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*PROPYL THIOURACIL
The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1727-1733
Copyright © 1997 by The Endocrine Society

Clinical Studies

Fifty Years of Experience with Propylthiouracil-Associated Hepatotoxicity: What Have We Learned?1

Katherine V. Williams, Sunil Nayak, Dorothy Becker, Jorge Reyes and Lynn A. Burmeister

Division of Endocrinology and Metabolism, Departments of Medicine (K.V.W., L.A.B.) and Pediatrics (S.N., D.B.), and The Thomas E. Starzl Transplantation Institute (J.R.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Lynn A. Burmeister, M.D., E1140 Biomedical Science Tower, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261. E-mail: Burmeist{at}Novell1.Dept-Med.Pitt.Edu


   Abstract
Top
 Abstract
Introduction
 Case Reports
 Materials and Methods
 Results
 Discussion
 References
 
The aim of this study was to determine the optimal management of patients with propylthiouracil (PTU) hepatotoxicity.

A MEDLINE search for English language cases of PTU hepatotoxicity between 1966 and April 1996 was performed, and additional cases were cross-referenced. Twenty-seven cases were selected based on the availability of information on patient management after the onset of hepatotoxicity. Eighty-five percent of the selected cases met this criterion. A detailed summary of the management of two cases of PTU hepatotoxicity at our institutions is also provided.

Although most patients recovered once PTU was stopped, seven patients died. Patients with PTU hepatotoxicity who survived were more likely to have received 131I during the course of their illness than those who died (P < 0.03, by Fisher’s exact test). In our two patients, hyperbilirubinemia was linearly associated with progressively decreasing T4 levels (r = 0.91; P < 0.001) despite the presence of clinical thyrotoxicosis in one of the patients. These findings demonstrate the need for appropriate clinical evaluation and treatment of thyroid disease during the course of hepatotoxicity. Additionally, we report the first pediatric patient with PTU hepatotoxicity to undergo liver transplantation. The emerging role of liver transplantation in these patients is discussed.


   Introduction
Top
 Abstract
 Introduction
Case Reports
 Materials and Methods
 Results
 Discussion
 References
 
HEPATOTOXICITY was first reported as a side-effect of propylthiouracil (PTU) therapy 50 years ago (1). However, despite subsequent case reports (2–24), there has been no systematic review of the management of this potentially fatal disorder (9, 13, 21, 22, 23, 24). Patients with PTU hepatotoxicity present unique challenges for the management of both hyperthyroidism and hepatic failure. We present two cases of hepatic failure in patients receiving PTU. One was successfully treated with a liver transplant, and the other died of multisystem organ failure. Medical advances and our review of the last 50 years of experience suggest the potential for new treatment of this disorder and offer new insight into the diagnosis and treatment of hyperthyroidism in the presence of hepatic disease.


   Case Reports
Top
 Abstract
 Introduction
 Case Reports
Materials and Methods
 Results
 Discussion
 References
 
Case 1

A 14-yr-old female of Latin American descent presented in April with complaints of heat intolerance, weight gain, tremor, restless sleep, intermittently loose stools, and a 5-kg weight gain. She noted diminished school performance due to poor concentration. There was progressive prominence of her eyes. Menarche had occurred at 10 yr, and she had noted a 1-yr history of menstrual irregularity. Her past medical history was unremarkable, and she took no medications. Family history was negative for thyroid or liver disease.

On initial examination she had tachycardia, tremor, exophthalmos, and a goiter with a prominent bruit. Laboratory evaluation showed thyrotoxicosis (Table 1Go), positive TSH receptor antibodies (66%; normal, <12%), and strongly positive antimicrosomal (5540 IU/mL; normal, <120) and antithyroglobulin (7625 IU/mL; normal, <120 IU/mL) antibodies. In addition, she had mild {gamma}-glutamyltransferase and alkaline phosphatase elevations (Table 1Go). She was diagnosed with Graves’ disease and was treated with 400 mg PTU daily (6.0 mg/kg·day) and 80 mg propranolol daily (1.2 mg/kg·day). During the subsequent 10 weeks, the PTU dosage was increased to 450 mg daily (6.7 mg/kg·day). Her symptoms and thyroid studies gradually improved, and {gamma}-glutamyltransferase normalized, but her other hepatic studies rose slightly (Table 1Go).


