- Email: [email protected]
Correspondence
AJG – October, 1999
Letters to the Editor
Developmental alteration of pancreaticobiliary ductal systems results in several kinds of congenital anomalies. The combination of two or more anomalies was rare. In the present case, a portion of the extrahepatic duct (EHD) was duplicated, which may account for dysfunction of normal physiological mechanisms and contribute to symptoms of recurrent right upper quadrant pain. The symptoms might be relieved by a sphincterotomy. Another biliary anatomic abnormality of the patient is APBD. It was found in 1.5–3% of ERCP examinations (1). APBD was thought to be associated with choledochal cyst, cholangiocarcinoma, and gallbladder carcinoma (2), which were not found in the present patient. About pancreatic duct abnormality, the patient was investigated to have incomplete pancreas divisum with evidence of small ventral duct draining via major papilla and large dorsal duct draining via minor papilla. There was a filamentous connection branch connecting the ventral and dorsal pancreas. This may result in impeding the flow of pancreatic secretion and predisposing to pancreatitis. A trial therapy of enlarging the orifice of the minor papilla using dilation, stenting, or sphincterotomy may give clinically helpful result (3). Chun-Hsiang Wang, M.D. Lein-Ray Mo, M.D. Department of Internal Medicine Tainan Municipal Hospital Tainan, Taiwan, Republic of China
REFERENCES 1. Misra SP, Gulati P, Thorat VK, et al. Pancreaticobiliary ductal union in biliary diseases: An endoscopic retrograde cholangiopancreatographic study. Gastroenterology 1989;96:907–12. 2. Kimura K, Ohto M, Saisho H, et al. Association of gallbladder carcinoma and anomalous pancreaticobiliary ductal union. Gastroenterology 1985;89:1258 – 65. 3. Madura JA, Fiore AC, O’Connor W, et al. Pancreas divisum: Detection and management. Am Surg 1985;51:353–7. Reprint requests and correspondence: Chun-Hsiang Wang, Department of Internal Medicine, Tainan Municipal Hospital, 670, Chung Te Road, Tainan, Taiwan, R.O.C. Received Apr. 19, 1999; accepted Apr. 29, 1999.
Interferon Plus Ribavirin: A Cautionary Note TO THE EDITOR: Recently, Barbaro et al. (1) reported on the efficacy of retreatment with interferon-␣ (IFN-␣) and ribavirin in patients with a previous lack of response to IFN-␣ alone. The combination arm of this randomized, controlled study included 152 patients for analysis. Also, Schalm et al. (2) demonstrated the enhancement in efficacy of ribavirin-interferon combination therapy for chronic hepatitis C. The metaanalysis was carried out based on the data available for 168 patients (78 under IFN ⫹ ribavirin).
3087
Curiously, both authors underlined that serious adverse effects of this combination therapy were not observed, and that discontinuation of therapy was registered in 9% of the patients (related to anemia, fatigue, and skin disorders) in the study by Schalm et al. and no patient was withdrawn from the study by Barbaro et al. Most surprising for us was the observation in this multicenter study, of absence of increase in serum bilirubin. However, in a series of 60 patients with combination therapy (INF, 3–5 million units (MU) t.i.w. ⫹ ribavirin 1000 –1200 mg/day for 6 –12 months), besides a 15% incidence of elevated (⬎2.5 mg/dl) bilirubin (always unconjugated, related to hemolysis), we also observed a life-threatening event that might be related to the combination of IFN plus ribavirin. The patient was a 49-yr-old man, presumably infected with hepatitis C virus (HCV) in a transfusion in 1969 while a posttraumatic nephrectomy was performed. He was referred to us 2 yr ago, after recognition of persistent transaminases fluctuation. He was then diagnosed with chronic active hepatitis C virus, genotype 2a. He was a normal weight, normotensive, nonsmoking patient, with normal physical examination and without family history of any cardiovascular event or diabetes. His blood tests were normal (besides transaminases), including lipid profile, serum creatinine and urea, and thyroid tests. He had a 6-month course of ␣ 2b interferon, 5 MU t.i.w., with normalization of transaminases in month 2 of therapy. Besides the usual flu-like syndrome during the early phases of treatment, therapy went