- Email: [email protected]
Acute hepatitis, autoimmune hemolytic anemia, and erythroblastocytopenia induced by ceftriaxone
836
BRIEF CASE REPORTS
allowed a tissue diagnosis to be established without subjecting the patient to laparotomy. The utility of EUSFNA in the diagnosis of pancreatic carcinoma is being established. Early reports (2, 3, 4, 7) support the contention that the procedure offers sensitivity of .80% and affords accurate TNM staging with low periprocedural morbidity and mortality. It is notable that a substantial number of patients included in these series had previously undergone PFNAB with CT guidance without obtaining diagnostic tissue. There are numerous reports discussing the role of percutaneous fine-needle aspiration biopsy in the diagnosis of lymphoma (8, 9). Debate remains, however, as to whether this technique is useful in establishing the primary diagnosis of lymphoma. In certain cases, the histologic pattern of the lymphoma is important in planning therapeutic regimens, thereby necessitating a surgical biopsy. Pilotti et al. (8) demonstrated that the accuracy of PFNAB was largely dependent on the histological type of lymphoma. Low grade NHL had a sensitivity of only 64%, whereas high grade NHL had a sensitivity of 100% and a typing accuracy of 93.7%. The sensitivity of PFNAB for HD was 92.3% with both of the false negatives occurring in cases of the lymphocyte predominant subtype. Silverman et al. (9) reported that 32 of 57 patients (56%) without a prior history of lymphoma received definitive therapy based on the results of image-guided PFNAB. The majority of the experience use EUS and EUSFNA in patients with lymphoma has been in the setting of primary gastric lymphoma (10, 11). Adequate data on the accuracy of EUSFNA for the diagnosis of lymphoma have not been reported. However, we expect that the accuracy of EUSFNA should at least be comparable with that of image-guided PFNAB, and possibly superior because of the ability to identify smaller abdominal mass lesions. This case demonstrates the use of EUSFNA in the diagnosis of abdominal lymphoma extrinsic to the luminal gastrointestinal tract and pancreas, and is the first case report of EUSFNA used to diagnose HD. This case highlights the utility of EUS with EUSFNA in diagnosing and managing patients with extrahepatic biliary obstruction. EUS, with possible EUSFNA, should be considered to accurately stage and obtain diagnostic tissue in the setting of extrahepatic biliary obstruction not caused by gallstones, and in patients with extraluminal lesions in close proximity to the digestive tract.
AJG – Vol. 93, No. 5, 1998 7. Chang KJ, Albers CG, Erickson RA, et al. Endoscopic ultrasoundguided fine needle aspiration of pancreatic carcinoma. Am J Gastroenterol 1994;89:263– 6. 8. Pilotti S, Di Palma S, Alasio L, et al. Diagnostic assessment of enlarged superficial lymph nodes by fine needle aspiration. Acta Cytologica 1993;37:853– 66. 9. Silverman SG, Lee BY, Mueller PR, et al. Impact of positive findings at image-guided biopsy of lymphoma on patient care: Evaluation of clinical history, needle size, and pathologic findings on biopsy performance. Radiology 1994;190:759 – 64. 10. Caletti G, Ferrari A, Bochi E, et al. Accuracy of endoscopic ultrasonography in the diagnosis and staging of gastric cancer and lymphoma. Surgery 1993;113:14 –27. 11. Palazzo L, Roseau G, Ruskone-Fourmestroux A, et al. Endoscopic ultrasonography in the local staging of primary gastric lymphoma. Endoscopy 1993;25:502– 8.
