0021-972X/00/$03.00/0
5
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
CLINICAL CASE SEMINAR
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,
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
A 62-yr-old Chinese man was transferred to the medical
intensive care unit of our university hospital because of he-
patic coma and severe hyperthyroidism. The software engi-
neer, 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 gas-
troscopy showed diffuse gastric bleeding due to erosive gas-
tritis. He was treated with ranitidine and metoclopramide iv.
The laboratory investigations at admission (Table 1) showed
markedly elevated liver enzymes, a prolonged prothrombin
time, and decreased serum levels of antithrombin III and
total protein. Glucose, electrolytes, blood urea nitrogen, cre-
atinine, creatine phosphokinase, amylase, lipase, uric acid,
complete blood count (with the exception of a reduced plate-
let count), and erythrocyte sedimentation rate were within
the normal range. Serologic tests for antibodies against hep-
atitis A (IgG and IgM) were positive, and the patient showed
marked hyperthyroidism (Table 1). Thyroid scintiscanning
revealed a diffusely increased thyroid 99mTc-pertechnetate
uptake without evidence for hyperfunctioning nodules. Dif-
fuse goiter with an irregular and slightly hypoechoic struc-
ture was diagnosed by thyroid sonography. The patient re-
ceived 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 devel-
oped, and he showed increased psychomotor activity. No
focal neurologic signs were noted. A cerebral computed to-
mography scan (without administration of iodine containing
Received October 13, 1999. Revision received December 1, 1999. Ac-
cepted December 6, 1999.
Address correspondence and requests for reprints to: Michael Eng-
hofer, M.D., Department of Medicine I, Johann Wolfgang Goethe Uni-
versity, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
1765
Vol. 85, No.
Printed in U.S.A.
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AND
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, fluni-
trazepam, and morphine sulfate were administered iv. The
following day, the patient was in a deep coma, and he was
transferred to our university hospital.
The patient’s wife reported a history of mild Graves’ dis-
ease for 5 yr. The patient had refused radioiodine therapy or
thyroidectomy and had been taking oral methimazole irreg-
ularly for 2 yr, although repeatedly serum T4 levels were
markedly elevated and thyrotropin was undetectable in se-
rum. 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. How-
ever, administration of iodine containing x-ray contrast me-
dium in the previous months could be ruled out as a pre-
disposing factor for the development of his thyrotoxicosis.
Furthermore, atrial fibrillation was present for 5 yr before
admission. The patient repeatedly refused digoxin treat-
ment, 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 dur-
ing 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 methima-
zole. 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
1766 ENGHOFER ET AL. JCE & M • 2000
Vol 85 • No 5

TABLE 1. Laboratory tests on admission to the first hospital this patient for hepatic failure induced by the hepatitis A
infection. Other infectious hepatitis types could be ruled out
Parameter Value unit Normal range
serologically and by PCRs (Table 3). There was no evidence
ALAT 1428 U/L ⬍23 for toxic liver damage by drugs or other toxins. The amount
ASAT 2540 U/L ⬍18
Lactate dehydrogenase 1889 U/L ⬍200 of alcohol consumed was less than 40 g per day. Thrombotic
Alkaline phosphatase 211 U/L 68 –195 occlusion of hepatic veins, the Budd-Chiari syndrome, was
GGT 48 U/L ⬍28 considered unlikely because the liver was not enlarged on
Choline esterase 2893 U/L 2300 –7400 ultrasonography and there was no ascites. The absence of
Bilirubin, total 5.21 mg/dL ⬍1.5
splenomegaly and ascitic fluid was evidence against portal
Bilirubin, direct 3.71 mg/dL ⬍0.56
C-reactive protein 1.4 mg/dL ⬍0.9 vein thrombosis. Because chronic atrial fibrillation was
Serum protein 5.7 g/dL 6.6 – 8.3 present and the patient had refused oral anticoagulation with
Cholesterol, total 45 mg/dL 130 –260 warfarin for years, thromboembolism to the hepatic artery