on uneventfully, and 3 months after concluding interferon monotherapy, he was diagnosed as a relapser, with transaminases five times normal. He began interferon 5 MU t.i.w., plus ribavirin 1200 mg/day. He had a steady drop on the hemoglobin level to 10.2 g/dl (normal leukocytes and platelets) and rise in indirect bilirubin to 2.2 mg/dl over the next 2 months, when he was admitted to the hospital with acute chest pain and diaphoresis. He had evidence (in the EKG and blood enzymes) of acute anterior myocardial infarction, and was submitted to thrombolysis and therapy with salicylates, heparin, and captopril. He had an uneventful recovery in 2 wk, and is now medicated with salicylates and captopril. A control coronary angiography was reported to be normal. Although some reports of myocardial infarction have been described as related to interferon monotherapy (3), generally it occurred in patients with a history of cardiovascular disease, hypertension, renal arterosclerosis, coronary bypass surgery, obesity, or diabetes mellitus. Our patient had an unremarkable history with no risk factors for coronary disease, and he had an uneventful 6-month period on interferon. Only after ribavirin combined with interferon (and after a progressive drop in hemoglobin levels) did myocardial infarction occur. Although we consider, as do others, that INF ⫹ ribavirin is a highly valuable approach in HCV-infected patients, particularly in those who have relapsed or have not responded to a first interferon course (1, 4), one should be aware of serious side effects overwhelming the classical low grade hemolysis and the
3088
Letters to the Editor
AJG – Vol. 94, No. 10, 1999
related discrete cosmetic changes. Any type of previous cardiovascular events should be considered a relative contraindication to the use of this combination therapy. Guilherme Macedo, M.D. Tome´ Ribeiro, Ph.D. Gastro Unit, Hospital S. Joa˜o Porto, Portugal
REFERENCES 1. Barbaro G, Di Lorenzo G, Soldini M, et al. Interferon ␣-2B and ribavirin in combination for chronic hepatitis C patients not responding to interferon ␣ alone: An Italian multicenter randomized, controlled, clinical study. Am J Gastroenterol 1998; 93:2445–51. 2. Schalm SW, Hansen DE, Chemello L, et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. J Hepatol 1997;26:961– 6. 3. Sonnenblick M, Rorin A. Cardiotoxicity of interferon—A review of 44 cases. Chest 1991;99:557– 61. 4. Brillanti S, Garson J, Foli M, et al. A pilot study of combination therapy with ribavirin plus interferon alpha for alpha interferon resistant chronic hepatitis C. Gastroenterology 1994;107: 812–7.
Reprint requests and correspondence: Guilherme Macedo, M.D., Gastro Unit, Hospital S. Joa˜o, 4200 Porto, Portugal. Received Apr. 20, 1999; accepted Apr. 29, 1999.
Cirrhosis and Diabetes: C, the Difference TO THE EDITOR: We read with great interest the observation by Mangia et al. (1) disproving hepatitis C virus (HCV) infection as a trigger factor for diabetes mellitus (DM). Their main finding was that, at multivariate analysis, only cirrhosis and age had an independent effect on the occurrence of DM, with a stronger impact of the former. They based their conclusions on the similar prevalence of DM in HBV-, HCV-, or alcohol-induced cirrhosis, and on the occurrence of DM at the some rate in chronic hepatitis as in the general population. They also claimed that the fact that all the cases of diabetes had hepatitis C was explained by the age differences. However, we think that, beyond the diabetogenic effect of cirrhosis itself, there must be a role for HCV in this setting: in fact, the findings in 100 cirrhotic patients, by Allison et al. (2), in which 34 patients with HCV-related cirrhosis had diabetes mellitus in 50%— contrasting to just 9% of the 66 patients with cirrhosis unrelated to HCV—were quite similar to ours. In fact, we had been surprised, while managing the candidates for liver transplantation, at the unusually high rate of diabetes in HCV
Table 1. Cirrhosis and Diabetes Mellitus (DM) Etiology
No. of Patients
No. of DM Patients
%
Alcohol HCV HBV Miscellaneous Prim. biliary cirrhosis Sclerosing cholangitis Cryptogenetic Total
43 38 20 15 6 4 5 116
6 15 2
14% 39% 10%
23
20%
HCV ⫽ hepatitis C virus; HBV ⫽ hepatitis B virus.
