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N Watanabe et al.
evocative of CAA. The lesions were hemosiderin deposits on the one hand and probable FSAH on the other.4 Indeed, cortical superficial hemosiderosis is a common and characteristic feature of CAA, and hemorrhage into the subarachnoid space could also contribute to hemosiderosis in CAA.4 Finally, the patient’s age (6th decade) was compatible with reports for CAA.5 However, FSAH is not in the Boston criteria.6 Usually, the subarachnoid hemorrhage is a result of lobar hematoma.7 Some authors suggest that FSAH be included in the diagnostic criteria for sporadic CAA in the elderly.8 The increase in tau protein and phosphorylated tau protein levels in the cerebrospinal fluid coupled with a decrease in amyloid-β-peptide-1–42 rate were in favor of AD (in addition to hippocampal atrophy) and sporadic CAA.9 The clinician should consider the possibility of CAA in the elderly, which is a contraindication to anticoagulant therapy.10
Acknowledgment The authors are grateful to Mr Philip Bastable.
Disclosure The authors declare no conflict of interest. Odile Guaquière-Bernard,1 Olivier Rouaud2 and Patrick Manckoundia3,4 1 Nursing Home «Valmy, Résidalya», Departments of 2Neurology, 3 Geriatrics and Internal Medicine, Hospital of Champmaillot, University Hospital, and 4Inserm/U1093 Motricity-Plasticity, University of Burgundy, Dijon, France
References 1 Feldman HH, Maia LF, Mackenzie IR, Forster BB, Martzke J, Woolfenden A. Superficial siderosis: a potential diagnostic marker of cerebral amyloid angiopathy in Alzheimer disease. Stroke 2008; 39: 2894–2897. 2 Manckoundia P, Disson-Dautriche A, Rouaud O, Richard D, Tavernier-Vidal B, Pfitzenmeyer P. Syndrome démentiel du sujet âgé lié à un traitement par acide valproïque : à propos d’un cas. Rev Med Interne 2008; 29: 827–829. 3 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939–944. 4 Charidimou A, Jäger RH, Fox Z et al. Prevalence and mechanisms of cortical superficial siderosis in cerebral amyloid angiopathy. Neurology 2013; 81: 626–632. 5 Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry 2012; 83: 124–137. 6 Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy. Validation of the Boston criteria. Neurology 2001; 56: 537–539. 7 Linn J, Wollenweber FA, Lummel N et al. Superficial siderosis is warning sign for future intracranial hemorrhage. J Neurol 2013; 260: 176–181. 8 Linn J, Halpin A, Demaerel P et al. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 2010; 74: 1346–1350. 9 Alonzo NC, Hyman BT, Rebeck GW, Greenberg SM. Progression of cerebral amyloid angiopathy: accumulation of amyloid-béta40 in affected vessels. J Neuropathol Exp Neurol 1998; 57: 353–359. 10 McCarron MO, Hoffmann KL, DeLong DM, Gray L, Saunders AM, Alberts MJ. Intracerebral hemorrhage outcome: apolipoprotein E genotype, hematoma, and edema volumes. Neurology 1999; 53: 2176–2179.
Reactivation of hepatitis B virus during treatment with hydroxyurea in an elderly patient with essential thrombocythemia Dear Editor, A 72-year-old woman with JAK2V617F mutationpositive essential thrombocythemia (ET) came to Juntendo University Hospital, Tokyo, Japan, in March 2003. She had been treated with 500 mg/day of hydroxyurea (HU) and low-dose aspirin since 1996 at another hospital. On first medical examination, hepatitis B surface (HBs) antigen (Ag) and antihepatitis B envelope (HBe) antibody (Ab) were positive, HBeAg was negative and hepatitis B virus (HBV)-DNA levels were undetect812 |
doi: 10.1111/ggi.12461
able, and she was observed as an inactive HBV carrier. The dose of HU was gradually increased at our hospital, maximized at 1500 mg/day. In April 2012, a slight increase of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of 64 IU/L and 48 IU/L was seen, respectively, and persisted at around the same levels thereafter. In February 2013, a further rise of AST and ALT of 276 IU/L and 139 IU/L was observed, respectively, and HU and aspirin administration were discontinued under the suspicion of drug-induced liver dysfunction. However, liver dysfunction exacerbated, © 2015 Japan Geriatrics Society
Letters to the Editor
