LIVER TRANSPLANTATION 00:00–00, 2014
LETTER TO THE EDITORS
Treatment of Persistent/Medically Refractory Covert Hepatic Encephalopathy With the Molecular Adsorbent Recirculating System Received January 18, 2014; accepted March 26, 2014.
TO THE EDITORS: A 66-year-old male with a medical history of liver transplantation for cryptogenic cirrhosis and hepatocellular carcinoma 5 years earlier presented to our transplant service with persistent hepatic encephalopathy. The patient’s postoperative course had been complicated by a bile leak, which had led to polymicrobial peritonitis, intra-abdominal abscesses, and portal vein thrombosis with subsequent portal hypertension. Complications of portal hypertension included ascites and hepatic encephalopathy. He had been listed for retransplantation with a Model for End-Stage Liver Disease score range of 18 to 24 (on anticoagulation for portal vein thrombosis), but he was deemed to be too malnourished and deconditioned for transplantation. The hepatic encephalopathy was categorized as persistent, covert hepatic encephalopathy punctuated by episodes of overt hepatic encephalopathy. The baseline medications for his hepatic encephalopathy were lactulose, rifaximin, and zinc. The patient had been hospitalized 11 times elsewhere over the past year while he was taking those medications. Thereafter, he titrated lactulose to achieve 10 stools per day (sometimes as many as 15-20 stools), and this required intravenous crystalloids scheduled thrice weekly. With this program, he was able to stay out of his local hospital for 6 months until the present admission to our center. Upon admission, he was noted to be minimally responsive to verbal stimuli and had just experienced hematochezia after he had received a lactulose enema in the emergency department. Head computed tomography in the emergency department was negative for a contributory pathology. His ammonia level was 349 lg N/dL. Flexible sigmoidoscopy was performed and demonstrated friable mucosa in the setting of a supratherapeutic international normalized ratio of 3.5 on warfarin for portal vein thrombosis, and there was no active hemorrhaging. He
continued to have persistent, covert hepatic encephalopathy despite lactulose, rifaximin, zinc, and appropriate nutrition and hydration. The features of hepatic encephalopathy were slowed and slurred speech, word-finding and verbal-formulation problems, mild irritability, difficulty in comprehending complex explanations and plans, and executive dysfunction. Physical examinations by multiple physicians from the hepatology, nephrology, and neurology divisions demonstrated a consistent absence of asterixis. After the exclusion of a large spontaneous portosystemic shunt with intravenous contrast–enhanced computed tomography scanning, therapy with the Molecular Adsorbent Recirculating System (MARS; Gambro) was pursued. MARS is Food and Drug Administration– approved for the treatment of hepatic encephalopathy (typically deep-grade overt hepatic encephalopathy), but it has not been reported for use in covert hepatic encephalopathy.1-4 Neuropsychometric testing performed 1 day before the initiation of MARS revealed cognitive impairment with significant slowing, inefficiency, and executive dysfunction consistent with his known hepatic encephalopathy. The executive dysfunction was apparent in his severely impaired performance on the ReyOsterrieth Complex Figure Test and in set-shifting errors on the Trail Making Test. His Grooved Pegboard speed was markedly slow bilaterally, and there was marked slowing on the Symbol Digit Modalities Test. His phonetic verbal fluency was slow and well below the baseline. He was fully oriented, but his memory was mildly below the baseline in verbal (Hopkins Verbal Learning Test) and nonverbal modalities (Benton Visual Retention Test). The MARS treatment was performed via a Mahurkar right internal jugular temporary dialysis catheter for 3 consecutive days (7 hours per treatment). His graft function was stable when MARS was started with the following liver biochemistries and synthetic function markers: total bilirubin, 1.1 mg/dL; direct bilirubin,
The study protocol received a prior approval by the institutional review board. Address reprint requests to Michael D. Leise, M.D., William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail: [email protected] DOI 10.1002/lt.23883 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION. DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
2 LETTER TO THE EDITORS
