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Successful liver transplantation for diffuse biliary papillomatosis
542
Letters to the Editor
After zafirlukast was withdrawn, the patient recovered clinical and analytically in a period of 6 weeks in a progressive manner (Table 1). A liver biopsy was not indicated. In the following controls, the liver enzymes remained normal, with no relapses. In our patient, the development of the symptoms 2 months after starting zafirlukast therapy, the detection of elevated liver enzymes levels one month later, and the course of these abnormalities after withdrawal were chronologically suggestive [7,8]. Before zafirlukast therapy the serum liver enzymes were normal and other causes of liver injury have been reasonably ruled out. Although the patient had use other medications (salbutamol, formoterol and budesonide), hepatotoxicity by these inhaled drugs is unlikely and she had use salbutamol and formoterol for the previous five years without complications. Therefore, in this case, the liver injury can be reasonably considered drug-related [9]. Asymptomatic increases in serum liver enzymes occurred in 1–4% of patients treated with zafirlukast in clinical trials [1–3]. Their values rarely are above five times the upper limit of normal [3]. Most of them have been observed in patients receiving high dosages of zafirlukast (80 mg twice daily) [1,2]. However, several cases of symptomatic hepatitis (with or without hyperbilirubinemia) and hyperbilirubinemia without other elevated liver function tests have been reported from post-marketing adverse event surveillance of patients who have received the recommended dose (20 mg twice daily) [4,5,10,11]. Moreover, Reinus et al. [6] have recently reported three patients with severe hepatitis, secondary to treatment with zafirlukast. Curiously, as our case, hepatic events have occurred predominantly in females and after several months of zafirlukast treatment [6,11]. In most post-marketing reports, the liver enzymes returned to normal after stopping zafirlukast. In rare cases, however, patients have progressed to hepatic failure [6,11]. The mechanism of zafirlukast-induced hepatotoxicity is not known. The presence of hepatic eosinophils in all three patients reported by Reinus et al. [6] suggests an immunologic mechanism. However, our patient did not present fever, rash, or eosinophilia; therefore in this patient, liver injury caused by zafirlukast seems to be idiosyncratic.
We believe that it is prudent to check liver enzymes during the treatment with leukotriene-receptor antagonists, especially in females with co-administration of many drugs or alcohol abuse. Jose´ Ramo´n Mole´s, Joaquı´ n Primo, Julio M. Ferna´ndez, Joaquı´ n E. Hinojosa Unidad de Digestivo, Hospital de Sagunto, Avenida Ramo´n y Cajal, s/n 46520 Sagunto, Valencia, Spain
References [1] Adkins JC, Brogden RN. Zafirlukast: a review of its pharmacology and therapeutic potential in the management of asthma. Drugs 1998;55:121–144. [2] Lipworth BJ. Leukotriene-receptor antagonists. Lancet 1999;353:57– 62. [3] Grossman J, Smith LJ, Wilson AM, Thyrum PT. Long-term safety and efficacy of zafirlukast in the treatment of asthma: interim results of an open-label extension trial. Ann Allergy Asthma Immunol 1999;82:361–369. [4] Editor’s Note. Correction: liver injury and rosiglitazone. Ann Intern Med 2000;133:237. [5] Physicians’ Desk Reference. Montvale, NJ: Medical Economics, 2000. p. 536. [6] Reinus JF, Persky S, Burkiewicz JS, Quan D, Bass NM, Davern TJ. Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast. Ann Intern Med 2000;133:964–968. [7] Benichou C. Criteria of drug-induced liver disorders. Report of an International Consensus Meeting. J Hepatol 1990;11:272–276. [8] Larrey D. Drug-induced liver diseases. J Hepatol 2000;32(Suppl 1):77–88. [9] Aithal GP, Rawlins MD, Day CP. Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic adverse drug reactions. J Hepatol 2000;33:949–952. [10] MedWatch. Revisions to the precautions and adverse events sections of the labeling for Accolate. http://www.fda.gov/medwatch/safety/ 2000/accola.htm [11] Zeneca Pharmaceuticals. Accolate w (zafirlukast) professional information brochure AC1295 Rev N 06/00. http://www.astrazeneca-us.com/ cgi-bin/az_pi.cgi?product ¼ accolate&country ¼ US&inframe ¼ no. Zeneca, 2000. PII: S0 168-8278(01 )00 124-6
Successful liver transplantation for diffuse biliary papillomatosis To the Editor: Diffuse biliary papillomatosis is a rare disease characterized by the diffuse replacement of the normal biliary epithelium by an adenomatous proliferation displaying various degrees of dysplasia and carrying a high risk of malignant transformation [1]. This condition is difficult to treat because of its diffuse character, its high risk of local recurrence, and its malignant potential. Theoretically, the only effective treatment would be to remove the whole biliary tract.