ACUTE HEPATITIS, AUTOIMMUNE HEMOLYTIC ANEMIA, AND ERYTHROBLASTOCYTOPENIA INDUCED BY CEFTRIAXONE Fabrice Longo, PH, Patrick Hastier, PH, Martin J.M. Buckley, M.R.C.P.I., Rose Marie Chichmanian, PH, and Jean-Pierre Delmont, PH Department of Hepato-Gastroenterology, Archet Hospital, Nice; and Regional Pharmacovigilance Center, Pasteur Hospital, Nice, France
An 80-yr-old man developed acute hepatitis shortly after ingesting oral ceftriaxone. Although the transaminases gradually returned to baseline after withholding the b lactam antibiotic, there was a gradual increase in serum bilirubin and a decrease in hemoglobin concentration caused by an autoimmune hemolytic anemia and erythroblastocytopenia. These responded to systemic steroids and immunoglobulins. Despite the widespread use of these agents this triad of side effects has not previously been reported in connection with b lactam antibiotics. (Am J Gastroenterol 1998;93:836 – 837. © 1998 by Am. Coll. of Gastroenterology) INTRODUCTION
Reprint requests and correspondence: Gregory G. Ginsberg, M.D., Assistant Professor of Medicine, University of Pennsylvania School of Medicine, Division of Gastroenterology, 3 Dulles, 3400 Spruce Street, Philadelphia, PA 19104-4283. REFERENCES 1. Dancygier H, Nattermann C. The role of endoscopic ultrasonography in biliary tract disease: Obstructive jaundice. Endoscopy 1994;26: 800 –2. 2. Wiersema MJ, Kochman ML, Cramer HM, et al. Endosonographyguided real-time fine-needle aspiration biopsy. Gastrointes Endosc 1994;40:700 –7. 3. Vilmann P, Hancke S, Henriksen F, et al. Endoscopic ultrasonographyguided fine-needle aspiration biopsy of lesions of the upper gastrointestinal tract. Gastrointest Endosc 1995;41:230 –5. 4. Faigel DO, Ginsberg GG, Bentz JS, et al. Endoscopic ultrasoundguided real-time fine-needle aspiration biopsy of the pancreas in cancer patients with pancreatic lesions. J Clin Oncol 1997;15:1439 – 43. 5. Birrer MJ, Young RC. Differential diagnosis of jaundice in lymphoma patients. Semin Liver Dis 1987;7:269 –77. 6. Mitty HA, Efremidis SC, Yeh H. Impact of fine-needle biopsy on management of patients with carcinoma of the pancreas. AJR 1981; 137:1119 –21.
Ceftriaxone, a third generation cephalosporin, is widely used because of its broad spectrum of action and ease of administration. We report, to our knowledge, the first case of acute hepatitis associated with autoimmune hemolytic anemia and erythroblastocytopenia occurring as a result of ceftriaxone. This side effect complex has not been reported previously with any of the b lactam antibiotics. CASE REPORT
An 80-yr-old man was hospitalized in November 1995 with a history of painless, afebrile, cholestatic jaundice. In October 1995 the patient had been treated with digoxin (0.25 mg/day) for atrial fibrillation. At the end of October, the patient presented with bronchopneumonia and was treated with oral ceftriaxone, 2 g/day. (10/31/95 to 11/12/95). Jaundice was first noticed on 11/15/95 and, 2 days later, liver function testing revealed elevated aspartate Received Dec. 5, 1997; accepted Jan. 28, 1998.
AJG – May 1998
BRIEF CASE REPORTS
837
transfusion. The patient was discharged on 1/5/96. The liver function tests were normal, apart from an elevated total bilirubin (N 3 10). On review on 4/22/96, total and conjugated bilirubin were normal. DISCUSSION
FIG. 1. Temporal relationship between ingestion of cefriaxone (10/31/95 to 11/12/95) and subsequent hepatic and hematological dysfunction. N 5 relative increase above normal values. -{- 5 ALAT; -h- 5 GGT; -‚- 5 Alkaline phosphatase; -X- 5 Total bilirubin.