and reanalysis showed that the HBeAg had turned positive, and the HBV-DNA viral load was above 1.0 × 109 copies/mL. Thus, she was hospitalized for acute hepatitis due to HBV reactivation. Entecavir was administered at a dose of 0.5 mg/day, and AST and ALT started to decrease after peaking out at 777 IU/L and 329 IU/L, respectively. Although the possibility that HU contributed to HBV reactivation could not be denied, platelets rose to 1407 × 109/L on day 40 of hospitalization, and HU was resumed at 1000 mg/day under concomitant entecavir administration. AST, ALT and platelet counts decreased to 70 IU/L, 37 IU/L, and 752 × 109/L, respectively, and she was discharged on day 56 of hospitalization. Anticancer therapy has been reported to induce HBV reactivation in 19–48% of HBsAg-positive patients and in 4–30% of HBsAg-negative and HBsAb and/or HBcAb-positive patients. HBV reactivation is a serious event, as it can lead to fulminant and fatal hepatitis in a significant proportion of patients. Chemotherapeutic agents known to induce HBV reactivation include antitumor antibiotics, plant alkaloids, alkylating agents, antimetabolites, corticosteroids and monoclonal antibodies. HU is an oral antimetabolite widely used for hematological disorders, such as ET, polycythemia vera, chronic myelogenous leukemia and sickle cell anemia. HU has a relatively low cytotoxic profile, and it is currently not designated as a drug contributing to HBV reactivation.1 However, we report for the first time HBV reactivation and hepatitis possibly induced by HU. HU has been reported to induce a cryptosporidium opportunistic infection in a sickle cell anemia patient, and the authors speculated that the direct cause was a low absolute CD4 count of 0.234 × 109/L (reference range 0.83 ± 0.29 × 109/L).2,3 The CD4+ T-cell count under HU treatment in the present case was also found to be suppressed at 0.352 × 109/L (measured at 1 year after HU resumption). These observations are in concordance with a report that HU administration suppresses CD4+ T-cell counts in HIV patients.4 In addition, Idoko et al. reported that in HIV and HBV coinfected patients, lower CD4+ T-cell counts were independently associated with higher HBV-DNA levels and HBeAg positivity.5 Thus, it was rationalized that HU administration probably contributed to HBV reactivation in the present case. HU treatment often concerns the elderly, because the median age of onset of ET is around 50–60 years,
© 2015 Japan Geriatrics Society
and once initiated, long-term administration is often the case with HU.6 The limitations of this report are that although a relatively rare event, we cannot rule out the possibility of spontaneous HBV reactivation. Hsu et al. reported that during a median follow-up period of 8.6 years after HBeAg seroconversion in 283 patients, HBeAg reversion was seen in 12 patients (4.2%), with eight patients (2.8%) eventually developing acute exacerbations.7 Although currently not acknowledged as one of the drugs associated with HBV reactivation, HU could induce reactivation of HBV through suppression of CD4+ T cells, and we strongly recommend close monitoring of HBV-DNA levels in patients with a positive HBsAg, HBsAb or HBcAb status.
Disclosure statement No potential conflicts of interest were disclosed. Naoki Watanabe,1 Hajime Yasuda,1 Yasuo Aota,1 Jun Ando,1 Tomonori Aoyama,2 Masaru Tanaka,1 Akihiko Gotoh1 and Norio Komatsu1 Divisions of 1Hematology and 2Gastroenterology, Department of Medicine, Juntendo University School of Medicine, Tokyo, Japan
References 1 Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology 2006; 43: 209–220. 2 Venigalla P, Motwani B, Allen S, Agarwal M, Westerman M, Feldman L. A patient on hydroxyurea for sickle cell disease who developed an opportunistic infection. Blood 2002; 100: 363–364. 3 Bofill M, Janossy G, Lee CA et al. Laboratory control values for CD4 and CD8 T lymphocytes. Implications for HIV-1 diagnosis. Clin Exp Immunol 1992; 88: 243–252. 4 Bloch MT, Smith DE, Quan D et al. The role of hydroxyurea in enhancing the virologic control achieved through structured treatment interruption in primary HIV infection: final results from a randomized clinical trial (Pulse). J Acquir Immune Defic Syndr 2006; 42: 192–202. 5 Idoko J, Meloni S, Muazu M et al. Impact of hepatitis B virus infection on human immunodeficiency virus response to antiretroviral therapy in Nigeria. Clin Infect Dis 2009; 49: 1268–1273. 6 Steven SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC, 2008. 7 Hsu YS, Chien RN, Yeh CT et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 2002; 35: 1522–1527.