A 61-year-old Caucasian woman was first admitted in December 1997 for right upper quadrant pain and jaundice. Serum total bilirubin was 225 mmol/l and alkaline phosphatase serum levels were 892 IU/l. Abdominal ultrasonography, computerized tomography (CT) and endoscopic ultrasonography showed dilated intra- and extrahepatic bile ducts and identified a nodular lesion of the upper common bile duct. Endoscopic retrograde cholangiography showed mucin discharge at the ampulla of Vater and
Letters to the Editor
revealed three filling defects, respectively in the lower common bile duct, the upper common bile duct and the proximal part of the left and right intrahepatic bile ducts. All biopsy samples showed replacement of the normal biliary epithelium by a papillary adenomatous proliferation, with low to high grade dysplasia. After endoscopic sphincterotomy, percutaneous drainage was performed from January 1998 to February 1999. Three series of additional biopsies did not identify invasive carcinoma. The decision to perform orthotopic liver transplantation, associated with cephalic duodenopancreatectomy, was made because of the risk of malignant transformation and the diffuse distribution of the lesions, which prevented any surgical resection. The patient underwent orthotopic liver transplantation after en bloc hepatectomy and cephalic duodenopancreatectomy in February 1999. At the time of transplantation, serum total bilirubin was 14 mmol/l, and carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within the normal values. Histological examination of the surgical specimen showed diffuse involvement of the extrahepatic biliary tree, including the whole common bile duct, the hepatic ducts and the initial part of the cystic duct. Large segments of the intrahepatic main bile ducts were involved. Three foci of invasive carcinoma limited to the biliary wall were detected in the common bile duct and the left hepatic duct, respectively. No lymph node metastasis was present. Induction immunosuppression consisted of prednisone, FK506 and mycophenolate mofetil. Recovery was uneventful. After 22 months of follow-up, the patient is asymptomatic, without evidence of tumor recurrence or metastasis. Patients with diffuse biliary papillomatosis usually present with obstructive jaundice or acute cholangitis [2– 4]. Ultrasonography and CT scan usually show only bile duct dilatation. The diagnostic value of cholangiographic and cholangioscopic examinations in the evaluation of extra- and intrahepatic involvement has been recently underlined [3,4]. Suggestive features include the finding of a dilated papillary orifice with mucin discharge, and the presence of multiple small, round-to-ovoid filling defects in the biliary tree, associated with ductal irregularities or stenoses. Biopsy specimens may be obtained after endoscopic sphincterotomy to confirm the diagnosis. Various therapeutic strategies have been proposed. For
543
inoperable patients, endoscopic evacuation of mucus and debris and/or stent placement may be useful [3]. Surgical treatment is controversial. A review of the literature reveals that, irrespective of the type of surgical resection performed, the course of the disease is severe, with a high incidence of local recurrence and malignant transformation [2,5]. Survivals of more than 12 months are exceedingly rare. This led us to consider our patient for orthotopic liver transplantation, which has been proposed as the only way to avoid recurrence and degeneration [2] but, to our knowledge, has not been reported so far. In this situation, combined hepatectomy and duodenopancreatectomy is necessary, because of the high risk of extension to the lower part of the common bile duct. In our patient, no evidence of disease recurrence or metastasis has been detected after a 22-month period. Our report suggests that liver transplantation after combined total hepatectomy and cephalic duodenopancreatectomy probably represents the most effective treatment of diffuse biliary papillomatosis. Je´roˆme Dumortier 1,2, Jean-Yves Scoazec 3, Pierre-Jean Valette 2, Thierry Ponchon 2, Olivier Boillot 1,2 1 Unite´ de Transplantation He´ patique, 2Fe´ de´ ration des Spe´ cialite´ s Digestives, 3Service Central d’Anatomie et Cytologie Pathologiques, Hoˆ pital Edouard Herriot, Lyon, France