aminotransferase (ASAT) (N 3 9), alanine aminotransferase (ALAT) (N 3 11), total bilirubin (N 3 22), conjugated bilirubin (N 3 15), g-glutamyl transpeptidase (N 3 15), alkaline phosphatase (N 3 6) (Fig. 1). On 11/25/95 abdominal ultrasound demonstrated a homogenous liver and no abnormality of the biliary ducts or gall bladder. The patient was admitted to our institution on 11/28/95 complaining of pruritus, pale stools, and darkened urine. On examination, the patient was afebrile and there was no evidence of hepatosplenomegaly or hepatic failure. Biochemistry revealed ASAT elevated (N 3 1.5), ALAT (N 3 2), total bilirubin (N 3 25), conjugated bilirubin (N 3 24), gGT (N 3 4), and alkaline phosphatase (N 3 3). Serological tests for hepatitis A, B, and C virus were negative. Immunological tests for antinuclear, antimitochondrial, antismooth muscle, and antimicrosomal antibodies were also negative. A diagnosis of drug-induced acute hepatitis due to ceftriaxone was made, and the patient was discharged on 12/5/95. At discharge, liver biochemistry was as follows: ASAT, N, ALAT, N, total bilirubin, N 3 50, gGT, N 3 2, and alkaline phosphatase, N 3 5. Ten days later the patient was readmitted with lethargy and increasing jaundice. Hematological tests demonstrated a hemoglobin of 5.8 mg/dl, hematocrit 17%, mean cell volume 87 fl, leucocytes 11,900/mm3, reticulocytes 5,600/mm3, and lactate dehydrogenase N 3 6. The direct Coombs IgG test was positive. Bone marrow biopsy showed a erythroblastocytopenia, normal maturation of the white cell and platelet precursors and no evidence of malignancy. Parvovirus B19 and Mycoplasma pneumoniae serology were negative. The final hematological diagnosis was an autoimmune hemolytic anemia of peripheral (hemolysis) and central (erythroblastocytopenia) origin, secondary to a drug-induced (ceftriaxone) acute hepatitis. The patient was treated initially with systemic steroids and immunoglobulins and subsequently with oral steroids and red cell
This is the first report of this complex of side effects occurring as a result of ingestion of a b lactam antibiotic. Ceftriaxone is a broad spectrum cephalosporin with a long half-life. It is excreted principally via the kidneys, but 20 – 40% of the administered dose is secreted in nonmetabolized form in bile. Disturbances of liver function have frequently been described in association with cephalosporins. Criteria have been proposed that are suggestive of drug-induced cholestatic acute hepatitis (1, 2). These criteria support the association between ceftriaxone and acute hepatitis in this case; the appearance of liver dysfunction 5–90 days after the start of treatment, a decrease of ALAT of .50% within 8 days of stopping the offending agent, and a decrease in the concentration of alkaline phosphatase and total bilirubin of .50% within 6 mo, in the presence of normal ultrasonographic and serological findings. The chronological relationship between ceftriaxone ingestion and autoimmune hemolytic anemia in this case also suggests that the latter was drug-induced (3); the appearance of hemolysis .1 month after the start of treatment, improvement within 2 months of cessation of the medication, a positive direct Coomb’s test, negative serology (Parvovirus B19 and Mycoplasma pneumoniae), and the absence of other hematological or lymphoproliferative disorders. Autoimmune hemolytic anemia, however, has been described only with ceftriaxone (one case) (4) and with cefalotine and ceftazidime (5). Erythroblastocytopenia due to red cell precursor autoimmunity is also a very rare cause of drug-induced autoimmune anaemia, and has not previously been described in association with ceftriaxone. In conclusion, we report the first case of acute cholestatic hepatitis, autoimmune hemolytic anemia, and erythroblastocytopenia occurring in association with ceftriaxone.
Reprint requests and correspondence: Patrick Hastier, M.D., Dept. of Hepato-Gastroenterology, Hoˆpital de l’Archet II, 151 Route de Saint Antoine de Ginestrire, 06202 Nice, France.
REFERENCES 1. Begaud B, Evreux JC, Jouglard J, et al. Unexpected or toxic drug reaction assessment. Actualisation of the methods used in France. Therapie 1985;40:111– 8. 2. Danan G. De´finition et crite`res d’imputation des atteintes he´patiques aigues me´dicamenteuses. Conclusion d’une re´union internationale de concensus. Gastroenterol Clin Biol 1991;15:845– 8. 3. Habibi B, Solal Celigny P, Benichou C, et al. Drug-induced haemolytic anaemia. Results of a consensus meeting. Therapy 1988;43: 121– 4. 4. Garraty G, Postoway N, Schwellenbach J, et al. A fatal case of ceftriaxone (Rocephin)-induced haemolytic anaemia associated with intravascular immune haemolytic. Transfusion 1991;31:176 –9. 5. Garraty G. Severe immune haemolytic anaemia associated with newer cephalosporins. Lancet 1991;337:119 –120.
