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Hepatic Injury during Propylthiouracil Therapy in Patients with Hyperthyroidism: A Cohort Study

Yun-Fan Liaw, MD; Miau-Ju Huang, MD; Kong-Dee Fan, MD; Kay-Lun Li, MD; Shyi-Shane Wu, MD; and Tong-Jong Chen, MD
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From Chang Gung Memorial Hospital and Chang Gung Medical College, Taipei, Taiwan. Requests for Reprints: Yun-Fan Liaw, M.D., Liver Unit, Chang Gung Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan, 105. Acknowledgments: The authors thank Ms. S. L. Lee for technical assistance and Ms. M. H. Tsai for secretarial assistance. Grant Support: By grants from the National Science Council (NSC79-0419-B182A-46, and NSC80-0412-B182A-45) and NMRP082(H), and by a grant from the Prosperous Foundation, Taipei, Taiwan.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1993;118(6):424-428. doi:10.7326/0003-4819-118-6-199303150-00005
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Objective: To evaluate the incidence, severity, and course of propylthiouracil-induced hepatic injury in patients with hyperthyroidism.

Design: Cohort study.

Setting: Outpatient clinic of a university-based hospital.

Patients: Fifty-four patients with normal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values and a definite diagnosis of hyperthyroidism.

Intervention: Treatment with propylthiouracil, 300 mg/d for 2 months followed by 100 to 150 mg/d for 3 months and a subsequent maintenance dose of 100 mg/d.

Measurements: Liver biochemical tests were studied before therapy and 2 months and 5 months after starting propylthiouracil therapy. The patients were monitored with clinical evaluation and weekly liver bio-chemical tests after AST or ALT levels became abnormal. Serologic markers of hepatitis A, B, C, and delta virus infection were also studied when appropriate.

Results: Fifteen (28%; 95% CI, 16% to 42%) of the 54 patients showed ALT elevations 2 months after propylthiouracil therapy. The mean peak ALT level for these patients was 1.35 µkat/L (range, 0.65 3.85 µkat/L). None of these patients had symptoms or hyperbilirubinemia. Liver biopsy in three patients showed mild perivenular focal necrosis or ill-defined granuloma composed of foamy histiocytes with ceroid pigment and mild fatty metamorphosis. Despite continued propylthiouracil therapy at a reduced dose, ALT levels returned to normal in 13 of 15 patients in the following 3 months. None of these ALT elevations resulted from hepatitis A, B, C, or delta virus infection. No statistical difference was seen in the pretreatment characteristics between patients with and those without ALT elevation, except that the former had a higher pretreatment T4 level (270 ± 12.9 compared with 237 ± 7.72 nmol/L, P = 0.027) and T3 level (7.22 ± 0.72 compared with 5.85 ± 0.39 nmol/L, P = 0.048).

Conclusions: Propylthiouracil-induced subclinical liver injury is common and is usually transient and asymptomatic. Therapy with propylthiouracil may be continued with caution in the absence of symptoms and hyperbilirubinemia.


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Figure 1.
Changes of alanine aminotransferase (ALT) levels over time for each of the 15 patients with ALT elevation during propylthiouracil therapy (—).

The solid line with open circles represents the mean level of ALT over time. The solid line with closed circles represents the ALT changes over time in the patient with the highest ALT elevations (231 U/L [3.85 µkat/L]), who received a liver biopsy 5 months after starting therapy.

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Figure 2.
Serial changes of serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) during propylthiouracil therapy in patients with hyperthyroidism.PP

Lines with open circles indicate 15 patients with abnormal ALT levels at 2 months; closed circles indicate patients without increased ALT. Data are expressed as mean ± SE. The shaded areas represent the normal ranges of serum ALT (< 36 U/L [< 0.60 µkat/L]) and ALP (28 to 94 U/L [0.47 to 1.57 µkat/L]). The overall time comparison of mean ALT levels is significant ( < 0.01 by repeated measures analysis). When the mean ALT levels at different time points are compared, that at month 2 is statistically greater than those at months 1, 3, 4, and 5, and the level at month 3 is also statistically greater than that at month 5 but not than that at month 4 ( < 0.01 by repeated measures analysis).

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Figure 3.
Histologic findings in patient with hyperthyroidism after propylthiouracil therapy.Panel A.Figure 1Panel B.

Liver biopsy of the patient shown in . Note irregular patches of necrosis in the perivenular region (hematoxylin and eosin, × 200). Liver biopsy of another patient showed ill-defined granuloma and mild fatty change (hematoxylin and eosin, × 400). V = central vein.

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