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  		Table 1. Laboratory values and clinical course of case 1

 
Three months after initiating therapy, the patient discontinued the antithyroid medications during a 2-week vacation to the Dominican Republic. While there, she and her family developed a diarrheal illness that resolved within 48 h. She presented to her endocrinologist in August with increased clinical thyrotoxicosis (Table 1Go, 8/11). PTU (450 mg daily) and propranolol (240 mg daily) were restarted, and within 2 weeks her thyroid function tests were improving (Table 1Go, 8/23).

One week later, she presented with fatigue, vomiting, diarrhea, yellow sclerae, and dark urine. She had tachycardia, icterus, exophthalmos, jaundice, goiter with a prominent bruit, and tremor. Laboratory evaluation showed continued thyrotoxicosis and severe hepatocellular damage (Table 1Go, 8/31). Hepatitis A, B, and C screen, and antinuclear and antismooth muscle antibodies were negative. PTU was discontinued, and propranolol was maintained at 240 mg/day. Radioiodine uptake was 42% at 24 h. The hepatic dysfunction progressed to fulminant hepatic failure (Table 1Go) with worsening coagulopathy and symptoms of hepatic encephalopathy. The patient was transferred to the Children’s Hospital of Pittsburgh. Thyroid studies showed normal total and free T4 levels (Table 1Go, 9/11). Viral hepatitis studies were again negative. Propranolol therapy was decreased to 120 mg/day, and Lugol’s solution (five drops, three times daily) was begun. She developed progressive hyperbilirubinemia with a declining total T4 level (Table 1Go). Open liver biopsy revealed virtually complete hepatocellular necrosis. The following day, she received an orthotopic liver transplant without complication.

Hepatic studies returned to normal within 2 days of transplantation (Table 1Go). Immunosuppression was maintained with tacrolimus and prednisone. Lugol’s solution and propranolol were continued, and she had further improvement of thyrotoxicosis and exophthalmos over the following 2 weeks. Eighteen days after liver transplantation she underwent a subtotal thyroidectomy. One year later, the patient is in good health and receiving thyroid hormone replacement and minimal immunosuppressive therapy.

Case 2

A 54-yr-old white man with a history of heavy alcohol use 15 yr previously presented in December with dyspnea on exertion, palpitations, nausea, pruritus, and right upper quadrant tenderness. Over the preceding 4 months he had lost 8.2 kg despite no change in his appetite. Two weeks before presentation he developed frequent stools. He also complained of heat intolerance, difficulty sleeping, and tremors. Although he readily admitted to drinking heavily in the past, he currently reported drinking six cans of beer per week. There was no history of medication use, hepatitis, blood transfusions, homosexual contact, iv drug use, or recent travel. He denied any significant past medical illnesses. Family history was negative for thyroid or liver diseases.

The patient was very anxious. The heart rate was 140 beats/min and irregular, with a blood pressure of 140/80 mm Hg. The skin was warm, and there were spider angiomas. The sclerae were anicteric, there was no proptosis, and extraocular muscle function was intact. The thyroid gland was not palpable. There were no cardiac murmurs, and the lungs were clear to auscultation. There was moderate right upper quadrant tenderness, but the liver was not enlarged. There was no peripheral edema. An electrocardiogram showed atrial fibrillation with a rapid ventricular rate. Laboratory evaluation showed elevation of hepatic enzymes and bilirubin as well as thyrotoxicosis (Table 2Go) with positive antimicrosomal antibodies (1:6400 titer; normal, <1:100) and normal thyroid-stimulating Ig (83%; normal, 70–150%). Right upper quadrant ultrasound showed diffuse dilation of intrahepatic ducts, normal extrahepatic ducts, and no gallstones. Computed tomography (CT) of the liver and spleen with oral gastrografin was normal. A hepatobiliary scan with cholecystokinin showed no findings to suggest acute cholecystitis. Hepatitis B surface antigen, hepatitis B surface antibodies, hepatitis B core antibodies, and hepatitis C antibodies were all negative.


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  		Table 2. Laboratory values and clinical course of case 2

 
Atrial fibrillation was treated initially with iv diltiazem and digoxin. When the results of the thyroid function tests became available, PTU (800 mg daily), metoprolol, and Lugol’s solution were started. He converted spontaneously to normal sinus rhythm and had some improvement of the thyroid function tests and transaminases (Table 2Go, 12/7). He was discharged on PTU and metoprolol treatment.