BRIEF CASE REPORTS
allowed a tissue diagnosis to be established without subjecting the patient to laparotomy. The utility of EUSFNA in the diagnosis of pancreatic carcinoma is being established. Early reports (2, 3, 4, 7) support the contention that the procedure offers sensitivity of .80% and affords accurate TNM staging with low periprocedural morbidity and mortality. It is notable that a substantial number of patients included in these series had previously undergone PFNAB with CT guidance without obtaining diagnostic tissue. There are numerous reports discussing the role of percutaneous fine-needle aspiration biopsy in the diagnosis of lymphoma (8, 9). Debate remains, however, as to whether this technique is useful in establishing the primary diagnosis of lymphoma. In certain cases, the histologic pattern of the lymphoma is important in planning therapeutic regimens, thereby necessitating a surgical biopsy. Pilotti et al. (8) demonstrated that the accuracy of PFNAB was largely dependent on the histological type of lymphoma. Low grade NHL had a sensitivity of only 64%, whereas high grade NHL had a sensitivity of 100% and a typing accuracy of 93.7%. The sensitivity of PFNAB for HD was 92.3% with both of the false negatives occurring in cases of the lymphocyte predominant subtype. Silverman et al. (9) reported that 32 of 57 patients (56%) without a prior history of lymphoma received definitive therapy based on the results of image-guided PFNAB. The majority of the experience use EUS and EUSFNA in patients with lymphoma has been in the setting of primary gastric lymphoma (10, 11). Adequate data on the accuracy of EUSFNA for the diagnosis of lymphoma have not been reported. However, we expect that the accuracy of EUSFNA should at least be comparable with that of image-guided PFNAB, and possibly superior because of the ability to identify smaller abdominal mass lesions. This case demonstrates the use of EUSFNA in the diagnosis of abdominal lymphoma extrinsic to the luminal gastrointestinal tract and pancreas, and is the first case report of EUSFNA used to diagnose HD. This case highlights the utility of EUS with EUSFNA in diagnosing and managing patients with extrahepatic biliary obstruction. EUS, with possible EUSFNA, should be considered to accurately stage and obtain diagnostic tissue in the setting of extrahepatic biliary obstruction not caused by gallstones, and in patients with extraluminal lesions in close proximity to the digestive tract.
AJG – Vol. 93, No. 5, 1998 7. Chang KJ, Albers CG, Erickson RA, et al. Endoscopic ultrasoundguided fine needle aspiration of pancreatic carcinoma. Am J Gastroenterol 1994;89:263– 6. 8. Pilotti S, Di Palma S, Alasio L, et al. Diagnostic assessment of enlarged superficial lymph nodes by fine needle aspiration. Acta Cytologica 1993;37:853– 66. 9. Silverman SG, Lee BY, Mueller PR, et al. Impact of positive findings at image-guided biopsy of lymphoma on patient care: Evaluation of clinical history, needle size, and pathologic findings on biopsy performance. Radiology 1994;190:759 – 64. 10. Caletti G, Ferrari A, Bochi E, et al. Accuracy of endoscopic ultrasonography in the diagnosis and staging of gastric cancer and lymphoma. Surgery 1993;113:14 –27. 11. Palazzo L, Roseau G, Ruskone-Fourmestroux A, et al. Endoscopic ultrasonography in the local staging of primary gastric lymphoma. Endoscopy 1993;25:502– 8.
