Fulminant Hepatitis A in a Patient with Severe Hyperthyroidism: Rapid Recovery from Hepatic Coma after Plasmapheresis and Total Thyroidectomy

Michael Enghofer, Klaus Badenhoop, Stefan Zeuzem, Andreas Schmidt-Matthiesen, Christoph Betz, Albrecht Encke and Klaus Henning Usadel

Departments of Medicine I (M.E., K.B., K.H.U.), II (S.Z.), and IV (C.B.), and Department of Surgery (A.S.-M., A.E.), Johann Wolfgang Goethe University, D-60590 Frankfurt am Main, Germany

Address correspondence and requests for reprints to: Michael Enghofer, M.D., Department of Medicine I, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.


    Introduction
 Top
 Introduction
 Differential Diagnosis
 Diagnostic Workup
 Clinical Course
 Discussion
 References
 
A 62-yr-old Chinese man was transferred to the medical intensive care unit of our university hospital because of hepatic coma and severe hyperthyroidism. The software engineer, who had lived in Germany for 10 yr, had been well until 3 days before admission, when he experienced acute onset of nausea, vomiting, and diarrhea. The next day, he started passing black, tarry stools. Jaundice, low-grade fever, and pronounced malaise developed. Three days after onset of symptoms he was admitted to another hospital, where gastroscopy showed diffuse gastric bleeding due to erosive gastritis. He was treated with ranitidine and metoclopramide iv. The laboratory investigations at admission (Table 1Go) showed markedly elevated liver enzymes, a prolonged prothrombin time, and decreased serum levels of antithrombin III and total protein. Glucose, electrolytes, blood urea nitrogen, creatinine, creatine phosphokinase, amylase, lipase, uric acid, complete blood count (with the exception of a reduced platelet count), and erythrocyte sedimentation rate were within the normal range. Serologic tests for antibodies against hepatitis A (IgG and IgM) were positive, and the patient showed marked hyperthyroidism (Table 1Go). Thyroid scintiscanning revealed a diffusely increased thyroid 99mTc-pertechnetate uptake without evidence for hyperfunctioning nodules. Diffuse goiter with an irregular and slightly hypoechoic structure was diagnosed by thyroid sonography. The patient received 40 mg methimazole per day iv. The coagulopathy was treated with 10 mg phytonadione (vitamine K1) per day iv and by infusion of a total of 400 mL fresh-frozen plasma. The patient had been weak and drowsy on admission to the other hospital, but was able to communicate. He was oriented to time, place, and self. However, his mental status rapidly deteriorated. Hepatic encephalopathy with confusion developed, and he showed increased psychomotor activity. No focal neurologic signs were noted. A cerebral computed tomography scan (without administration of iodine containing contrast medium) was normal. A central line was inserted, and the patient received glucose, an amino acid solution enriched with branched amino acids, electrolyte solutions, and ornithine aspartate iv. For sedation, midazolam, flunitrazepam, and morphine sulfate were administered iv. The following day, the patient was in a deep coma, and he was transferred to our university hospital.


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Table 1. Laboratory tests on admission to the first hospital

 
The patient’s wife reported a history of mild Graves’ disease for 5 yr. The patient had refused radioiodine therapy or thyroidectomy and had been taking oral methimazole irregularly for 2 yr, although repeatedly serum T4 levels were markedly elevated and thyrotropin was undetectable in serum. His general practitioner had recommended a dose of 20 mg methimazole per day. Due to compliance problems, he also did not follow the recommendation to minimize his iodine intake, but continued to eat seafood regularly. However, administration of iodine containing x-ray contrast medium in the previous months could be ruled out as a predisposing factor for the development of his thyrotoxicosis. Furthermore, atrial fibrillation was present for 5 yr before admission. The patient repeatedly refused digoxin treatment, cardioversion, or anticoagulation for this condition. However, he was able to work hard up to 12 h a day and had just arrived from a 4-week business trip to southern China and Beijing 1 month before the onset of his current illness. His German business partner, who accompanied the patient during the whole trip to China, as well as his wife and daughter, stayed well. There was no known history of contact with persons infected with hepatitis A. The patient drank one to two bottles of beer a day. He did not take acetaminophen or other potentially hepatotoxic drugs, apart from methimazole. He had never had symptoms suggestive of hepatitis or other liver diseases and had never been hospitalized before. Three months before admission, liver function tests had been normal, but hyperthyroidism was present.

