb tested negative, which could eliminate transient liver dysfunction caused by autoimmune thyroiditis. Since the main component of LTA and LTB is levothyroxine, their differences arise from their different additives. LTA additives are corn starch, gelatin, lactose, and stearic acid magnesium, while those of LTB are calcium bicarbonate, dextrin, long-chain glycerate, sodium carboxymethyl starch, and microcrystalline cellulose. Corn starch, gelatin, lactose, and stearic acid magnesium may have caused liver injury after considering RUCAM evaluation.[1]

In 1986, Shibata et al[2] reported that triiodothyronine (4 months) and levothyroxine (4 days) caused liver damage in a patient; Ohmori et al[3] and Kawakami et al[4] reported a case of liver injury caused by levothyroxine (27 days and 2 months, respectively). The mechanism may involve levothyroxine being a hapten-carrier protein complex where in the presenting cells are incorporated and digested. Some complexes are recognized by T lymphocytes, eventually causing liver damage. Recently, liver damage caused by levothyroxine tablets containing different additives has been reported. Per Toki et al,[5] liver damage may be caused by levothyroxine tablets containing Fe2O3.

In summary, the patient developed liver damage after taking LTA. Liver function gradually returned to normal after liver protection and switching to LTB. Liver dysfunction caused by additives is rare. We suggested that patients with adverse reactions to additives should avoid taking subsequent additive-containing treatments.

Open access here:

journals.lww.com/cmj/Fullte...

See also:

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

healthunlocked.com/thyroidu....

Liver Injury Induced by Levothyroxine in a Patient with Primary Hypothyroidism

healthunlocked.com/thyroidu...

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helvella
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BB001 profile image
BB001

Thank you, I found this interesting. Note to self, have liver function tests 6 monthly. So now we know levothyroxine can cause liver damage.

From other research we know that excess of thyroid hormones causes macular degeneration.

Wonderful (sarcastic). What's next?

This bit was interesting:

'transient liver dysfunction caused by autoimmune thyroiditis'

and made me wonder whether the same applies to kidney dysfunction. I keep having episodes of impaired kidney functon, that recovers, luckily (so far). It landed me in A&E in July with kidney function of 27% which is classed as renal failure. 30 hours later it was 100%. Kidney consultant said 'kidneys don't recover'. He thought it was a clot in the blood supply to the kidneys that resolved.

So folks, watch out for kidney problems too. Though to be fair, I am triple positive for the antiphospholipid antibodies, so that is thought to be the cause of the clot.

jgelliss profile image
jgelliss

Helvella Thank you so much for another Great and very Valuable post.Thyroid patients have yet another worry to worry about. Medication that we rely on for our well being is now we find out might hurt us ? My daughter in-law just donated part of her liver for her OBGYN.

Now I'm wondering if she was dosing with T4. I know that my daughter in-law is.

Heaven Help Us.

TiggerMe profile image
TiggerMeAmbassador

This is fascinating! My liver results have crept up since adding levo, ALP improved adding Tiromel though ALT rose and then both elevated since swapping to Roma.... I've managed to bring them back down by taking Reduced L-glutathione and Tudca

Question is do I continue or rock the boat and trial a swap to Teva T3

Roma contains...

Liothyronine sodium 5 micrograms Capsules

Each capsule contains 5 micrograms of the active substance liothyronine sodium.

The other ingredients are: maize starch, magnesium stearate (E572).

Liothyronine sodium 5 micrograms capsule shell contains: gelatin.

I'm thinking magnesium stearate is harder to avoid (contained in both) but I could lose the gelatin capsules

I do know that I'm genetically prone to low L-glutathione levels and they were low before supplementing

Teva 20mcg excipients
helvella profile image
helvellaAdministrator in reply toTiggerMe

I think the Hapten issue is one which needs further investigation. The Wiki article looks as if it was written by someone who understands the issues! But it isn't that easy to read and understand. I'm sure I missed some important points.

Hapten

en.wikipedia.org/wiki/Hapten

It appears to me that this sort of thing could well be why we see particular issues such as lactose-intolerance when an ingredient of levothyroxine - but not the rest of the time. And possibly why mannitol splits us into those who tolerate and those who do not in levothyroxine tablets. But all speculation!

Thelostboys profile image
Thelostboys

Hi everyone you asked me to share my thoughts on Levothyroxine the only thing i can say is the first time i was put on the tablets i was very sick.I had every one of the side effects.I was on the brand Accord i lost one and a half stone in three weeks .And i once almost phoned for a ambulance to get to a hospital.My Dr told me to stop taking them after i’m sorry i can’t remember how many weeks i waited for them to get out of my system.I had a blood test it came back very bad and my doctor said i had to start as quickly as possible his excact words were i can’t believe you are still standing. He put me on a different brand Eltroxin and i have had no side affects at all so i can only think that you have to find a brand that suits you. I hope that’s ok ⭐️

helvella profile image
helvellaAdministrator in reply toThelostboys

I hope your prescription is written for Eltroxin specifically?

If ever you are forced to change, make sure you look on the packet for the PL Holder. Accord product is packed for at least two other companies. It will say this and you can see without opening the pack. But all too many pharmacists have managed to miss this. Let alone the rest of us.

Thelostboys profile image
Thelostboys in reply tohelvella

I never knew that such a tiny tablet could cause so much trouble it does say Eltroxin on my prescription.I really don’t want to be so poorly again ⭐️

posthinking01 profile image
posthinking01 in reply toThelostboys

I had terrible trouble with tablets didn’t realise I was lactose intolerant and it wasn’t being absorbed as was going through me via the loo -now on sugar free liquid !

Thelostboys profile image
Thelostboys in reply toposthinking01

Oh no hope you’re feeling better now it’s hard to find the one brand that suits you ⭐️

posthinking01 profile image
posthinking01 in reply toThelostboys

Thank you for your kind thought- yes much better thanks.

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