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Triglycerides 67 mg/dL 50 –150
Platelet count 73 nL 150 – 450
Prothrombin time 22% 70 –100
INR 3.12 0.75–1.3
PTT 40 s 26 – 40
Fibrinogen 222 mg/dL 150 – 450
Antithrombin III 34% 86 –122
TSH 0.005 IU/mL 0.3– 4.5
Free T4 77.2 pmol/L 10 –26
ALAT, alanine aminotransferase; ASAT, aspartate aminotrans-
ferase; GGT, ␥-glutamyl transpeptidase; PTT, partial thromboplastin
time; INR, international normalized ratio.
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 nae-
vus in the left clavicular region, no peripheral signs of
chronic liver disease were seen. The thyroid was diffusely
enlarged. Neither endocrine ophthalmopathy nor dermop-
athy was present. The liver and spleen were not palpable,
and there were no clinical signs indicating the presence of
ascites.
Differential Diagnosis
This 62-yr-old Chinese man had no history of previous
liver disease. He presented with rapidly deteriorating he-
patic 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 hep-
atotoxic 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 la-
tency period of more than 2 yr between the start of antithy-
roid therapy and the induction of associated hepatotoxicity
has not been reported in the literature yet. Fatal methima-
zole-induced hepatitis has been described in a patient with
micronodular cirrhosis and persistent hepatitis B antigen-
emia, 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 hep-
atitis 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
might have occurred. Liver failure induced by thromboem-
bolic 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.
Diagnostic Workup
Laboratory testing in our hospital (Table 2) confirmed the
presence of severe hepatitis and Graves’ hyperthyroidism.
Thyrotropin receptor autoantibodies showed markedly ele-
vated levels (Table 2). Glucose, electrolytes, blood urea ni-
trogen, creatinine, creatine phosphokinase, amylase, and the
complete blood count (with the exception of a reduced plate-
let count; Table 2) were within the normal range. Acute
hepatitis A was diagnosed serologically (Table 3). There was
no history of exposure to hepatotoxins apart from the meth-
imazole 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 ab-
dominal ultrasound study. The condition of the comatose
patient was critical. Liver function tests deteriorated rapidly
(Table 2). 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.
Clinical Course
The ventricular rate was slowed by continuous infusion of
esmolol, and 100 mg prednisone were administered iv. Par-
enteral nutrition was instituted. It was postulated that the
high levels of thyroid hormones resulted in increased met-
abolic stress of hepatocytes, thereby potentiating the hepa-
totoxic effect of hepatitis A infection. Continued adminis-
tration 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 plasma-
pheresis treatment was performed to rapidly lower thyroid
hormone levels before surgery (Table 4). Fifty milliliters of
plasma/kg body weight were exchanged. The removed
plasma (3094 mL) was replaced by fresh-frozen plasma from
 FULMINANT HEPATITIS A AND THYROTOXICOSIS 1767

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

Parameter Unit Admission Follow-up Normal range

ALAT U/L 860 9 ⬍23
ASAT U/L 570 13 ⬍18
Lactate dehydrogenase U/L 358 123 ⬍200
Alkaline phosphatase U/L 297 103 68 –195
GGT U/L 48 13 ⬍28
Choline esterase U/L 2773 3735 2300 –7400
Bilirubin, total mg/dL 15.5 1.0 ⬍1.5
Lactic acid mg/dL 13.4 n.m. 9 –16
Ammonia ␮g/dL 474 n.m. ⬍90
C-reactive protein mg/dL 0.7 0.1 ⬍0.9
Platelet count /nL 71 123 150 – 450