References [1] Caroli J, Corvos V. Papillomatose des voies biliaires intrahe´ patiques. Maladies des voies biliaires intrahe´ patiques segmentaires, Paris: Masson, 1964. pp. 151–181. [2] Rambaud S, Nores JM, Paolaggi JA. Papillomatose des voies biliaires. Presse Med 1989;18:1329–1332. [3] Dabrigeon G, Blanc P, Bauret P, Diaz D, Durand L, Michel J, Larrey D. Diagnostic and therapeutic aspects of endoscopic retrograde cholangiography in papillomatosis of the bile ducts: analysis of five cases. Gastrointest Endosc 1997;46:237–243. [4] Kim YS, Myung SJ, Kim SY, Kim HJ, Kim JS, Park ET, et al. Biliary papillomatosis: clinical, cholangiographic and cholangioscopic findings. Endoscopy 1998;30:763–767. [5] Lam CM, Yuen ST, Yuen WK, Fan ST. Biliary papillomatosis. Br J Surg 1996;83:1715–1716. PII: S0168 -8 278(01)00126 -X
Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis To the Editor: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology that occurs mainly in middle-aged women. One of the most distressing complications of PBC is the development of osteodystrophy and bone fractures [1]. However, the effects of therapy for osteoporosis associated with PBC are still controversial. Patients with
PBC have decreased secretion of bile acids, which are required for absorption of fat-soluble vitamins from the intestines [2]. Of the fat-soluble vitamins, vitamins D and K are known to modulate bone metabolism. Shiraki et al. [3] reported that vitamin K2 increases bone mineral density (BMD) and decreases the incidence of bone fracture in patients with osteoporosis. Since blood vitamin K concen-
Letters to the Editor
After zafirlukast was withdrawn, the patient recovered clinical and analytically in a period of 6 weeks in a progressive manner (Table 1). A liver biopsy was not indicated. In the following controls, the liver enzymes remained normal, with no relapses. In our patient, the development of the symptoms 2 months after starting zafirlukast therapy, the detection of elevated liver enzymes levels one month later, and the course of these abnormalities after withdrawal were chronologically suggestive [7,8]. Before zafirlukast therapy the serum liver enzymes were normal and other causes of liver injury have been reasonably ruled out. Although the patient had use other medications (salbutamol, formoterol and budesonide), hepatotoxicity by these inhaled drugs is unlikely and she had use salbutamol and formoterol for the previous five years without complications. Therefore, in this case, the liver injury can be reasonably considered drug-related [9]. Asymptomatic increases in serum liver enzymes occurred in 1–4% of patients treated with zafirlukast in clinical trials [1–3]. Their values rarely are above five times the upper limit of normal [3]. Most of them have been observed in patients receiving high dosages of zafirlukast (80 mg twice daily) [1,2]. However, several cases of symptomatic hepatitis (with or without hyperbilirubinemia) and hyperbilirubinemia without other elevated liver function tests have been reported from post-marketing adverse event surveillance of patients who have received the recommended dose (20 mg twice daily) [4,5,10,11]. Moreover, Reinus et al. [6] have recently reported three patients with severe hepatitis, secondary to treatment with zafirlukast. Curiously, as our case, hepatic events have occurred predominantly in females and after several months of zafirlukast treatment [6,11]. In most post-marketing reports, the liver enzymes returned to normal after stopping zafirlukast. In rare cases, however, patients have progressed to hepatic failure [6,11]. The mechanism of zafirlukast-induced hepatotoxicity is not known. The presence of hepatic eosinophils in all three patients reported by Reinus et al. [6] suggests an immunologic mechanism. However, our patient did not present fever, rash, or eosinophilia; therefore in this patient, liver injury caused by zafirlukast seems to be idiosyncratic.
