The below case focuses on a patient with a diagnosis of moderately severe Graves’ disease, who was able to rapidly replenish low vitamin D levels despite serious challenges to liver function and a sudden unexpected setback.

Presenting Symptoms

A woman in her mid-50’s presented with a medical diagnosis of Graves’ disease. She had been experiencing typical symptoms of thyrotoxicosis, in particular palpitations, tremors, nervousness, weight loss, and painful ophthalmology. The patient had no history of prior health complaints and had long-standing healthy lifestyle habits. Over the last 18 months she had faced heightened stress due to prolonged COVID-19 lockdowns, work stress and the sudden death of a close friend. 

She had been urgently referred to an endocrinologist based on the following test results:

Serum assays for thyroid hormones confirmed the clinical diagnosis of moderately severe hyperthyroidism.

• Free thyroxine (Free T4) - 38.8 pmol/L (10-23 pmol/L)
• Free triiodothyronine (Free T3) - 21.1 pmol/L (< 0.55 pmol/L)
• Thyroid stimulating hormone (TSH) - < 0.3 mIU/L (0.5-4.0 mIU/L)

Immunoassays for thyroid antibodies further confirmed autoimmunity and the diagnosis of Graves’ disease.

• TSH receptor antibodies (TRAb) - 19.20 IU/L (< 6 IU/L)
• Anti-thyroid peroxidase (TPOAb) - 262 IU/mL (< 60 IU/L)

Test results also showed low vitamin D levels of 32 nmol/L (> 50 nmol/L) and poor liver function due to high liver enzyme levels, indicating hepatocyte damage and cholestasis. No other abnormalities were noted except for upper range ferritin, blood glucose and serum lipids - another expected part of the wider disease course.

Treatment and developments over 7 weeks:

The endocrinologist prescribed propranolol (beta blocker) 10 mg BD and carbimazole 20 mg BD.

In addition, the patient sought naturopathic support for a review of her diet in week 1 but wanted to wait until her medications were established before reviewing further treatments. 

Dietary Recommendations:

Her dietary advice included nutrient dense (including bitters), high protein (including plant based), low carbohydrate and gluten-free foods. The autoimmune protocol (AIP) diet was also discussed. 

Prescription:

She was happy to take vitamin D in the meantime to raise her levels and was prescribed calcifediol (25-hydroxyvitamin D3 or 25(OH)D3) 10 mg BD in a tablet form, which was continued throughout the 7 weeks.

Further Testing:

A second liver function test (LFT) was taken at week 3 and the patient continued with her drug medications until week 5 and her second consultation with the endocrinologist. Test results indicated a sudden lethal hike in the already elevated liver enzymes. Carbimazole was stopped immediately and an adverse event was lodged with the therapeutic goods administration (TGA). Questran (bile acid-binding resin) 4.7 g BD was prescribed as an immediate replacement and propranolol was continued.

LFTs were again assessed at week 7 and vitamin D levels were also tested on request (calcifediol was stopped at least 48 hours prior to testing). A summary of the 3 test results can be seen in Table 1.

Discussion

The relationship between thyroid hormone metabolism and the liver is elaborate. Thyroid hormones regulate hepatocyte basal metabolism, but the liver also metabolises thyroid hormones for systemic endocrine effects.¹ As a result, raised liver enzymes are quite common in newly diagnosed Graves’ disease patients due to excessive and persistent levels of thyroid hormones, plus autoimmune factors.^2,3

As we can see, LFTs from a high pre-treatment baseline were further increased by an adverse hepatobiliary reaction to a medication. This added problem overwhelmed the patient’s liver function, health and her ability to respond to treatment. Of particular concern was the dramatic increase in all parameters (which were very likely higher by week 5), especially GGT, a predictive indicator of liver damage.

In addition to poor liver function, the patient also followed the common pattern of low levels of vitamin D in Graves’ disease.⁴ Although there is little research as to the cause, there are many studies that show poor hepatic function causes a reduced ability to convert colecalciferol and ergocalciferol via the 25-hydroxylase enzyme in the liver to the more active form - calcifediol.⁵

Calcifediol, the prohormone of the metabolically active form of vitamin D however bypasses the liver,⁶ which is why in this case it raised blood levels of vitamin D rapidly. Despite 5 weeks of serious liver dysfunction worsened by an ADR, the patient was able to gain an increase of 84 nmoL/L of serum vitamin D within 7 weeks. She is now on a maintenance dose of 10 mg calcifediol twice a week to maintain her levels, with further tests pending.

She has also started naturopathic treatment for her condition (including liver support) and is showing a gradual yet promising improvement.

References

1. Cicatiello AG, Di Girolamo D, Dentice M. Metabolic effects of the intracellular regulation of thyroid hormone: old players, new concepts. Front Endocrinol. 2018;9:474.

2. Lee SY. Liver enzymes are commonly elevated in untreated hyperthyroidism and improve after correction of the hyperthyroidism. Clin Thyroidol. 2021;33(2):70-3.

3. Hsieh A, Adelstein S, McLennan SV et al. Liver enzyme profile and progression in association with thyroid autoimmunity in Graves' disease. Endocrinol, Diiabetes, Metabol. 2019;2(4): e00086.

4. Xu MY, Cao B, Yin J et al. Vitamin D and Graves’ disease: a meta-analysis update. Nutrients. 2015;7(5):3813-27.

5. Keane JT, Elangovan H, Stokes RA et al. Vitamin D and the liver—correlation or cause? Nutrients. 2018;10(4):496.

6. Cesareo R, Falchetti A, Attanasio R et al. Hypovitaminosis D: is it time to consider the use of calcifediol? Nutrients. 2019;11(5):1016.