On arrival in our intensive care unit, the jaundiced and dehydrated patient was deeply comatose (Glasgow coma scale, 3/15) and did not show any reaction to painful stimuli. He was breathing spontaneously, and his respirations were 28/min. His rectal temperature was 36.3 C (96.7 F), the blood pressure was 100/70 mm Hg, and the pulse was arrhythmic. Atrial fibrillation with a ventricular response of 100–120 bpm was present. There were no murmurs or rubs. The lungs were clear. The lips and oral mucosa showed old encrusted blood, but no active bleeding. Apart from one isolated spider naevus in the left clavicular region, no peripheral signs of chronic liver disease were seen. The thyroid was diffusely enlarged. Neither endocrine ophthalmopathy nor dermopathy was present. The liver and spleen were not palpable, and there were no clinical signs indicating the presence of ascites.


    Differential Diagnosis
 Top
 Introduction
 Differential Diagnosis
 Diagnostic Workup
 Clinical Course
 Discussion
 References
 
This 62-yr-old Chinese man had no history of previous liver disease. He presented with rapidly deteriorating hepatic encephalopathy. Graves’ hyperthyroidism was known for 5 yr. He had been on methimazole for more than 2 yr when he developed fulminant hepatitis. It seemed highly unlikely that in this case acute hepatitis was caused by hepatotoxic adverse effects of antithyroid drugs alone. He had been taking methimazole more or less regularly for more than 2 yr before the rapid onset of acute severe liver disease, but even 3 months before admission there was no laboratory evidence for adverse hepatotoxicity of this treatment. A latency period of more than 2 yr between the start of antithyroid therapy and the induction of associated hepatotoxicity has not been reported in the literature yet. Fatal methimazole-induced hepatitis has been described in a patient with micronodular cirrhosis and persistent hepatitis B antigenemia, who had no evidence for hepatitis B reactivation or chronic hepatitis B (1). Our patient had acute hepatitis A, as shown by demonstration of IgM antibodies against the hepatitis A virus. A fulminant course with the development of acute liver dystrophy is a very rare complication of hepatitis A (2). Hence, preexisting hyperthyroidism and/or chronic treatment with antithyroid drugs apparently predisposed this patient for hepatic failure induced by the hepatitis A infection. Other infectious hepatitis types could be ruled out serologically and by PCRs (Table 3Go). There was no evidence for toxic liver damage by drugs or other toxins. The amount of alcohol consumed was less than 40 g per day. Thrombotic occlusion of hepatic veins, the Budd-Chiari syndrome, was considered unlikely because the liver was not enlarged on ultrasonography and there was no ascites. The absence of splenomegaly and ascitic fluid was evidence against portal vein thrombosis. Because chronic atrial fibrillation was present and the patient had refused oral anticoagulation with warfarin for years, thromboembolism to the hepatic artery might have occurred. Liver failure induced by thromboembolic impairment of hepatic arterial blood supply, however, has not been reported so far. There was no history of acute hypotension due to any type of shock in this patient. The absence of leukocytosis, of leukopenia, and of fever more than 38 C, as well as the almost normal levels of acute phase proteins, was evidence against septic liver failure.


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Table 3. Serologic tests on admission to our hospital

 

    Diagnostic Workup
 Top
 Introduction
 Differential Diagnosis
 Diagnostic Workup
 Clinical Course
 Discussion
 References
 
Laboratory testing in our hospital (Table 2Go) confirmed the presence of severe hepatitis and Graves’ hyperthyroidism. Thyrotropin receptor autoantibodies showed markedly elevated levels (Table 2Go). Glucose, electrolytes, blood urea nitrogen, creatinine, creatine phosphokinase, amylase, and the complete blood count (with the exception of a reduced platelet count; Table 2Go) were within the normal range. Acute hepatitis A was diagnosed serologically (Table 3Go). There was no history of exposure to hepatotoxins apart from the methimazole the patient was taking irregularly for 2 yr. Thyroid sonography showed diffuse goiter with a very patchy and irregular hypoechogenic texture. The thyroid volume was 105 mL (normal, <25 mL). Abdominal sonography excluded the presence of ascites or splenomegaly and demonstrated a homogenous and slightly hypoechogenic liver of normal shape and size. There was no other pathology in this abdominal ultrasound study. The condition of the comatose patient was critical. Liver function tests deteriorated rapidly (Table 2Go). Free T4 levels in serum were extremely high. A liver biopsy was not performed initially because of the high risk of bleeding and the impossibility to obtain informed consent from the patient.