We believe that it is prudent to check liver enzymes during the treatment with leukotriene-receptor antagonists, especially in females with co-administration of many drugs or alcohol abuse. Jose´ Ramo´n Mole´s, Joaquı´ n Primo, Julio M. Ferna´ndez, Joaquı´ n E. Hinojosa Unidad de Digestivo, Hospital de Sagunto, Avenida Ramo´n y Cajal, s/n 46520 Sagunto, Valencia, Spain
References [1] Adkins JC, Brogden RN. Zafirlukast: a review of its pharmacology and therapeutic potential in the management of asthma. Drugs 1998;55:121–144. [2] Lipworth BJ. Leukotriene-receptor antagonists. Lancet 1999;353:57– 62. [3] Grossman J, Smith LJ, Wilson AM, Thyrum PT. Long-term safety and efficacy of zafirlukast in the treatment of asthma: interim results of an open-label extension trial. Ann Allergy Asthma Immunol 1999;82:361–369. [4] Editor’s Note. Correction: liver injury and rosiglitazone. Ann Intern Med 2000;133:237. [5] Physicians’ Desk Reference. Montvale, NJ: Medical Economics, 2000. p. 536. [6] Reinus JF, Persky S, Burkiewicz JS, Quan D, Bass NM, Davern TJ. Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast. Ann Intern Med 2000;133:964–968. [7] Benichou C. Criteria of drug-induced liver disorders. Report of an International Consensus Meeting. J Hepatol 1990;11:272–276. [8] Larrey D. Drug-induced liver diseases. J Hepatol 2000;32(Suppl 1):77–88. [9] Aithal GP, Rawlins MD, Day CP. Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic adverse drug reactions. J Hepatol 2000;33:949–952. [10] MedWatch. Revisions to the precautions and adverse events sections of the labeling for Accolate. http://www.fda.gov/medwatch/safety/ 2000/accola.htm [11] Zeneca Pharmaceuticals. Accolate w (zafirlukast) professional information brochure AC1295 Rev N 06/00. http://www.astrazeneca-us.com/ cgi-bin/az_pi.cgi?product ¼ accolate&country ¼ US&inframe ¼ no. Zeneca, 2000. PII: S0 168-8278(01 )00 124-6
Successful liver transplantation for diffuse biliary papillomatosis To the Editor: Diffuse biliary papillomatosis is a rare disease characterized by the diffuse replacement of the normal biliary epithelium by an adenomatous proliferation displaying various degrees of dysplasia and carrying a high risk of malignant transformation [1]. This condition is difficult to treat because of its diffuse character, its high risk of local recurrence, and its malignant potential. Theoretically, the only effective treatment would be to remove the whole biliary tract.
A 61-year-old Caucasian woman was first admitted in December 1997 for right upper quadrant pain and jaundice. Serum total bilirubin was 225 mmol/l and alkaline phosphatase serum levels were 892 IU/l. Abdominal ultrasonography, computerized tomography (CT) and endoscopic ultrasonography showed dilated intra- and extrahepatic bile ducts and identified a nodular lesion of the upper common bile duct. Endoscopic retrograde cholangiography showed mucin discharge at the ampulla of Vater and
Letters to the Editor
revealed three filling defects, respectively in the lower common bile duct, the upper common bile duct and the proximal part of the left and right intrahepatic bile ducts. All biopsy samples showed replacement of the normal biliary epithelium by a papillary adenomatous proliferation, with low to high grade dysplasia. After endoscopic sphincterotomy, percutaneous drainage was performed from January 1998 to February 1999. Three series of additional biopsies did not identify invasive carcinoma. The decision to perform orthotopic liver transplantation, associated with cephalic duodenopancreatectomy, was made because of the risk of malignant transformation and the diffuse distribution of the lesions, which prevented any surgical resection. The patient underwent orthotopic liver transplantation after en bloc hepatectomy and cephalic duodenopancreatectomy in February 1999. At the time of transplantation, serum total bilirubin was 14 mmol/l, and carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within the normal values. Histological examination of the surgical specimen showed diffuse involvement of the extrahepatic biliary tree, including the whole common bile duct, the hepatic ducts and the initial part of the