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Prothrombin time % 35 74 70 –100
PTT s 46 38 26 – 40
Fibrinogen mg/dL 193 236 150 – 450
Antithrombin III % 23 70 86 –122
TSH IU/mL ⬍0.01 0.04 0.3– 4.5
Free T4 ng/dL ⬎13 1.5 0.8 –1.8
Total T4 ␮g/dL 24.2 n.m. 4.5–12.5
TRAb — 50 8 ⬍13
Serum iron ␮g/dL 84.2 113 60 –188
Serum ferritin ␮g/L 469 n.m. 34 –310
Transferrin mg/dL 188.3 n.m. 200 –360
Transferrin saturation % 35.2 n.m. 15–50
Haptoglobin mg/dL ⬍30.3 n.m. 30 –200
ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; GGT, ␥-glutamyl transpeptidase; PTT, partial thromboplastin time;
TRAb, TSH receptor antibodies; n.m., not measured.

TABLE 3. Serologic tests on admission to our hospital plasma had to be administered repeatedly. Lactulose was
given via a gastric tube, and ornithine aspartate 40 g/24 h
Parameter Result
was infused iv to lower ammonia levels. Normocaloric par-
ANA Negative enteral nutrition, including an amino acid solution enriched
AMA Negative
ASMA Negative with branched chain amino acids and with a low content in
Anti-LKM Negative aromatic amino acids, was resumed on postoperative day 2.
Anti-HAV-IgM Reactive, index 9.6 The patient could be extubated in the morning of the 3rd day
Anti-HBc-IgG Reactive, index 9.7 of his hospital stay in our institution. His mental status
HBs-Ag Nonreactive
slowly improved. Although ammonia levels and liver en-
Anti-HBs-IgG Reactive, 19 mE/mL
HBV-DNA (PCR) Negative zymes rapidly normalized in the early postoperative course,
Anti-HCV-IgG Nonreactive the patient developed severe direct hyperbilirubinemia (Fig.
HCV-RNA (PCR) Negative 1) and continued to require infusions of fresh-frozen plasma
Anti-HEV-IgG Nonreactive to keep international normalized ratio values below 2.0 and
Anti-CMV-IgG Reactive, 1:2500
Anti-CMV-IgM Nonreactive antithrombin III levels above 30%. Oral levothyroxine re-
Anti-EBV-IgG Reactive, 1:1280 placement therapy was started on the 6th day. On the 10th
Anti-EBV-IgM Nonreactive hospital day, the patient was transferred to a medical ward.
Anti-HIV1/2-IgG Nonreactive The patient refused liver biopsy. Bilirubin levels peaked at
ANA, Antinuclear antibodies; AMA, antimitochondrial antibodies; 42.3 mg/dL, and there was no tendency for a decline when
ASMA, antismooth muscle antibodies; LKM, liver, kidney, and mi- the patient decided to leave the hospital against our advice
crosomes; IgM, immunoglobulin M; IgG, immunoglobulin G; HAV, on the 30th hospital day. He traveled to China to be treated
hepatitis A virus; HBV, hepatitis B virus; HBc, hepatitis B virus core
protein; HBs, hepatitis B virus surface protein; HCV, hepatitis C there according to the rules of traditional Chinese medicine.
virus; HEV, hepatitis E virus; CMV, cytomegalovirus; EBV, Epstein- However, he had to be admitted to an intensive care unit of
Barr virus. a major hospital in Beijing soon after his arrival due to ex-
treme hyperbilirubinemia and coagulopathy. The patient
matched blood donors. Before and 10 min after plasma sep- was treated there for 4 months before he was transferred to
aration, blood was collected to quantify the reduction of a traditional Chinese medical facility for rehabilitation.
circulating levels of T4 and thyronine (Table 4). After plas- Meanwhile, he has returned to Germany and has started to
mapheresis, the patient was given 1000 units antithrombin III work again. His mental status, liver function, and most other
and 2000 units prothrombin complex iv before surgery. Two laboratory results have returned to normal 12 months after
hours after plasmapheresis the patient was transferred to the the acute onset of hepatic coma (Table 2).
operating room, where total thyroidectomy was performed
in general anesthesia without complications.
Discussion
After thyroidectomy the patient was treated in the medical
intensive care unit for 10 days. Following surgery he was Disturbances of hepatic function are known complications
sedated and mechanically ventilated for 28 h. Fresh-frozen of antithyroid drug treatment for hyperthyroidism (3). The
1768 ENGHOFER ET AL. JCE & M • 2000
Vol 85 • No 5