Twelve days later he presented with jaundice, right upper quadrant pain, worsening hepatic enzyme abnormalities, and persistent thyrotoxicosis (Table 2Go, 12/20). PTU was discontinued. Hepatitis A antibodies and hepatitis C PCR were negative. A repeat ultrasound of the liver showed no dilated intra- or extrahepatic ducts. A CT scan of the abdomen with iv contrast showed slight prominence of the intrahepatic ducts. Methimazole was given on the seventh hospital day, but was discontinued on the ninth hospital day due to persistent hepatic enzyme elevations. He received Lugol’s solution (three drops daily) for 2 days.

He was transferred to the University of Pittsburgh Medical Center on December 29. On arrival, he did not appear clinically thyrotoxic despite an elevated free T4 index of 24.5 (Table 2Go). Serologies were again negative for hepatitis A, B, and C. Antinuclear, antimitochondrial, and antismooth muscle antibodies were negative. Liver biopsy revealed chronic liver disease with an acute insult and mild eosinophilia due to a drug, viral, or autoimmune reaction. He was placed on the transplant waiting list and discharged.

Three days later he was readmitted with nausea and vomiting due to a duodenal ulcer. He appeared clinically euthyroid, but the free T4 index remained elevated at 17.6 (Table 2Go, 1/14). He developed progressive hyperbilirubinemia with a declining total T4 level (Table 2Go). Liver transplantation was delayed due to atrial fibrillation, hypotension, fever, and acute renal failure. The possibility of thyroid storm was considered. Radioiodine uptake was 8.24% at 24 h. A trial of propranolol treatment induced hypotension. He was given hydrocortisone (150 mg daily) and supersaturated potassium iodide (five drops every 6 h). Antibiotics were given for subacute bacterial peritonitis and a urinary tract infection. Recurrent fevers and unstable hemodynamics continued despite repeatedly negative blood, peritoneal, and urine cultures. He died of multisystem organ failure within 5 weeks of presentation. A free T4 level was high on the day of death (Table 2Go, 1/26).


   Materials and Methods
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
Results
 Discussion
 References
 
MEDLINE was searched, reviewed, and cross-referenced for all reported cases of antithyroid drug-associated hepatotoxicity. All available English language case reports of PTU-associated hepatotoxicity that included details on the duration of antithyroid drug treatment, dosage of drug, management of hepatic failure, and outcome were analyzed.

Thyroid function tests on the two cases presented were obtained through five different institutions. The specific tests used are reported in Tables 1Go and 2Go.

Statistical analysis was performed with the Statistical Package for the Social Sciences using t tests, Wilcoxon rank sum test, ANOVA, {chi}2, and Fisher’s exact test where appropriate. P < 0.05 is considered significant.


   Results
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
 Results
Discussion
 References
 
A literature review found 28 cases of PTU-associated hepatotoxicity (1–24). Including the 2 cases presented herein, there were a total of 30 cases. Several more incidental reports of antithyroid drug-associated hepatoxicity exist, but did not provide enough detail for analysis (25, 26, 27, 28, 29). The initial case report of hepatocellular jaundice is not included in the data analysis because jaundice was not noted until after discontinuation of PTU (1).

The characteristics of the patients who developed PTU-associated hepatic disease are shown in Table 3Go. One female who received PTU via transplacental passage and manifested symptoms at the age of 5 days was not included (6). There were more case reports of PTU hepatotoxicity in women than men, with an overall female to male ratio of 8.3:1. When patients who survived were compared to those who died, there was no difference in age, dose of PTU, or months of continuous PTU therapy before the onset of PTU hepatotoxicity (Table 3Go). Most patients (75.0%) did not have hepatic function tests performed before the initiation of PTU therapy (Table 3Go). Baseline hepatic function test abnormalities were reported in our two cases and three others (2, 14, 20).


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  		Table 3. Characteristics of patients with propylthiouracil-associated hepatotoxicity

 
Diagnosis and treatment of thyrotoxicosis

PTU was discontinued in all reported cases once hepatotoxicity was recognized. Thyroid function studies at presentation with hepatoxicity were not described in 38.1% of the reports (Table 4Go). When noted, the thyroidal state was either normal or thyrotoxic. The rationale for treatment of hyperthyroidism at the time patients presented with hepatotoxicity was not always stated. Some cases were described as being euthyroid but received treatment for hyperthyroidism, whereas others were described as hyperthyroid yet received no treatment for hyperthyroidism.