cirrhotic patients. The recognition of that fact prompted us to make some changes in the antibiotic regimen for prevention of sepsis and in the immunosuppressive protocols (e.g., changing prednisone to mycophenolate [Mofetil]). We then reviewed retrospectively 106 adult patients with a diagnosis of cirrhosis established histologically, and obtained information on the etiology, presence of diabetes mellitus, and previous or current use of steroids and -blockade. The diagnosis of DM was based on the ongoing use of an oral hypoglycemic agent or insulin, or a random blood sugar ⬎12 mmol/L. We have limited the inclusion according to the etiological diagnosis only in cases of alcohol-, hepatitis C-, or hepatitis B virus-induced cirrhosis and a miscellaneous group (with primary biliary cirrhosis, sclerosing cholangitis, and cryptogenic cirrhosis), to avoid other causes such as hemochromatosis, known to be highly associated with DM. Of the 116 cirrhotic patients, 23 (20%) had diabetes mellitus, a rate similar to that observed by Allison et al. (2) and del Olmo et al. (3). However, instead of a proportional distribution of DM in all etiological groups, as in the del Olmo et al. study (3), we found that in the 38 HCV infected patients, 15 (39%) had DM, whereas the prevalence in HBV patients was 10% (two of 20); in alcoholic induced cirrhosis it was 14% (six of 43) and in the miscellaneous group it was 0% (zero of 15) (Table 1). We noticed that the mean age of the different etiological groups was similar (58.3 yr for HCV, 60.2 yr for HBV, and 53.8 yr for alcoholic patients), testifying that patient age, per se, did not influence our findings. It has long been known that there is an association between cirrhosis, glucose intolerance, and DM, and several contributive factors have been pointed out: hyperinsulinemia, increase of gluconeogenesis, insulin resistance, and reduced glucose uptake by cirrhotic livers (4). DM is also a common observation in autoimmune disorders, and HCV is associated with several autoimmune phenomena. Our findings support the idea of a genuine link between HCVinduced cirrhosis and DM, and we think that despite the fact that the underlying mechanisms have not yet been defined, DM should be considered a comorbid condition that follows
Letters to the Editor
Developmental alteration of pancreaticobiliary ductal systems results in several kinds of congenital anomalies. The combination of two or more anomalies was rare. In the present case, a portion of the extrahepatic duct (EHD) was duplicated, which may account for dysfunction of normal physiological mechanisms and contribute to symptoms of recurrent right upper quadrant pain. The symptoms might be relieved by a sphincterotomy. Another biliary anatomic abnormality of the patient is APBD. It was found in 1.5–3% of ERCP examinations (1). APBD was thought to be associated with choledochal cyst, cholangiocarcinoma, and gallbladder carcinoma (2), which were not found in the present patient. About pancreatic duct abnormality, the patient was investigated to have incomplete pancreas divisum with evidence of small ventral duct draining via major papilla and large dorsal duct draining via minor papilla. There was a filamentous connection branch connecting the ventral and dorsal pancreas. This may result in impeding the flow of pancreatic secretion and predisposing to pancreatitis. A trial therapy of enlarging the orifice of the minor papilla using dilation, stenting, or sphincterotomy may give clinically helpful result (3). Chun-Hsiang Wang, M.D. Lein-Ray Mo, M.D. Department of Internal Medicine Tainan Municipal Hospital Tainan, Taiwan, Republic of China
REFERENCES 1. Misra SP, Gulati P, Thorat VK, et al. Pancreaticobiliary ductal union in biliary diseases: An endoscopic retrograde cholangiopancreatographic study. Gastroenterology 1989;96:907–12. 2. Kimura K, Ohto M, Saisho H, et al. Association of gallbladder carcinoma and anomalous pancreaticobiliary ductal union. Gastroenterology 1985;89:1258 – 65. 3. Madura JA, Fiore AC, O’Connor W, et al. Pancreas divisum: Detection and management. Am Surg 1985;51:353–7. Reprint requests and correspondence: Chun-Hsiang Wang, Department of Internal Medicine, Tainan Municipal Hospital, 670, Chung Te Road, Tainan, Taiwan, R.O.C. Received Apr. 19, 1999; accepted Apr. 29, 1999.
