Y. Liaw, Miau-ju Huang, K. Fan
Mar 15, 1993
Citations
6
Influential Citations
128
Citations
Quality indicators
Journal
Annals of Internal Medicine
Abstract
Propylthiouracil (PTU), a thiourea derivative, has been used widely in the treatment of hyperthyroidism. Despite its widespread use, isolated propylthiouracil-induced hepatic injuries have been described in fewer than 20 cases in the English language literature [1-15]. The reported hepatic injuries are clinically apparent with the onset of jaundice, are usually histologically severe, and are sometimes associated with hepatic failure or death [6, 9, 12, 13]. The pathogenesis of propylthiouracil hepatotoxicity remains obscure but has been considered to be an allergic host response [4, 6, 11, 14, 16]. Discontinuation of the drug leads to complete recovery in most cases [2-5, 7, 8, 11]. Drug-induced hepatitis is difficult to diagnose, however, and is often established by exclusion. The possibility of hepatitis C virus (HCV) infection has not been excluded in all reported patients because serologic markers for HCV were not available before 1989 [17]. On the other hand, propylthiouracil has been shown to decrease rat hepatic cytochrome P-450 levels and to inhibit benzphetamine metabolism, suggesting that the active metabolites of PTU may interact with the macromolecules of the endoplasmic reticulum and lead to centrilobular hepatic necrosis [18]. Conceivably, hepatic injury due to metabolites of PTU may also occur in humans. Therefore we conducted this study to examine the incidence, severity, and clinical course of propylthiouracil-induced hepatic injury and to determine whether the injury could be explained by viral hepatitis infection. Methods Patients Between July 1990 and August 1991, 95 patients with hyperthyroidism were screened for serum aspartate aminotransferase (AST) (normal, <0.57 kat/L), alanine aminotransferase (ALT) (normal, <0.60 kat/L), bilirubin (normal, <22.2 mol/L), and alkaline phosphatase (ALP) (normal, <1.57 kat/L) levels as well as for hepatitis B surface antigen (HBsAg) and antibodies to HCV (anti-HCV) before antithyroid therapy. Of these 95 patients, 60 [63%] showed normal AST and ALT levels; these patients formed the basis of our study. The diagnosis of hyperthyroidism was made based on 1) typical symptoms (asthenia, nervousness, heat intolerance, palpitation, and weight loss), and signs [thyroid enlargement, hand tremor, and eye signs]; 2) high serum thyroxine (T4), triiodothyronine (T3), and free T4 levels and low thyroid-stimulating hormone [TSH] levels; and 3) increased Technetium-99m (Technetium-99m) thyroid uptake with diffuse uptake noted on a thyroid scan. No patient had evidence of cardiovascular complications. Patients who had previously been treated for hyperthyroidism were excluded from this study. Treatment All patients with hyperthyroidism received 300 mg/d oral propylthiouracil (Procil, Nysco Co. LTD., Taipei, Taiwan) for 2 months. The dose of propylthiouracil was subsequently reduced to 100 to 150 mg/d according to the results of follow-up thyroid function tests and was maintained at 100 mg/d when a euthyroid state was achieved. Follow-up Serum AST, ALT, ALP, and bilirubin studies were scheduled in all patients 2 and 5 months after the start of propylthiouracil therapy. After a serum AST or ALT elevation was detected, patients were monitored closely with clinical evaluation and weekly serum AST, ALT, ALP, and bilirubin measurements until improvements were seen. It was determined before the study that PTU was to be discontinued promptly if clinical symptoms of hepatitis or hyperbilirubinemia developed. Serologic markers of hepatitis A virus (HAV), B virus (HBV), delta virus (HDV), and HCV as well as anti-nuclear antibody and anti-smooth muscle antibody were also studied when appropriate. Liver biopsy was routinely advised when abnormal AST or ALT levels were detected but was done in only three patients who gave written, informed consent. Laboratory Methods Tests of serum AST, ALT, ALP, and bilirubin were done in the clinical pathology laboratories of Chang Gung Memorial Hospital using routine automated techniques. Hepatitis markers, including IgM class antibody to HAV (IgM anti-HAV) and hepatitis B core antigen (IgM anti-HBc), HBsAg, and antibody to HDV (anti-HD) were assayed using commercial radioimmunoassays (HAVABM, CORABM, Ausria II, Anti-delta, Abbott Laboratories, North Chicago, Illinois). Antibody to HCV (anti-HCV) was assayed using a second-generation enzyme immunoassay (UBI HCV EIA, United Biomedical Inc., New York, New York). We assayed T4, T3, FT4, TSH, and thyroxine binding globulin (TBG) using radioimmunoassays. Thyroid scans and thyroid uptake were studied using Technetium-99m. Statistical Analysis Data were expressed with 95% confidence intervals (CIs) or as mean SE. The Student t-test, repeated measures analysis of ANOVA, and the Fisher exact test were used to test the statistical significance of observed differences in rates or means. Results Of the 60 patients with normal