ACUTE HEPATITIS, AUTOIMMUNE HEMOLYTIC ANEMIA, AND ERYTHROBLASTOCYTOPENIA INDUCED BY CEFTRIAXONE Fabrice Longo, PH, Patrick Hastier, PH, Martin J.M. Buckley, M.R.C.P.I., Rose Marie Chichmanian, PH, and Jean-Pierre Delmont, PH Department of Hepato-Gastroenterology, Archet Hospital, Nice; and Regional Pharmacovigilance Center, Pasteur Hospital, Nice, France
An 80-yr-old man developed acute hepatitis shortly after ingesting oral ceftriaxone. Although the transaminases gradually returned to baseline after withholding the b lactam antibiotic, there was a gradual increase in serum bilirubin and a decrease in hemoglobin concentration caused by an autoimmune hemolytic anemia and erythroblastocytopenia. These responded to systemic steroids and immunoglobulins. Despite the widespread use of these agents this triad of side effects has not previously been reported in connection with b lactam antibiotics. (Am J Gastroenterol 1998;93:836 – 837. © 1998 by Am. Coll. of Gastroenterology) INTRODUCTION
Reprint requests and correspondence: Gregory G. Ginsberg, M.D., Assistant Professor of Medicine, University of Pennsylvania School of Medicine, Division of Gastroenterology, 3 Dulles, 3400 Spruce Street, Philadelphia, PA 19104-4283. REFERENCES 1. Dancygier H, Nattermann C. The role of endoscopic ultrasonography in biliary tract disease: Obstructive jaundice. Endoscopy 1994;26: 800 –2. 2. Wiersema MJ, Kochman ML, Cramer HM, et al. Endosonographyguided real-time fine-needle aspiration biopsy. Gastrointes Endosc 1994;40:700 –7. 3. Vilmann P, Hancke S, Henriksen F, et al. Endoscopic ultrasonographyguided fine-needle aspiration biopsy of lesions of the upper gastrointestinal tract. Gastrointest Endosc 1995;41:230 –5. 4. Faigel DO, Ginsberg GG, Bentz JS, et al. Endoscopic ultrasoundguided real-time fine-needle aspiration biopsy of the pancreas in cancer patients with pancreatic lesions. J Clin Oncol 1997;15:1439 – 43. 5. Birrer MJ, Young RC. Differential diagnosis of jaundice in lymphoma patients. Semin Liver Dis 1987;7:269 –77. 6. Mitty HA, Efremidis SC, Yeh H. Impact of fine-needle biopsy on management of patients with carcinoma of the pancreas. AJR 1981; 137:1119 –21.
Ceftriaxone, a third generation cephalosporin, is widely used because of its broad spectrum of action and ease of administration. We report, to our knowledge, the first case of acute hepatitis associated with autoimmune hemolytic anemia and erythroblastocytopenia occurring as a result of ceftriaxone. This side effect complex has not been reported previously with any of the b lactam antibiotics. CASE REPORT
An 80-yr-old man was hospitalized in November 1995 with a history of painless, afebrile, cholestatic jaundice. In October 1995 the patient had been treated with digoxin (0.25 mg/day) for atrial fibrillation. At the end of October, the patient presented with bronchopneumonia and was treated with oral ceftriaxone, 2 g/day. (10/31/95 to 11/12/95). Jaundice was first noticed on 11/15/95 and, 2 days later, liver function testing revealed elevated aspartate Received Dec. 5, 1997; accepted Jan. 28, 1998.
AJG – May 1998
BRIEF CASE REPORTS
837
transfusion. The patient was discharged on 1/5/96. The liver function tests were normal, apart from an elevated total bilirubin (N 3 10). On review on 4/22/96, total and conjugated bilirubin were normal. DISCUSSION
FIG. 1. Temporal relationship between ingestion of cefriaxone (10/31/95 to 11/12/95) and subsequent hepatic and hematological dysfunction. N 5 relative increase above normal values. -{- 5 ALAT; -h- 5 GGT; -‚- 5 Alkaline phosphatase; -X- 5 Total bilirubin.
