A girl being treated with Tiotil (propylthiouracil) 1x3 for Hashimoto thyroiditis and hyperthyroidi

Fråga: A girl being treated with Tiotil (propylthiouracil) 1x3 for Hashimoto thyroiditis and hyperthyroidism has presented with leukopenia (1-2 x10 9/L), slight hemolytic anemia, and splenomegaly. Bone marrow examination was normal. She experienced urticaria with previous Neomercazole (carbimazole) treatment.

Can this clinical picture be seen with Tiotil therapy? Cross-reaction between Tiotil and Neo-Mercazole?

Sammanfattning: Leucopenia and agranulocytosis are well known adverse effects of propylthiouracil and other antithyroid drugs. Splenomegaly has been reported to occur in association with leucopenia as an adverse effect of propylthiouracil treatment. Agranulocytosis as a cross reaction between propylthiouracil and methimazole has been reported as a rare event.

Svar: Leucopenia may occur with both thyroid disease and its treatment. Untreated hyperthyroidism is often accompanied by mild leucopenia. Transient leucopenia, e.g., white blood cell count (WBC) lower than 4x10 9/L, occurs in up to 12 per cent of adults and 25 per cent of children taking antithyroid drugs. This condition is benign and transient, and is not usually detected unless the WBC is monitored closely. Drug-induced leucopenia is not a harbinger of agranulocytosis (less than 0.5x10 9/L), is not associated with infection, and is not ordinarily a reason to discontinue treatment (1).

Agranulocytosis, however, is a specific syndrome characterized by fever, systemic toxicity, evidence of bacterial infection (usually in the oropharynx), and a granulocyte count of less than 0.25x10 9/L. Commonly stated estimates place the risk for agranulocytosis from 1 per 100 to 1 per 1000 patients taking antithyroid drugs (1). More recently, an international case control study (2) estimated the risk with one year of use at about 3 per 10000 antithyroid drug users. Risk estimates for antithyroid drug-induced agranulocytosis vary by two orders of magnitude, most probably as a result of the use of less stringent case definition criteria. Agranulocytosis almost always develops within the first three months of therapy, although it has been reported after a somewhat longer period (1). Routine monitoring of WBC is not considered as useful, since the onset is sudden and explosive. An autoimmune mechanism has been shown for drug-induced agranulocytosis, with circulating antineutrophil antibodies and lymphocyte sensitization to antithyroid drugs (1,3,4).

A review of the literature has identified six case reports (5-10) of propylthiouracil therapy associated with both leucopenia and splenomegaly, as well as other clinical manifestations, such as fever, rash, and arthralgia. The WBC counts ranged from 0.7x10 9/L to 3.6x10 9/L. Agranulocytosis was present in one report (9) and a case of hemolytic anemia was reported in another (6). All but one patient were female. Duration of treatment prior to onset of the clinical picture ranged from 1.5 to 6 years. Although not uniformly found or reported, the following serologic evidence of immunologic phenomena were reported: antibodies against autologous WBC (5), antinuclear antibodies (6), immune complex deposition (IgM and C3) (7), serum opsonic antineutrophil antibodies (8), and slight hypergammaglobulinemia with low C4 level (9).

Benign skin rash is a common side effect of antithyroid drugs (1). Although mild dermatologic reactions often disappear despite continued therapy with the same drug, it nevertheless indicates an allergic reaction and discontinuation of treatment is required (11).

Propylthiouracil, methimazole, and carbimazole are heterocyclic compounds containing a thioamide group. On the basis of structural similarity, cross reactions may be expected. However, current estimates of risk are not consistent. Cross sensitivity has been stated to occur in up to 50 per cent of cases for mild skin reactions in one review (1), as contrasted to the statement that it is uncommon in a reference textbook (12). Recurrence of agranulocytosis was reported to occur in one patient following substitution of methimazole for prophylthiouracil (13). Carbimazole is a derivative of methimazole and is converted in vivo into the latter. Thus, when serious reactions occur, because of the possibility of cross reaction, therapy with another thioamide is not recommended.

Propylthiouracil-related blood dyscrasias reported to the National Board of Health and Welfare concern 26 cases of agranulocytosis, five cases of leucopenia, three cases of neutropenia, one case of pancytopenia, and one case of thrombocytopenia. There have been no reports of splenomegaly.

We recommend that this case should be reported to the Swedish Adverse Drug Reactions Committee.