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  		Table 4. Prevalence of thyroid function test abnormalities and management of hyperthyroidism at presentation with propylthiouracil hepatotoxicity

 
Most patients with PTU-associated hepatotoxicity received 131I (2, 4, 5, 7, 8, 9, 12, 14, 16, 20) after presentation with hepatotoxicity (Table 4Go). Two patients were pregnant at presentation and could not receive 131I (8, 15). There was an association between 131I treatment of hyperthyroidism and survival (P = 0.024, by Fisher’s exact test). No patient who died received 131I. The timing of 131I ranged from 1–15 weeks (mean, 32 ± 8 days) after presentation with hepatotoxicity. Ten of the 12 patients who received 131I therapy were treated before the hepatic function test abnormalities resolved.

Propranolol alone (9, 11, 21, 22) or methimazole (8, 15, 16) was used without complication in a total of seven cases. Including our two patients, four patients received oral iodide either as the primary treatment of hyperthyroidism before thyroidectomy or after 131I therapy (7, 14). The first case presented is the first reported patient to undergo thyroidectomy as part of the management of hyperthyroidism.

Diagnosis and treatment of hepatotoxicity

The diagnosis of PTU hepatotoxicity was supported by either liver biopsy in our 2 cases and 14 others (3, 10, 14, 16, 18, 19, 20, 21, 22, 23) or postmortem examination (9, 24). Liver histology showed varying degrees of liver necrosis, although exceptions were found (10, 19). The association between PTU and hepatic injury was confirmed by rechallenge with PTU in 1 case (16). Nine patients had lymphocyte sensitization studies performed at various times after the onset of hepatotoxicity. Lymphocyte sensitization to PTU was positive in 5 patients (6, 10, 14, 15, 18) and negative in 4 patients (4, 11, 12, 19).

Most of the patients had resolution of hepatic function abnormalities upon discontinuation of the antithyroid drug followed by supportive therapy alone (2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). Three patients received steroids, but the reasons for steroid therapy were not uniform and included treatment for possible autoimmune hepatitis (3), rash (10), or unexplained hypotension in the second case presented here. Two patients, including the first case presented here, underwent liver transplantation for PTU-associated hepatic failure. The other patient who received a liver transplant was pregnant when she developed PTU hepatotoxicity and successfully received a liver transplant while pregnant, but suffered fetal death (8). Seven patients died of PTU hepatotoxicity (9, 13, 21, 22, 23, 24). The deaths occurred between 1–17 weeks (mean, 39 ± 14 days) after presentation with hepatotoxicity. Deaths were attributed to complications of hepatic failure, such as deepening coma with brain death (9, 21), hepatorenal syndrome (22), sepsis (13, 24), or gastrointestinal bleeding (23).


   Discussion
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
 Results
 Discussion
References
 
PTU-associated hepatotoxicity is a rare and life-threatening complication of antithyroid drug treatment of hyperthyroidism. The estimated incidence of antithyroid drug-associated hepatotoxicity is less than 0.5% (30), although the true incidence is unknown (31, 32). We report two cases of PTU-associated hepatotoxicity and a review of the English language literature.

PTU hepatotoxicity occurs at all ages and, like thyroid disease (33), shows a female predominance. The ranges for both PTU dose and duration of therapy in the patients who developed hepatotoxicity are wide. The presentation of PTU hepatotoxicity is clinically nonspecific. Abnormalities or worsening of liver function tests suggest the diagnosis. However, a search for other potential causes of hepatic dysfunction remains necessary. Nonspecific hepatocellular necrosis is typically found on liver biopsy (3, 9, 14, 16, 20, 21, 22, 23, 24). Based on the severity of the disease process, the pathological findings may range from early signs of hepatocellular inflammation and swelling to submassive hepatic necrosis. The mechanism of antithyroid drug hepatotoxicity is not known, although positive lymphocyte sensitization studies in some patients who developed PTU hepatotoxicity suggest an immune reaction to PTU. Because both hyperthyroidism and hepatic dysfunction may progress despite discontinuation of PTU, appropriate management of both diseases is critical.

