Tong-Jong Chen

Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism. A cohort study.

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

Acute exacerbation in hepatitis B e antigen positive chronic type B hepatitis: a clinicopathological study

During a 6-year (mean 24.5 months) follow-up study of 237 HBeAg-positive patients with biopsy-verified chronic type B hepatitis, 199 episodes of acute exacerbation (SGPT greater than 300 IU/l) were observed in 148 patients. The clinical and laboratory findings of these acute exacerbations were less severe than classic acute viral hepatitis (P less than 0.001) but with remarkable overlapping. The main histological changes of acute exacerbations were those of lobular hepatitis, even with bridging hepatic necrosis which predicted subsequent HBeAg clearance. Anti-HBc IgM was positive in 14.4% of the exacerbations. All of these findings made acute exacerbation of chronic type B hepatitis indistinguishable from acute viral hepatitis aside from chronic clinical history. Hepatitis A virus, delta agent and possibly non-A, non-B virus(es) were responsible for some of the episodes of clinical exacerbations.

Hepatocellular carcinoma presenting as bone metastasis

In a consecutive series of 395 patients with pathologically verified hepatocellular carcinoma, 20 patients (5%) had bone metastasis at initial presentation. Of these, 16 were men and four women ranging from 26 to 64 years of age (median, 50 years). The age, sex, hepatitis B surface antigen seroposivity, alpha‐fetoprotein level, and frequency of associated cirrhosis were not statistically different from those in patients without initial bone metastasis. Initial presentation was usually the result of spinal lesion with neurologic compression, and chest wall or scalp mass. Metastasis most commonly involved spine and ribs, and occurred as osteolytic lesions or extrapleural mass. Computed tomography proved best for demonstrating an expansile soft tissue mass with bony destruction. Angiography showed hypervascular appearance over the destructive bone area. Treatment results were poor. The follow‐up period ranged from 3 weeks to 14 months with a median survival of 5 months. The data suggested that hepatocellular carcinoma be ruled out in patients with osteolytic lesions.

Beneficial effect of prednisolone withdrawal followed by human lymphoblastoid interferon on the treatment of chronic type B hepatitis in Asians: a randomized controlled trial.

To evaluate the effect of interferon and the benefit of prednisolone pretreatment in Oriental patients with chronic active hepatitis B, 120 male Chinese patients were randomly allocated to receive: 1) group A: a 4-week course of prednisolone followed by 2 weeks of no treatment and then a 12-week course of human lymphoblastoid interferon, 4 to 6 MU/m2 intramuscularly; 2) group B: as group A, but with placebo given instead of prednisolone; 3) group C: an 18-week course of placebo. Clearance of serum hepatitis B virus-DNA and HBeAg (complete response) was achieved in 21% of group A, 5% of group B and none of group C at the end of therapy (A vs B: p = 0.054; A vs C: p < 0.01). When assessed 12 months after the end of therapy, the complete response rate was 46% in group A, 24% in group B and 25% in group C (p < 0.05). Those with baseline alanine transaminase < or = 200 U/l showed a better response to interferon following prednisolone withdrawal (48%) than with interferon therapy alone (20%, p = 0.056) and no treatment (9%, p < 0.01). Those with a baseline serum hepatitis B virus-DNA < or = 1000 pg/ml also showed a higher complete response rate when pretreated with prednisolone (59%) than when treated with interferon alone (29%, p = 0.084) or untreated (22%, p < 0.03). The strongest independent predictor of a response to treatment was prednisolone withdrawal (p < 0.05). None of the responders lost hepatitis B surface antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute hepatitis delta virus superinfection in patients with liver cirrhosis

A clinicopathologic study in a total of 164 patients with acute hepatitis delta virus (HDV) infection showed that nine male patients (5.5%) had evidence of liver cirrhosis prior to or during the episode of acute hepatitis. All nine patients had typical clinical presentations and laboratory findings of acute viral hepatitis. Four of them had prolonged prothrombin time, three developed ascites and one finally died of hepatic failure. Clinical ascites occurred more frequently in cirrhotic patients with severe but non-fulminant hepatitis than their non-cirrhotic counterparts (p less than 0.05). In addition, histologic studies in five patients with cirrhosis disclosed diffuse lobular necrotizing inflammatory activity, with four showing bridging hepatic necrosis, which also occurs more frequently in cirrhotic than in non-cirrhotic patients (p less than 0.05). The data suggest that HBsAg positive patients with cirrhosis are susceptible to acute HDV infection which may lead to extensive necrosis or even decompensation and failure, simulating decompensation of the underlying liver disease. Therefore, careful clinicopathologic work-ups are required for accurate diagnosis and correct assessment of their outcomes.

