What are the warning symptoms of agranulocytosis and liver injury?

The short version: the warning signs of carbimazole-induced agranulocytosis and liver injury are specific and well-documented, but the evidence for how to spot them early comes from case reports, not large trials.

For agranulocytosis, the most common presenting signs are high fever and sore throat [3]. About 15% of patients have no symptoms at the time their blood count shows the problem [3]. The condition is defined as an absolute neutrophil count below 500 per microliter [3]. It usually strikes within the first three months of treatment, though cases have been reported from 5 days to over 10 years after starting the drug [3]. One case report describes a 35-year-old woman who developed a fever and sore throat after two weeks on 20 mg of thiamazole (carbimazole's active form) daily; her neutrophil count was zero [4]. Another patient presented with a skin lesion on her forehead, chills, and fever, with a white blood cell count of 700 per microliter [5]. The infection can become severe: one woman developed facial cellulitis and ecthyma gangrenosum from Pseudomonas aeruginosa, requiring a 12-day hospital stay [5].

For liver injury, the pattern varies. A 2023 systematic review of 271 patients found that about half had cholestatic (bile-flow blockage) injury and half had hepatocellular (liver-cell damage) injury [7]. The median time from starting the drug to liver injury was 30 days [7]. The median peak bilirubin was 21.4 mg/dL, and median peak ALT was 426.5 IU/L [7]. One case report describes a patient on carbimazole who developed acute cholestatic hepatitis simultaneously with agranulocytosis: her total bilirubin hit 12.4 mg/dL, AST 210 IU/L, ALT 123 IU/L, and ALP 630 IU/L [1]. Another case of propylthiouracil-induced hepatitis in pregnancy showed ALT rising to 1796 IU/L and bilirubin to 367 mmol/L [6]. The key point: liver injury can be severe, but the systematic review found that 74 of 100 patients with outcome data had complete resolution [7].

The evidence base is thin: it comes from case reports and one systematic review of 271 patients across 100 mostly retrospective studies [7]. There are no large prospective trials that tracked these complications systematically. The burden of proof for a drug taken long-term is higher than what is presented here.

My call: if you develop fever, sore throat, jaundice, or unexplained fatigue in the first few months of carbimazole, get a blood count and liver enzymes checked immediately. Confidence: moderate.