Upon recognition of hepatotoxicity, PTU should be discontinued. With supportive therapy, most patients should recover. However, death due to complications of liver failure occurred in 25% of the population reported herein. Thus, early recognition of fulminant hepatic failure and intervention may be necessary. Several early prognostic factors are known to be associated with survival rates of less than 20% in fulminant hepatic failure (34). These include patient age (<11 and >40 yr), duration of jaundice (>7 days) before the onset of encephalopathy, serum bilirubin concentration (>300 µmol/L), and prothrombin time (>50 s). The etiology of fulminant hepatic failure may be the most important variable predicting outcome in medically managed patients, with a survival rate of only 13.6% in patients with idiosyncratic drug reactions (34). If patients who receive a liver transplant are included in this group, the overall survival rate is increased to 20–30% (35). Thus, liver transplantation should be considered based on close clinical and laboratory follow-up in patients with PTU hepatotoxicity. This procedure proved necessary and was lifesaving in two patients, including the pediatric patient reported herein (8). To this end, early referral to a transplantation center may improve the chances of finding a suitable donor organ (34). The presence of encephalopathy, hypoprothrombinemia, or the hepatorenal syndrome may hasten the need for transplantation (36). Lastly, plasmapheresis or hemodialysis with hemoperfusion for correction of coagulopathy and encephalopathy may be effective in providing time for recovery of the liver or as a bridge to transplantation (37).

The interpretation of thyroid function tests and the treatment of hyperthyroidism in the unique setting of PTU-associated hepatotoxicity presents another challenge. Interactions between both thyroid and hepatic disease as well as the patient’s clinical status must be considered. Biochemical tests alone may not reflect the patient’s true thyroid status. Acute hepatitis may increase the concentration of thyroid hormone-binding globulin, causing an increase in the total T4 level and a decrease in the thyroid hormone binding ratio (38). With progressive hepatic dysfunction, the interaction between thyroid and hepatic disease becomes even more important. Both cases presented showed an inverse linear relationship between total T4 level and serum bilirubin (r = 0.91; P < 0.001) (Fig. 1Go). This relationship has been observed in other patient populations (39). Yet, in case 2, when total T4 was unmeasurable, free T4 (by equilibrium dialysis) was markedly elevated, suggesting persistent, insufficiently treated hyperthyroidism. The low total T4 level may have been due to a decreased concentration of thyroid hormone-binding proteins (40, 41). Bilirubin may also have interfered with the measurement of T4 by lowering the affinity of T4 for thyroid hormone-binding proteins (42). Furthermore, because bilirubin is a marker of the severity of hepatic dysfunction, the correlation between bilirubin and total T4 may only reflect the progression of nonthyroidal illness (40). Because free T4 may be elevated when total T4 is normal, low, or unmeasurable in hyperthyroidism associated with severe illness (40, 43, 44), the measurement of free T4 levels may aid in the interpretation of the patient’s thyroidal status.



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  		Figure 1. Regression plot of bilirubin vs.total thyroxine for cases 1 and 2; r = 0.91, P < 0.001.

 
The options for treatment of hyperthyroidism in such patients are limited. PTU is contraindicated because of the unknown mechanism of hepatotoxicity and the reported recurrence of hepatic injury with PTU rechallenge (16). The majority of patients received definitive treatment with 131I, and this form of treatment was significantly associated with survival. However, because the average timing of this treatment was later than the duration of survival in patients who succumbed to PTU hepatotoxicity, the positive effects of 131I cannot be firmly established from the available data. It is possible that patients treated with 131I had a less severe form of hepatotoxicity than the patients who did not receive treatment, thus reflecting selection bias. Nevertheless, the ideal treatment may be immediate 131I therapy when PTU hepatotoxicity is suspected. Radioiodine treatment should be completed before the administration of iodine contrast for abdominal CT scans to evaluate the cause of hepatic dysfunction or iodide therapy for the thyrotoxic state. Although 131I may take several weeks to be effective, oral iodide may be started 1 week after 131I therapy to hasten the return of the euthyroid state (30), as reported in two previous cases of PTU hepatotoxicity (8, 15). Propranolol may be used to control the symptoms of hyperthyroidism until 131I has its full effect (30). Alternatively, methimazole has been used successfully after hepatic enzyme levels normalize. Additional treatment modalities that have not yet been described in the special circumstance of PTU hepatotoxicity include ipodate, iopanoate, lithium carbonate, plasmapheresis, and dialysis (45).