Interferon Plus Ribavirin: A Cautionary Note TO THE EDITOR: Recently, Barbaro et al. (1) reported on the efficacy of retreatment with interferon-␣ (IFN-␣) and ribavirin in patients with a previous lack of response to IFN-␣ alone. The combination arm of this randomized, controlled study included 152 patients for analysis. Also, Schalm et al. (2) demonstrated the enhancement in efficacy of ribavirin-interferon combination therapy for chronic hepatitis C. The metaanalysis was carried out based on the data available for 168 patients (78 under IFN ⫹ ribavirin).
3087
Curiously, both authors underlined that serious adverse effects of this combination therapy were not observed, and that discontinuation of therapy was registered in 9% of the patients (related to anemia, fatigue, and skin disorders) in the study by Schalm et al. and no patient was withdrawn from the study by Barbaro et al. Most surprising for us was the observation in this multicenter study, of absence of increase in serum bilirubin. However, in a series of 60 patients with combination therapy (INF, 3–5 million units (MU) t.i.w. ⫹ ribavirin 1000 –1200 mg/day for 6 –12 months), besides a 15% incidence of elevated (⬎2.5 mg/dl) bilirubin (always unconjugated, related to hemolysis), we also observed a life-threatening event that might be related to the combination of IFN plus ribavirin. The patient was a 49-yr-old man, presumably infected with hepatitis C virus (HCV) in a transfusion in 1969 while a posttraumatic nephrectomy was performed. He was referred to us 2 yr ago, after recognition of persistent transaminases fluctuation. He was then diagnosed with chronic active hepatitis C virus, genotype 2a. He was a normal weight, normotensive, nonsmoking patient, with normal physical examination and without family history of any cardiovascular event or diabetes. His blood tests were normal (besides transaminases), including lipid profile, serum creatinine and urea, and thyroid tests. He had a 6-month course of ␣ 2b interferon, 5 MU t.i.w., with normalization of transaminases in month 2 of therapy. Besides the usual flu-like syndrome during the early phases of treatment, therapy went on uneventfully, and 3 months after concluding interferon monotherapy, he was diagnosed as a relapser, with transaminases five times normal. He began interferon 5 MU t.i.w., plus ribavirin 1200 mg/day. He had a steady drop on the hemoglobin level to 10.2 g/dl (normal leukocytes and platelets) and rise in indirect bilirubin to 2.2 mg/dl over the next 2 months, when he was admitted to the hospital with acute chest pain and diaphoresis. He had evidence (in the EKG and blood enzymes) of acute anterior myocardial infarction, and was submitted to thrombolysis and therapy with salicylates, heparin, and captopril. He had an uneventful recovery in 2 wk, and is now medicated with salicylates and captopril. A control coronary angiography was reported to be normal. Although some reports of myocardial infarction have been described as related to interferon monotherapy (3), generally it occurred in patients with a history of cardiovascular disease, hypertension, renal arterosclerosis, coronary bypass surgery, obesity, or diabetes mellitus. Our patient had an unremarkable history with no risk factors for coronary disease, and he had an uneventful 6-month period on interferon. Only after ribavirin combined with interferon (and after a progressive drop in hemoglobin levels) did myocardial infarction occur. Although we consider, as do others, that INF ⫹ ribavirin is a highly valuable approach in HCV-infected patients, particularly in those who have relapsed or have not responded to a first interferon course (1, 4), one should be aware of serious side effects overwhelming the classical low grade hemolysis and the
3088
Letters to the Editor
AJG – Vol. 94, No. 10, 1999
related discrete cosmetic changes. Any type of previous cardiovascular events should be considered a relative contraindication to the use of this combination therapy. Guilherme Macedo, M.D. Tome´ Ribeiro, Ph.D. Gastro Unit, Hospital S. Joa˜o Porto, Portugal
REFERENCES 1. Barbaro G, Di Lorenzo G, Soldini M, et al. Interferon ␣-2B and ribavirin in combination for chronic hepatitis C patients not responding to interferon ␣ alone: An Italian multicenter randomized, controlled, clinical study. Am J Gastroenterol 1998; 93:2445–51. 2. Schalm SW, Hansen DE, Chemello L, et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. J Hepatol 1997;26:961– 6. 3. Sonnenblick M, Rorin A. Cardiotoxicity of interferon—A review of 44 cases. Chest 1991;99:557– 61. 4. Brillanti S, Garson J, Foli M, et al. A pilot study of combination therapy with ribavirin plus interferon alpha for alpha interferon resistant chronic hepatitis C. Gastroenterology 1994;107: 812–7.