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Table 2. Routine laboratory tests on admission to our hospital and at follow-up 12 months later

 

    Clinical Course
 Top
 Introduction
 Differential Diagnosis
 Diagnostic Workup
 Clinical Course
 Discussion
 References
 
The ventricular rate was slowed by continuous infusion of esmolol, and 100 mg prednisone were administered iv. Parenteral nutrition was instituted. It was postulated that the high levels of thyroid hormones resulted in increased metabolic stress of hepatocytes, thereby potentiating the hepatotoxic effect of hepatitis A infection. Continued administration of antithyroid agents would have carried the risk of additional drug-induced hepatotoxicity. Therefore, we strongly recommended immediate thyroidectomy. Informed consent was obtained from the patient’s wife. One plasmapheresis treatment was performed to rapidly lower thyroid hormone levels before surgery (Table 4Go). Fifty milliliters of plasma/kg body weight were exchanged. The removed plasma (3094 mL) was replaced by fresh-frozen plasma from matched blood donors. Before and 10 min after plasma separation, blood was collected to quantify the reduction of circulating levels of T4 and thyronine (Table 4Go). After plasmapheresis, the patient was given 1000 units antithrombin III and 2000 units prothrombin complex iv before surgery. Two hours after plasmapheresis the patient was transferred to the operating room, where total thyroidectomy was performed in general anesthesia without complications.


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Table 4. Thyroid laboratory parameters before and after plasmapheresis

 
After thyroidectomy the patient was treated in the medical intensive care unit for 10 days. Following surgery he was sedated and mechanically ventilated for 28 h. Fresh-frozen plasma had to be administered repeatedly. Lactulose was given via a gastric tube, and ornithine aspartate 40 g/24 h was infused iv to lower ammonia levels. Normocaloric parenteral nutrition, including an amino acid solution enriched with branched chain amino acids and with a low content in aromatic amino acids, was resumed on postoperative day 2. The patient could be extubated in the morning of the 3rd day of his hospital stay in our institution. His mental status slowly improved. Although ammonia levels and liver enzymes rapidly normalized in the early postoperative course, the patient developed severe direct hyperbilirubinemia (Fig. 1Go) and continued to require infusions of fresh-frozen plasma to keep international normalized ratio values below 2.0 and antithrombin III levels above 30%. Oral levothyroxine replacement therapy was started on the 6th day. On the 10th hospital day, the patient was transferred to a medical ward. The patient refused liver biopsy. Bilirubin levels peaked at 42.3 mg/dL, and there was no tendency for a decline when the patient decided to leave the hospital against our advice on the 30th hospital day. He traveled to China to be treated there according to the rules of traditional Chinese medicine. However, he had to be admitted to an intensive care unit of a major hospital in Beijing soon after his arrival due to extreme hyperbilirubinemia and coagulopathy. The patient was treated there for 4 months before he was transferred to a traditional Chinese medical facility for rehabilitation. Meanwhile, he has returned to Germany and has started to work again. His mental status, liver function, and most other laboratory results have returned to normal 12 months after the acute onset of hepatic coma (Table 2Go).



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Figure 1. Liver function tests before and after plasmapheresis and thyroidectomy performed on day 1 (arrow).

 

    Discussion
 Top
 Introduction
 Differential Diagnosis
 Diagnostic Workup
 Clinical Course
 Discussion
 References
 
Disturbances of hepatic function are known complications of antithyroid drug treatment for hyperthyroidism (3). The spectrum of observed changes ranges from mild and asymptomatic elevation of cholestatic and cytosolic liver enzymes (3) to fulminant and fatal necrotizing hepatitis (4, 5, 6). Namely, propylthiouracil has been described to be able to cause severe toxic hepatopathies (5, 6, 7), whereas cholestatic jaundice, without evidence of hepatic necrosis on liver biopsy, has been typically associated with methimazole (8). In one study, the incidence of toxic hepatitis due to hepatotoxic adverse reactions against propylthiouracil was 6% (9). Others, however, found a much lower incidence of severe propylthiouracil-induced hepatitis, whereas asymptomatic elevation of liver enzymes under this therapy occurs in up to 28% of patients (3). Nevertheless, there are occasional reports on severe and even fatal cases of drug-induced hepatitis under treatment of hyperthyroidism with methimazole (10) and carbimazole (4). It is also well known that hyperthyroidism itself may cause elevations of liver enzymes (11).

We assume that the chronic hyperthyroidism, which was present in our patient for at least 5 yr before admission, as well as the necessary treatment with antithyroid drugs, imposed such a significant metabolic and possibly toxic stress on the liver that it predisposed him for a fulminant course of viral hepatitis. We, therefore, recommended plasmapheresis, followed by immediate total thyroidectomy, to definitively eliminate the need for further antithyroid treatment and to rapidly lower the concentration of circulating free T4 and T3. In a German survey (12), early thyroidectomy has been reported to reduce the mortality of thyrotoxicosis with coma from 20–40% under conservative treatment to less than 10%.