TABLE 4. Thyroid laboratory parameters before and after plasmapheresis

Value before Value after

Parameter Unit Normal range
plasmapheresis plasmapheresis
TSH ⬍0.01 0.3 IU/mL 0.3– 4.5
T4, total 24.2 16.1 ␮g/dL 4.5–12.5
T4, free ⬎12 5.1 ng/dL 0.8 –1.8
T3, total 3.4 4.9 ng/mL 0.8 –2.0
T3, free ⬎22 20.5 pg/mL 2.3– 4.2
TRAb 50 21 — ⬍13
Anti-TPO-IgG 927 214 IU/mL ⬍100
Anti-TG-IgG 71 55 IU/mL ⬍100
The blood tests before plasmapheresis were performed with serum of venous blood samples obtained 3 h before plasma exchange. The second
blood samples were drawn 30 min after the end of plasmapheresis, but before surgery.

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TRAb, TSH receptor antibodies; TPO, thyroid peroxidase; TG, thyroglobulin; IgG, immunoglobulin G.

one study, the incidence of toxic hepatitis due to hepatotoxic

FIG. 1. Liver function tests before and after plasmapheresis and thy-
roidectomy performed on day 1 (arrow).
spectrum of observed changes ranges from mild and asymp-
tomatic elevation of cholestatic and cytosolic liver enzymes
(3) to fulminant and fatal necrotizing hepatitis (4 – 6).
Namely, propylthiouracil has been described to be able to
cause severe toxic hepatopathies (5–7), whereas cholestatic
jaundice, without evidence of hepatic necrosis on liver bi-
opsy, has been typically associated with methimazole (8). In
adverse reactions against propylthiouracil was 6% (9). Oth-
ers, however, found a much lower incidence of severe pro-
pylthiouracil-induced hepatitis, whereas asymptomatic ele-
vation 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 hyperthy-
roidism 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, im-
posed 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 re-
ported 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 pa-
tients 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 4). The
small increase of total T3 and TSH immediately after plas-
mapheresis 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. 1). If the infection with hepatitis A had been the only
relevant pathogenetic factor in this case, a much more pro-
longed period of liberation of cytosolic liver enzymes from
necrotic hepatocytes would have been expected. Apparently,
the course of fulminant hepatitis A was significantly atten-
uated by a single plasmapheresis treatment, followed by
thyroidectomy, in the case under discussion. However, pro-
gressive and severe hyperbilirubinemia could not be pre-
vented. Cholestatic hepatitis is a rare, albeit well recognized,
variant of hepatitis A. Protracted cholestatic jaundice may
last several months and is typically observed in extraordi-
narily severe hepatitis A, like in our patient. There was no
evidence for underlying hemolytic anemia because lactate
dehydrogenase levels rapidly normalized and the hematocrit
 FULMINANT HEPATITIS A AND THYROTOXICOSIS
was stable. One year after surgery, bilirubin levels were
measured within the normal range and the patient had fully 4.
recovered.
In conclusion, preexisting hyperthyroidism and its treat- 5.
ment with thionamides might predispose patients for acute 6.
liver failure after infection with the hepatitis A virus. Due to
possible hepatotoxic side effects, treatment with antithyroid 7.
drugs should be avoided in hyperthyroid patients with viral 8.
hepatitis. We recommend immediate institution of plasma-
pheresis, followed by thyroidectomy, in such patients be- 9.
cause it is the most rapid and reliable way to lower circu-
lating levels of thyroid hormones. 10.
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