cystic duct. Large segments of the intrahepatic main bile ducts were involved. Three foci of invasive carcinoma limited to the biliary wall were detected in the common bile duct and the left hepatic duct, respectively. No lymph node metastasis was present. Induction immunosuppression consisted of prednisone, FK506 and mycophenolate mofetil. Recovery was uneventful. After 22 months of follow-up, the patient is asymptomatic, without evidence of tumor recurrence or metastasis. Patients with diffuse biliary papillomatosis usually present with obstructive jaundice or acute cholangitis [2– 4]. Ultrasonography and CT scan usually show only bile duct dilatation. The diagnostic value of cholangiographic and cholangioscopic examinations in the evaluation of extra- and intrahepatic involvement has been recently underlined [3,4]. Suggestive features include the finding of a dilated papillary orifice with mucin discharge, and the presence of multiple small, round-to-ovoid filling defects in the biliary tree, associated with ductal irregularities or stenoses. Biopsy specimens may be obtained after endoscopic sphincterotomy to confirm the diagnosis. Various therapeutic strategies have been proposed. For
543
inoperable patients, endoscopic evacuation of mucus and debris and/or stent placement may be useful [3]. Surgical treatment is controversial. A review of the literature reveals that, irrespective of the type of surgical resection performed, the course of the disease is severe, with a high incidence of local recurrence and malignant transformation [2,5]. Survivals of more than 12 months are exceedingly rare. This led us to consider our patient for orthotopic liver transplantation, which has been proposed as the only way to avoid recurrence and degeneration [2] but, to our knowledge, has not been reported so far. In this situation, combined hepatectomy and duodenopancreatectomy is necessary, because of the high risk of extension to the lower part of the common bile duct. In our patient, no evidence of disease recurrence or metastasis has been detected after a 22-month period. Our report suggests that liver transplantation after combined total hepatectomy and cephalic duodenopancreatectomy probably represents the most effective treatment of diffuse biliary papillomatosis. Je´roˆme Dumortier 1,2, Jean-Yves Scoazec 3, Pierre-Jean Valette 2, Thierry Ponchon 2, Olivier Boillot 1,2 1 Unite´ de Transplantation He´ patique, 2Fe´ de´ ration des Spe´ cialite´ s Digestives, 3Service Central d’Anatomie et Cytologie Pathologiques, Hoˆ pital Edouard Herriot, Lyon, France
References [1] Caroli J, Corvos V. Papillomatose des voies biliaires intrahe´ patiques. Maladies des voies biliaires intrahe´ patiques segmentaires, Paris: Masson, 1964. pp. 151–181. [2] Rambaud S, Nores JM, Paolaggi JA. Papillomatose des voies biliaires. Presse Med 1989;18:1329–1332. [3] Dabrigeon G, Blanc P, Bauret P, Diaz D, Durand L, Michel J, Larrey D. Diagnostic and therapeutic aspects of endoscopic retrograde cholangiography in papillomatosis of the bile ducts: analysis of five cases. Gastrointest Endosc 1997;46:237–243. [4] Kim YS, Myung SJ, Kim SY, Kim HJ, Kim JS, Park ET, et al. Biliary papillomatosis: clinical, cholangiographic and cholangioscopic findings. Endoscopy 1998;30:763–767. [5] Lam CM, Yuen ST, Yuen WK, Fan ST. Biliary papillomatosis. Br J Surg 1996;83:1715–1716. PII: S0168 -8 278(01)00126 -X
Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis To the Editor: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology that occurs mainly in middle-aged women. One of the most distressing complications of PBC is the development of osteodystrophy and bone fractures [1]. However, the effects of therapy for osteoporosis associated with PBC are still controversial. Patients with
PBC have decreased secretion of bile acids, which are required for absorption of fat-soluble vitamins from the intestines [2]. Of the fat-soluble vitamins, vitamins D and K are known to modulate bone metabolism. Shiraki et al. [3] reported that vitamin K2 increases bone mineral density (BMD) and decreases the incidence of bone fracture in patients with osteoporosis. Since blood vitamin K concen-