Plasmapheresis has been used successfully to treat patients with very severe thyrotoxicosis for more than 25 yr (13). In our patient, plasma exchange significantly reduced the levels of circulating free thyroid hormones (Table 4Go). The small increase of total T3 and TSH immediately after plasmapheresis was the result of the administration of donor plasma containing TSH and albumin that binds free T3. Furthermore, plasma exchange not only resulted in a rapid and lasting decline of alanine aminotransferase and aspartate aminotransferase levels, but also reduced hyperammonemia (Fig. 1Go). If the infection with hepatitis A had been the only relevant pathogenetic factor in this case, a much more prolonged period of liberation of cytosolic liver enzymes from necrotic hepatocytes would have been expected. Apparently, the course of fulminant hepatitis A was significantly attenuated by a single plasmapheresis treatment, followed by thyroidectomy, in the case under discussion. However, progressive and severe hyperbilirubinemia could not be prevented. Cholestatic hepatitis is a rare, albeit well recognized, variant of hepatitis A. Protracted cholestatic jaundice may last several months and is typically observed in extraordinarily severe hepatitis A, like in our patient. There was no evidence for underlying hemolytic anemia because lactate dehydrogenase levels rapidly normalized and the hematocrit was stable. One year after surgery, bilirubin levels were measured within the normal range and the patient had fully recovered.

In conclusion, preexisting hyperthyroidism and its treatment with thionamides might predispose patients for acute liver failure after infection with the hepatitis A virus. Due to possible hepatotoxic side effects, treatment with antithyroid drugs should be avoided in hyperthyroid patients with viral hepatitis. We recommend immediate institution of plasmapheresis, followed by thyroidectomy, in such patients because it is the most rapid and reliable way to lower circulating levels of thyroid hormones.

Received October 13, 1999.

Revised December 1, 1999.

Accepted December 6, 1999.


    References
 Top
 Introduction
 Differential Diagnosis
 Diagnostic Workup
 Clinical Course
 Discussion
 References
 

  1. Kang H, Choi JD, Jung IG, et al. 1990 A case of methimazole-induced acute hepatic failure in a patient with chronic hepatitis B carrier status. Korean J Intern Med. 5:69–73.[Medline]
  2. Ghoshal UC, Mukherjee S, Dey BK, Das P, Sarkar S, Mazumder DN. 1997 Subacute hepatic failure in hepatitis A. Indian J Gastroenterol. 16:109.
  3. Liaw YF, Huang MJ, Fan KD, Li KL, Wu SS, Chen TJ. 1993 Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism. A cohort study. Ann Intern Med. 118:424–428.[Abstract/Free Full Text]
  4. Binder C, Lang W. 1993 Necrotizing hepatitis with a fatal outcome after carbimazole therapy. Dtsch Med Wochenschr. 118:1515–1519.[Medline]
  5. Hanson JS. 1984 Propylthiouracil and hepatitis. Two cases and a review of the literature. Arch Intern Med. 144:994–996.[Abstract]
  6. Limaye A, Ruffolo PR. 1987 Propylthiouracil-induced fatal hepatic necrosis. Am J Gastroenterol. 82:152–154.[Medline]
  7. Weiss M, Hassin D, Bank H. 1980 Propylthiouracil-induced hepatic damage. Arch Intern Med. 140:1184–1185.[Abstract]
  8. Fischer MG, Nayer HR, Miller A. 1973 Methimazole-induced jaundice. J Am Med Assoc. 223:1028–1029.[CrossRef][Medline]
  9. Romaldini JH, Bromberg N, Werner RS, et al. 1983 Comparison of effects of high and low dosage regimens of antithyroid drugs in the management of Graves’ hyperthyroidism. J Clin Endocrinol Metab. 57:563–570.[Abstract]
  10. Baker B, Shapiro B, Fig LM, Woodbury D, Sisson JC, Beierwaltes WH. 1989 Unusual complications of antithyroid drug therapy: four case reports and review of literature. Thyroidology. 1:17–26.[Medline]
  11. Gurlek A, Cobankara V, Bayraktar M. 1997 Liver tests in hyperthyroidism: effect of antithyroid therapy. J Clin Gastroenterol. 24:180–183.[CrossRef][Medline]
  12. Hintze G, Köbberling J, Usadel KH. 1989 Schwere jodinduzierte Hyperthyreose und Thyreoidektomie. Innere Medizin. 16:161–164.
  13. Ashkar FS, Katims RB, Smoak WM, Gilson AJ. 1970 Thyroid storm treatment with blood exchange and plasmapheresis. J Am Med Assoc. 214:1275–1279.[CrossRef][Medline]




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