Reprint requests and correspondence: Guilherme Macedo, M.D., Gastro Unit, Hospital S. Joa˜o, 4200 Porto, Portugal. Received Apr. 20, 1999; accepted Apr. 29, 1999.
Cirrhosis and Diabetes: C, the Difference TO THE EDITOR: We read with great interest the observation by Mangia et al. (1) disproving hepatitis C virus (HCV) infection as a trigger factor for diabetes mellitus (DM). Their main finding was that, at multivariate analysis, only cirrhosis and age had an independent effect on the occurrence of DM, with a stronger impact of the former. They based their conclusions on the similar prevalence of DM in HBV-, HCV-, or alcohol-induced cirrhosis, and on the occurrence of DM at the some rate in chronic hepatitis as in the general population. They also claimed that the fact that all the cases of diabetes had hepatitis C was explained by the age differences. However, we think that, beyond the diabetogenic effect of cirrhosis itself, there must be a role for HCV in this setting: in fact, the findings in 100 cirrhotic patients, by Allison et al. (2), in which 34 patients with HCV-related cirrhosis had diabetes mellitus in 50%— contrasting to just 9% of the 66 patients with cirrhosis unrelated to HCV—were quite similar to ours. In fact, we had been surprised, while managing the candidates for liver transplantation, at the unusually high rate of diabetes in HCV
Table 1. Cirrhosis and Diabetes Mellitus (DM) Etiology
No. of Patients
No. of DM Patients
%
Alcohol HCV HBV Miscellaneous Prim. biliary cirrhosis Sclerosing cholangitis Cryptogenetic Total
43 38 20 15 6 4 5 116
6 15 2
14% 39% 10%
23
20%
HCV ⫽ hepatitis C virus; HBV ⫽ hepatitis B virus.
cirrhotic patients. The recognition of that fact prompted us to make some changes in the antibiotic regimen for prevention of sepsis and in the immunosuppressive protocols (e.g., changing prednisone to mycophenolate [Mofetil]). We then reviewed retrospectively 106 adult patients with a diagnosis of cirrhosis established histologically, and obtained information on the etiology, presence of diabetes mellitus, and previous or current use of steroids and -blockade. The diagnosis of DM was based on the ongoing use of an oral hypoglycemic agent or insulin, or a random blood sugar ⬎12 mmol/L. We have limited the inclusion according to the etiological diagnosis only in cases of alcohol-, hepatitis C-, or hepatitis B virus-induced cirrhosis and a miscellaneous group (with primary biliary cirrhosis, sclerosing cholangitis, and cryptogenic cirrhosis), to avoid other causes such as hemochromatosis, known to be highly associated with DM. Of the 116 cirrhotic patients, 23 (20%) had diabetes mellitus, a rate similar to that observed by Allison et al. (2) and del Olmo et al. (3). However, instead of a proportional distribution of DM in all etiological groups, as in the del Olmo et al. study (3), we found that in the 38 HCV infected patients, 15 (39%) had DM, whereas the prevalence in HBV patients was 10% (two of 20); in alcoholic induced cirrhosis it was 14% (six of 43) and in the miscellaneous group it was 0% (zero of 15) (Table 1). We noticed that the mean age of the different etiological groups was similar (58.3 yr for HCV, 60.2 yr for HBV, and 53.8 yr for alcoholic patients), testifying that patient age, per se, did not influence our findings. It has long been known that there is an association between cirrhosis, glucose intolerance, and DM, and several contributive factors have been pointed out: hyperinsulinemia, increase of gluconeogenesis, insulin resistance, and reduced glucose uptake by cirrhotic livers (4). DM is also a common observation in autoimmune disorders, and HCV is associated with several autoimmune phenomena. Our findings support the idea of a genuine link between HCVinduced cirrhosis and DM, and we think that despite the fact that the underlying mechanisms have not yet been defined, DM should be considered a comorbid condition that follows