aminotransferase (ASAT) (N 3 9), alanine aminotransferase (ALAT) (N 3 11), total bilirubin (N 3 22), conjugated bilirubin (N 3 15), g-glutamyl transpeptidase (N 3 15), alkaline phosphatase (N 3 6) (Fig. 1). On 11/25/95 abdominal ultrasound demonstrated a homogenous liver and no abnormality of the biliary ducts or gall bladder. The patient was admitted to our institution on 11/28/95 complaining of pruritus, pale stools, and darkened urine. On examination, the patient was afebrile and there was no evidence of hepatosplenomegaly or hepatic failure. Biochemistry revealed ASAT elevated (N 3 1.5), ALAT (N 3 2), total bilirubin (N 3 25), conjugated bilirubin (N 3 24), gGT (N 3 4), and alkaline phosphatase (N 3 3). Serological tests for hepatitis A, B, and C virus were negative. Immunological tests for antinuclear, antimitochondrial, antismooth muscle, and antimicrosomal antibodies were also negative. A diagnosis of drug-induced acute hepatitis due to ceftriaxone was made, and the patient was discharged on 12/5/95. At discharge, liver biochemistry was as follows: ASAT, N, ALAT, N, total bilirubin, N 3 50, gGT, N 3 2, and alkaline phosphatase, N 3 5. Ten days later the patient was readmitted with lethargy and increasing jaundice. Hematological tests demonstrated a hemoglobin of 5.8 mg/dl, hematocrit 17%, mean cell volume 87 fl, leucocytes 11,900/mm3, reticulocytes 5,600/mm3, and lactate dehydrogenase N 3 6. The direct Coombs IgG test was positive. Bone marrow biopsy showed a erythroblastocytopenia, normal maturation of the white cell and platelet precursors and no evidence of malignancy. Parvovirus B19 and Mycoplasma pneumoniae serology were negative. The final hematological diagnosis was an autoimmune hemolytic anemia of peripheral (hemolysis) and central (erythroblastocytopenia) origin, secondary to a drug-induced (ceftriaxone) acute hepatitis. The patient was treated initially with systemic steroids and immunoglobulins and subsequently with oral steroids and red cell
This is the first report of this complex of side effects occurring as a result of ingestion of a b lactam antibiotic. Ceftriaxone is a broad spectrum cephalosporin with a long half-life. It is excreted principally via the kidneys, but 20 – 40% of the administered dose is secreted in nonmetabolized form in bile. Disturbances of liver function have frequently been described in association with cephalosporins. Criteria have been proposed that are suggestive of drug-induced cholestatic acute hepatitis (1, 2). These criteria support the association between ceftriaxone and acute hepatitis in this case; the appearance of liver dysfunction 5–90 days after the start of treatment, a decrease of ALAT of .50% within 8 days of stopping the offending agent, and a decrease in the concentration of alkaline phosphatase and total bilirubin of .50% within 6 mo, in the presence of normal ultrasonographic and serological findings. The chronological relationship between ceftriaxone ingestion and autoimmune hemolytic anemia in this case also suggests that the latter was drug-induced (3); the appearance of hemolysis .1 month after the start of treatment, improvement within 2 months of cessation of the medication, a positive direct Coomb’s test, negative serology (Parvovirus B19 and Mycoplasma pneumoniae), and the absence of other hematological or lymphoproliferative disorders. Autoimmune hemolytic anemia, however, has been described only with ceftriaxone (one case) (4) and with cefalotine and ceftazidime (5). Erythroblastocytopenia due to red cell precursor autoimmunity is also a very rare cause of drug-induced autoimmune anaemia, and has not previously been described in association with ceftriaxone. In conclusion, we report the first case of acute cholestatic hepatitis, autoimmune hemolytic anemia, and erythroblastocytopenia occurring in association with ceftriaxone.
Reprint requests and correspondence: Patrick Hastier, M.D., Dept. of Hepato-Gastroenterology, Hoˆpital de l’Archet II, 151 Route de Saint Antoine de Ginestrire, 06202 Nice, France.
REFERENCES 1. Begaud B, Evreux JC, Jouglard J, et al. Unexpected or toxic drug reaction assessment. Actualisation of the methods used in France. Therapie 1985;40:111– 8. 2. Danan G. De´finition et crite`res d’imputation des atteintes he´patiques aigues me´dicamenteuses. Conclusion d’une re´union internationale de concensus. Gastroenterol Clin Biol 1991;15:845– 8. 3. Habibi B, Solal Celigny P, Benichou C, et al. Drug-induced haemolytic anaemia. Results of a consensus meeting. Therapy 1988;43: 121– 4. 4. Garraty G, Postoway N, Schwellenbach J, et al. A fatal case of ceftriaxone (Rocephin)-induced haemolytic anaemia associated with intravascular immune haemolytic. Transfusion 1991;31:176 –9. 5. Garraty G. Severe immune haemolytic anaemia associated with newer cephalosporins. Lancet 1991;337:119 –120.