baseline AST and ALT levels, 54 had adequate follow-up studies, and of these 54 patients, 15 (28%, CI 16% to 42%) showed ALT elevations 2 months after the start of PTU therapy. None of these patients had clinical symptoms or signs. The peak ALT level in these 15 patients ranged from 0.65 to 3.85 kat/L (mean, 1.35 0.32 kat/L). Under close monitoring, the ALT levels of these 15 patients moved toward normal during the following 3 months of propylthiouracil therapy and returned to normal in 13 of the 15 patients (mean, 0.24 0.04 kat/L) at a reduced dose according to the study protocol (Figure 1). None of these ALT elevations was associated with increased serum bilirubin. Patients with and without ALT elevations showed a similar degree and duration of ALP elevations (Figure 2). Serologic studies showed that none of these episodes was the result of hepatitis A, B, C, or delta virus infection. Autoantibodies indicating autoimmune hepatitis were also not found. Figure 1. Changes of alanine aminotransferase (ALT) levels over time for each of the 15 patients with ALT elevation during propylthiouracil therapy (). Figure 2. Serial changes of serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) during propylthiouracil therapy in patients with hyperthyroidism. P P Liver biopsy was done in only three patients, whose peak ALT levels were 3.85, 0.97, and 0.83 kat/L, respectively. Biopsy was done when ALT levels were declining (0.87, 0.60, and 0.63 kat/L, respectively). Histologic examinations showed irregular patches of hemorrhagic necrosis Figure 3 A or ill-defined granulomas Figure 3 B in the perivenular region. The necrotic foci consisted of aggregates of pigmented foamy histocytes and epithelioid cells, with few other inflammatory cell infiltrates. Abundant ceroid and lipofuscin pigments were present in the pigmented foamy histocytes. Cholestasis, endophlebitis, microthrombus, hemosiderin deposition, and tissue eosinophilia were not noted. Mild fatty change was noted in two patients. The portal and periportal regions were unaffected. Figure 3. Histologic findings in patient with hyperthyroidism after propylthiouracil therapy. Panel A. Panel B. No statistical difference was observed in age, sex, duration of symptoms before therapy, pretreatment FT4, TBG, anti-thyroid antibody, and anti-microsomal antibody between patients with and without ALT elevation after propylthiouracil therapy. None of the patients with ALT elevations was positive for HBsAg or anti-HCV. Patients with ALT elevations after propylthiouracil therapy, however, had higher pretreatment levels of T4 (270 12.9 compared with 237 7.72 nmol/L, P = 0.027) and T3 (7.22 0.72 compared with 5.85 0.39 nmol/L, P = 0.048) (Table 1). Table 1. Pretreatment Characteristics of Patients with or without Serum Aminotransferase Elevation after Propylthiouracil Therapy Discussion The results of our study showed that ALT elevations developed in nearly 30% of patients after 2 months of propylthiouracil administration. Without an untreated control group, which is not possible because of the ethical concerns involved in withholding treatment, one may argue that patients with normal AST and ALT levels at baseline could develop transaminase abnormality due to hyperthyroidism per se [19], as did the patients with ALT elevations before therapy. Such an event is not likely because the mean duration of symptoms before therapy in patients showing ALT elevations during propylthiouracil administration was 2.5 months, 0.2 months longer than in patients with ALT elevations before treatment (data not shown) and 2 months shorter than in patients without ALT elevations after propylthiouracil therapy (see Table 1). If ALT elevations 2 months after propylthiouracil therapy were due to hyperthyroidism per se, the interval between symptom onset and development of ALT elevations would be much greater than that in patients with ALT elevations before therapy. Therefore, the temporal relation suggests that the ALT elevations were induced by propylthiouracil, reflecting subclinical acute hepatocellular injury or at least transaminase abnormality [20]. Although ALP, but not bilirubin, levels also increased in these patients, the liver injury was not considered to be cholestatic [20] because elevation of ALP is a common phenomenon, as shown in patients without ALT elevations (see Figure 2), possibly caused by increased osteoblastic activity after anti-thyroid therapy [21]. The ALP elevations seen in our patients were also due mainly to the increase of bone isoenzyme (Huang MJ. Unpublished data). Results of serologic studies in the patients with ALT elevations after propylthiouracil therapy also confirmed that these changes were not related to hepatitis A, B, C, or delta virus infection. In addition, the six HBsAg-positive patients and two anti-HCV-positive patients all had normal AST and ALT levels during propylthiouracil therapy (Table 1). The latter findings, although not statistically significant, suggest that these ALT elevations were not related to HBV or HCV. The re