"WHY AM I SO YELLOW??" - LATE ONSET SEVERE HYPERBILIRUBINEMIA DUE TO CARBIMAZOLE THERAPY.

Editor,

We present the case of a 38 year old male with late onset of severe hyperbilirubinemia 1 year after commencing carbimazole therapy. He had a history of hyperthyroidism, diagnosed in May 2019. His thyroid function tests (TFTs) were difficult to stabilize on carbimazole titration. Therefore, he was switched to block and replace treatment with carbimazole 40 mg and levothyroxine 100 micrograms daily after 3 months. TSH receptor antibodies were strongly positive in keeping with Graves’ disease.

He presented to hospital in June 2020 with a 6 week history of jaundice, mild abdominal pain and feeling generally unwell. He had no prior history of liver disease and had a normal bilirubin in March 2020, with mildly cholestatic pattern of liver function tests. On admission, his bilirubin was 129 with a mixed cholestatic-hepatitic pattern of liver enzymes. Prothrombin time (PT) was raised at 15. Ultrasound imaging revealed normal liver structure with no biliary dilatation. Carbimazole was stopped and a full liver screen sent. He initially discharged himself against advice, however, he was re-admitted in July when his jaundice worsened and bilirubin had risen to 459 on repeat bloods with PT of 18.6. He did not have any other evidence of decompensated liver disease. MRCP showed no abnormalities within the biliary tree. Bilirubin continued to rise and liver biopsy was undertaken which revealed features of a mixed cholestatic-hepatitic liver injury, with the cholestatic injury significantly more prominent. It was considered most likely to represent a drug related liver injury. The patient had taken no other prescribed or over the counter medication and no illicit substances. Over time, liver function slowly improved and the jaundice resolved completely. Propylthiouracil was considered inappropriate for treatment given risk of hepatotoxicity and iodine was not practicable due to social circumstances. The patient went on to have a total thyroidectomy.

summary of LFTs

trend of bilirubin levels

Discussion:

Methimazole (active metabolite of carbimazole) has been associated with transient, asymptomatic elevations in serum aminotransferase levels, typically during the first 3 months after starting high dose, induction therapy.1

It can also cause a clinically apparent, idiosyncratic liver injury. Onset is usually within 2 to 12 weeks of starting therapy and typically causes a cholestatic or mixed pattern of enzyme elevations, without evidence of hepatic necrosis on liver biopsy.2 Most patients recover on drug discontinuation. There are, however, occasional reports of severe and fatal cases. The proposed mechanism of carbimazoled-induced cholestasis is not fully understood.1

This patient developed severe hyperbilirubinemia 1 year after starting treatment with carbimazole. His bilirubin level peaked at 518, significantly higher than reported levels in the literature to date. It then began to slowly settle over a period of 4 weeks. Although hepatotoxicity is a rare side effect of antithyroid medication, it can be a significant one. It is important to remember to consider it as a cause of jaundice, with the potential to occur many months after starting treatment. Patient awareness is very important and they should be counselled about the potential side effect and to consult a doctor if they notice jaundice developing. This patient waited for 6 weeks before seeking medical attention, without realising that his medication could be causing this problem.