The use of iodide alone after recognition of hepatotoxicity merits further comment. In most patients, iodide doses of 114 mg produce maximal suppression of thyroid hormone levels within 7–14 days and last from 1 to more than 50 days (46, 47). Because iodide can also provide substrate for thyroid hormone synthesis, it is usually used in combination with antithyroid drugs. In the two cases presented, iodide was administered in isolation because of PTU hepatotoxicity. However, because the cause of hyperthyroidism is variable (Graves’ disease vs. toxic multinodular goiter), this therapy cannot be recommended in all patients. In the first case presented, who had Graves’ disease, iodide treatment controlled thyrotoxicosis until a thyroidectomy could be performed. The etiology of hyperthyroidism in the second case may not have been Graves’ disease but, rather, toxic multinodular goiter, and it is theoretically possible, although undocumented, that iodide treatment may have exacerbated his thyrotoxic condition.

An important question that could not be answered by this study is whether patients with preexisting liver function test abnormalities or hepatic disease are at increased risk of developing hepatotoxicity. PTU has been administered in a clinical trial to patients with alcoholic hepatitis with associated decreased mortality and without reported worsening of liver function (48). PTU hepatotoxicity has been reported in patients with both normal and abnormal baseline liver function tests. Up to 72% of patients with hyperthyroidism and presumably normal liver function may have an elevation of at least one hepatic enzyme (49). Alkaline phosphatase elevations are most commonly reported; however, the bone isoenzyme predominates (50, 51). Transaminase elevations may be due to thyrotoxicosis-induced increased hepatic oxygen consumption (52, 53) with inadequate compensatory hepatic blood flow (52). In one prospective study, thyrotoxic patients with mild baseline alanine aminotransferase (ALT) elevations had either an increase or a decrease in ALT with PTU treatment. When PTU was continued at a reduced dose, ALT levels normalized in most patients (31). Liver function test elevations were present in both of our cases before the initiation of PTU therapy; however, the second case had a greater elevation of ALT before starting PTU therapy than those previously reported (49). Marked baseline elevations in liver enzymes require investigation for underlying liver disease.

This report does not include data on methimazole hepatotoxicity, for which there have been 21 reported cases (7, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70) and 3 (14%) reported deaths (7, 69, 70). The percentage of deaths from methimazole hepatotoxicity did not reach statistical significance compared to the percentage of reported deaths in patients with PTU hepatotoxicity (by {chi}2 analysis using Fisher’s exact test, P = 0.48). Patients with methimazole hepatotoxicity more commonly have cholestatic changes on liver biopsy.

In summary, in the past 50 years there have been several changes that can affect the management of PTU-associated hepatotoxicity, including improvements in thyroid hormone assays, additional forms of antithyroid therapy, and liver transplantation. Recommendations for the management of these patients are shown in Table 5Go. No specific factors identify the risk of hepatotoxicity in an individual patient. Baseline hepatic function abnormalities may be related to hyperthyroidism (31, 49) and do not necessarily contraindicate the use of antithyroid drugs. The available data are insufficient to establish whether baseline hepatic function test abnormalities are more common in patients with PTU hepatotoxicity. If significant hepatic enzyme abnormalities develop during the course of PTU therapy, the drug should be discontinued immediately, and definitive treatment of the hyperthyroidism should consist of 131I therapy. Because of the possible autoimmune etiology of PTU hepatotoxicity (6, 18) and recurrence of hepatotoxicity with drug rechallenge (16), PTU should not be reinstituted even after resolution of hepatotoxicity or liver transplantation. Appropriate evaluation of the patient’s thyroid status requires assessment of both physical findings and accurate measurement of free T4 levels. Close clinical follow-up is necessary because hepatic failure can progress despite discontinuation of PTU. Recognition of the need for liver transplantation and prompt referral to a transplant center may be lifesaving. Using these combined approaches it is possible that deaths from PTU-associated hepatotoxicity might be reduced over the next 50 years.


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  		Table 5. Summary of recommendations for management of propylthiouracil hepatotoxicity

 


   Acknowledgments
 
Appreciation is expressed to Malcom S. Schwartz, D.O., for his assistance with the management of the first case.


   Footnotes
 
1 This work was supported in part by Grant 2T32DK07052–22 from the NIH Research Training in Diabetes and Endocrinology (to K.V.W.), Grant IT32-DK-07729 from the NIDDK, NIH (to S.N.), Grant DK-02147–03 from NIDDK and American Liver Foundation (to L.A.B.). Back

Received September 18, 1996.

Revised December 12, 1996.

Accepted January 26, 1997.


   References
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
 Results
 Discussion
 References
 

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