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N Watanabe et al.
evocative of CAA. The lesions were hemosiderin deposits on the one hand and probable FSAH on the other.4 Indeed, cortical superficial hemosiderosis is a common and characteristic feature of CAA, and hemorrhage into the subarachnoid space could also contribute to hemosiderosis in CAA.4 Finally, the patient’s age (6th decade) was compatible with reports for CAA.5 However, FSAH is not in the Boston criteria.6 Usually, the subarachnoid hemorrhage is a result of lobar hematoma.7 Some authors suggest that FSAH be included in the diagnostic criteria for sporadic CAA in the elderly.8 The increase in tau protein and phosphorylated tau protein levels in the cerebrospinal fluid coupled with a decrease in amyloid-β-peptide-1–42 rate were in favor of AD (in addition to hippocampal atrophy) and sporadic CAA.9 The clinician should consider the possibility of CAA in the elderly, which is a contraindication to anticoagulant therapy.10
Acknowledgment The authors are grateful to Mr Philip Bastable.
Disclosure The authors declare no conflict of interest. Odile Guaquière-Bernard,1 Olivier Rouaud2 and Patrick Manckoundia3,4 1 Nursing Home «Valmy, Résidalya», Departments of 2Neurology, 3 Geriatrics and Internal Medicine, Hospital of Champmaillot, University Hospital, and 4Inserm/U1093 Motricity-Plasticity, University of Burgundy, Dijon, France
References 1 Feldman HH, Maia LF, Mackenzie IR, Forster BB, Martzke J, Woolfenden A. Superficial siderosis: a potential diagnostic marker of cerebral amyloid angiopathy in Alzheimer disease. Stroke 2008; 39: 2894–2897. 2 Manckoundia P, Disson-Dautriche A, Rouaud O, Richard D, Tavernier-Vidal B, Pfitzenmeyer P. Syndrome démentiel du sujet âgé lié à un traitement par acide valproïque : à propos d’un cas. Rev Med Interne 2008; 29: 827–829. 3 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939–944. 4 Charidimou A, Jäger RH, Fox Z et al. Prevalence and mechanisms of cortical superficial siderosis in cerebral amyloid angiopathy. Neurology 2013; 81: 626–632. 5 Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry 2012; 83: 124–137. 6 Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy. Validation of the Boston criteria. Neurology 2001; 56: 537–539. 7 Linn J, Wollenweber FA, Lummel N et al. Superficial siderosis is warning sign for future intracranial hemorrhage. J Neurol 2013; 260: 176–181. 8 Linn J, Halpin A, Demaerel P et al. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 2010; 74: 1346–1350. 9 Alonzo NC, Hyman BT, Rebeck GW, Greenberg SM. Progression of cerebral amyloid angiopathy: accumulation of amyloid-béta40 in affected vessels. J Neuropathol Exp Neurol 1998; 57: 353–359. 10 McCarron MO, Hoffmann KL, DeLong DM, Gray L, Saunders AM, Alberts MJ. Intracerebral hemorrhage outcome: apolipoprotein E genotype, hematoma, and edema volumes. Neurology 1999; 53: 2176–2179.
Reactivation of hepatitis B virus during treatment with hydroxyurea in an elderly patient with essential thrombocythemia Dear Editor, A 72-year-old woman with JAK2V617F mutationpositive essential thrombocythemia (ET) came to Juntendo University Hospital, Tokyo, Japan, in March 2003. She had been treated with 500 mg/day of hydroxyurea (HU) and low-dose aspirin since 1996 at another hospital. On first medical examination, hepatitis B surface (HBs) antigen (Ag) and antihepatitis B envelope (HBe) antibody (Ab) were positive, HBeAg was negative and hepatitis B virus (HBV)-DNA levels were undetect812 |
doi: 10.1111/ggi.12461
able, and she was observed as an inactive HBV carrier. The dose of HU was gradually increased at our hospital, maximized at 1500 mg/day. In April 2012, a slight increase of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of 64 IU/L and 48 IU/L was seen, respectively, and persisted at around the same levels thereafter. In February 2013, a further rise of AST and ALT of 276 IU/L and 139 IU/L was observed, respectively, and HU and aspirin administration were discontinued under the suspicion of drug-induced liver dysfunction. However, liver dysfunction exacerbated, © 2015 Japan Geriatrics Society
Letters to the Editor