Clinicopathological response of HBsAg-positive chronic active hepatitis to adenine arabinoside: Lack of correlation with DNA polymerase response

SummaryFifteen patients with HBsAg-positive, severe chronic active heptatitis, nine DNA polymerase (DNAP)-positive and six negative were treated with intravenous adenine arabinoside (Ara-A) in a dose of 10 mg/kg/day for five consecutive days during each of two consecutive weeks. Of the DNAP-positive patients, two responded with histological and clinical remission as well as permanent loss of DNAP. However, histological and clinical remission were also observed in patients with unsatisfactory DNAP response and even in DNAP-negative patients. It is suggested that, in addition to its antiviral effect, Ara-A might have another mechanism, such as immunosuppression, that induced histological and clinical remission. Alternatively, the discrepancy of response might relate to the natural course of chronic type B hepatitis. Accordingly, controlled trial is mandatory for assessing the effect of Ara-A or any other agent in the treatment of chronic type B hepatitis.ZusammenfassungFünfzehn Patienten mit HBsAg-positiver, schwerer chronisch aktiver Hepatitis, von denen neun DNS-Polymerase (DNAP)-positiv und sechs -negativ waren, erhielten eine intravenöse Therapie mit Adenin-Arabinosid (Ara-A) in einer Dosis von 10 mg/kg/Tag an fünf aufeinanderfolgenden Tagen während zwei aufeinanderfolgenden Wochen. Von den DNAP-positiven Patienten sprachen zwei mit einer histologischen und klinischen Remission an, sie wurden außerdem anhaltend DNAP-negativ. Es wurden jedoch auch histologische und klinische Remissionen bei Patienten mit einer unbefriedigenden DNAP-Antwort und sogar bei DNAP-negativen Patienten beobachtet. Es wird angenommen, daß Ara-A möglicherweise außer seinem antiviralen Effekt noch einen anderen Wirkmechanismus hat, wie etwa immunsuppressive Aktivität, durch den die histologische und klinische Remission induziert wurde. Auf der anderen Seite kann das unterschiedliche Verhalten mit dem natürlichen Verlauf der chronischen Hepatitis B in Zusammenhang stehen. Kontrollierte Studien zur Feststellung der Wirksameit von Ara-A oder anderen Substanzen in der Therapie der chronischen Heptatitis B sind daher dringend erforderlich.

Prednisolone withdrawal followed by recombinant alfainterferon in chronic non-A, non-B hepatitis: An interim results of a randomized controlled trial

SummaryTo determine the efect of a recombinant α interferon 2b (Intron-A) and possible benefit of prednisolone pretreatment in chronic non-A, non-B hepatitis, 75 Chinese patients with clinico-histologically proven chronic hepatitis were randomly allocated to one of the following regimens: (A) 3 million units of Intron-A trice weekly for 6 months; (B) dose titration according to ALTAST values; (C) prednisolone withdrawal followed by regimen A; (D) control group: no treatment for 6 months but followed by alternating treatment with 3 million units of Intron-A trice weekly for 2 weeks followed by 2 weeks no treatment for 6 months. Up to September 30, 1990, 67 patients have been followed for a minimum of 2 months. At the end of the second month, compelte response (normal ALT) was achieved in 71% of group A, 50% of groupB, 50% of group C and 0% of group D. At the end of the 6th month, the compelte response rate was 62%, 47% and 64% respectively in groups A, B and C. The response rates in groups A and C were significantly better than the 7% in the control group. Complete resonse usually (91%) occurred within 2 months after the first dose of interferon. Relapse occurred in 40% of the compelte responders, usually within 2 months of the last dose. The cumulative relapse rate was significantly lower in responders of group C (11% vs 43% in group A and 86% in group B during a period of 6 months). Only mild adverse effects were reported though two patients withdrew because of intolerable fatigue. The interim results appear very promising, particularly those pretreated with prednisolone.