and reanalysis showed that the HBeAg had turned positive, and the HBV-DNA viral load was above 1.0 × 109 copies/mL. Thus, she was hospitalized for acute hepatitis due to HBV reactivation. Entecavir was administered at a dose of 0.5 mg/day, and AST and ALT started to decrease after peaking out at 777 IU/L and 329 IU/L, respectively. Although the possibility that HU contributed to HBV reactivation could not be denied, platelets rose to 1407 × 109/L on day 40 of hospitalization, and HU was resumed at 1000 mg/day under concomitant entecavir administration. AST, ALT and platelet counts decreased to 70 IU/L, 37 IU/L, and 752 × 109/L, respectively, and she was discharged on day 56 of hospitalization. Anticancer therapy has been reported to induce HBV reactivation in 19–48% of HBsAg-positive patients and in 4–30% of HBsAg-negative and HBsAb and/or HBcAb-positive patients. HBV reactivation is a serious event, as it can lead to fulminant and fatal hepatitis in a significant proportion of patients. Chemotherapeutic agents known to induce HBV reactivation include antitumor antibiotics, plant alkaloids, alkylating agents, antimetabolites, corticosteroids and monoclonal antibodies. HU is an oral antimetabolite widely used for hematological disorders, such as ET, polycythemia vera, chronic myelogenous leukemia and sickle cell anemia. HU has a relatively low cytotoxic profile, and it is currently not designated as a drug contributing to HBV reactivation.1 However, we report for the first time HBV reactivation and hepatitis possibly induced by HU. HU has been reported to induce a cryptosporidium opportunistic infection in a sickle cell anemia patient, and the authors speculated that the direct cause was a low absolute CD4 count of 0.234 × 109/L (reference range 0.83 ± 0.29 × 109/L).2,3 The CD4+ T-cell count under HU treatment in the present case was also found to be suppressed at 0.352 × 109/L (measured at 1 year after HU resumption). These observations are in concordance with a report that HU administration suppresses CD4+ T-cell counts in HIV patients.4 In addition, Idoko et al. reported that in HIV and HBV coinfected patients, lower CD4+ T-cell counts were independently associated with higher HBV-DNA levels and HBeAg positivity.5 Thus, it was rationalized that HU administration probably contributed to HBV reactivation in the present case. HU treatment often concerns the elderly, because the median age of onset of ET is around 50–60 years,
© 2015 Japan Geriatrics Society
and once initiated, long-term administration is often the case with HU.6 The limitations of this report are that although a relatively rare event, we cannot rule out the possibility of spontaneous HBV reactivation. Hsu et al. reported that during a median follow-up period of 8.6 years after HBeAg seroconversion in 283 patients, HBeAg reversion was seen in 12 patients (4.2%), with eight patients (2.8%) eventually developing acute exacerbations.7 Although currently not acknowledged as one of the drugs associated with HBV reactivation, HU could induce reactivation of HBV through suppression of CD4+ T cells, and we strongly recommend close monitoring of HBV-DNA levels in patients with a positive HBsAg, HBsAb or HBcAb status.
Disclosure statement No potential conflicts of interest were disclosed. Naoki Watanabe,1 Hajime Yasuda,1 Yasuo Aota,1 Jun Ando,1 Tomonori Aoyama,2 Masaru Tanaka,1 Akihiko Gotoh1 and Norio Komatsu1 Divisions of 1Hematology and 2Gastroenterology, Department of Medicine, Juntendo University School of Medicine, Tokyo, Japan
References 1 Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology 2006; 43: 209–220. 2 Venigalla P, Motwani B, Allen S, Agarwal M, Westerman M, Feldman L. A patient on hydroxyurea for sickle cell disease who developed an opportunistic infection. Blood 2002; 100: 363–364. 3 Bofill M, Janossy G, Lee CA et al. Laboratory control values for CD4 and CD8 T lymphocytes. Implications for HIV-1 diagnosis. Clin Exp Immunol 1992; 88: 243–252. 4 Bloch MT, Smith DE, Quan D et al. The role of hydroxyurea in enhancing the virologic control achieved through structured treatment interruption in primary HIV infection: final results from a randomized clinical trial (Pulse). J Acquir Immune Defic Syndr 2006; 42: 192–202. 5 Idoko J, Meloni S, Muazu M et al. Impact of hepatitis B virus infection on human immunodeficiency virus response to antiretroviral therapy in Nigeria. Clin Infect Dis 2009; 49: 1268–1273. 6 Steven SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC, 2008. 7 Hsu YS, Chien RN, Yeh CT et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 2002; 35: 1522–1527.
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