0.5 mg/dL; aminotransferases, normal; international normalized ratio, 1.4; and albumin, 3.4 g/dL. The lactulose dose and frequency were decreased during the MARS treatment. A clinical benefit was noted on day 2 by the attending physician and was more evident in the clarity of his conversation noted by family members on day 3. His calorie intake also improved after he had begun MARS with a mean intake of 1723 kcal before MARS (3 days) and a mean intake of 2661 kcal (3 days) after MARS. The MARS treatment was well tolerated with no complications. Neuropsychometric testing performed 1.5 days after the completion of the MARS treatment demonstrated significantly improved executive functions. This was seen in marked improvements on the Rey-Osterrieth Complex Figure Test, on which he improved from very impaired (1st percentile) to normal (60th percentile), and in his error-free set-shifting performance on part B of the Trail Making Test. His semantic fluency and word-list delayed recall improved by 1 standard deviation with no improvement in word-list recognition. His psychomotor speed remained significantly slowed (Grooved Pegboard and Symbol Digit Modalities Test). In conclusion, this is the first known report of the use of MARS for persistent covert hepatic encephalopathy refractory to medical therapy. The expense of central-line placement and MARS therapy makes this option problematic for the masses. However, there may be a role for select patients with refractory covert hepatic encephalopathy who gain enough benefit from MARS to participate in physical rehabilitation or a chemical dependency/psychiatric assessment in order to make liver transplantation viable. This patient had dramatic clinical improvements along with neuropsychometric test improvements, and this allowed participation in physical therapy, which had been previously impossible. Subsequently, the patient underwent a second cycle of MARS (3 sessions
LIVER TRANSPLANTATION, Month 2014
for 7 hours each), was dismissed to home to participate in outpatient rehabilitation, and was able to meet peroral calorie requirements. On the basis of this encouraging case report, the further evaluation of MARS for select patients with covert hepatic encephalopathy refractory to medical therapy is warranted. Michael D. Leise, M.D.1 Nelson Leung, M.D.2 Ziad El-Zoghby, M.D.2 Humberto C. Gonzalez Gonzalez, M.D.1 Jane H. Cerhan, Ph.D.3 Scott L. Nyberg, M.D., Ph.D.1 1 William J. von Liebig Center for Transplantation and Clinical Regeneration, 2Division of Nephrology and Hypertension, and 3Department of Psychiatry and Psychology Mayo Clinic Rochester, MN
REFERENCES 1. Ba~ nares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M, et al.; for RELIEF Study Group. Extracorporeal albumin dialysis with the Molecular Adsorbent Recirculating System in acute-on-chronic liver failure: the RELIEF trial. Hepatology 2013;57:1153-1162. 2. Hassanein TI, Tofteng F, Brown RS Jr, McGuire B, Lynch P, Mehta R, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology 2007;46:1853-1862. 3. Par es A, Deulofeu R, Cisneros L, Escorsell A, Salmer on JM, Caballerıa J, Mas A. Albumin dialysis improves hepatic encephalopathy and decreases circulating phenolic aromatic amino acids in patients with alcoholic hepatitis and severe liver failure. Crit Care 2009;13:R8. 4. Leise MD, Poterucha JJ, Kamath PS, Kim WR. Management of hepatic encephalopathy in the hospital. Mayo Clin Proc 2014;89:241-253.
LETTER TO THE EDITORS
Treatment of Persistent/Medically Refractory Covert Hepatic Encephalopathy With the Molecular Adsorbent Recirculating System Received January 18, 2014; accepted March 26, 2014.
TO THE EDITORS: A 66-year-old male with a medical history of liver transplantation for cryptogenic cirrhosis and hepatocellular carcinoma 5 years earlier presented to our transplant service with persistent hepatic encephalopathy. The patient’s postoperative course had been complicated by a bile leak, which had led to polymicrobial peritonitis, intra-abdominal abscesses, and portal vein thrombosis with subsequent portal hypertension. Complications of portal hypertension included ascites and hepatic encephalopathy. He had been listed for retransplantation with a Model for End-Stage Liver Disease score range of 18 to 24 (on anticoagulation for portal vein thrombosis), but he was deemed to be too malnourished and deconditioned for transplantation. The hepatic encephalopathy was categorized as persistent, covert hepatic encephalopathy punctuated by episodes of overt hepatic encephalopathy. The baseline medications for his hepatic encephalopathy were lactulose, rifaximin, and zinc. The patient had been hospitalized 11 times elsewhere over the past year while he was taking those medications. Thereafter, he titrated lactulose to achieve 10 stools per day (sometimes as many as 15-20 stools), and this required intravenous crystalloids scheduled thrice weekly. With this program, he was able to stay out of his local hospital for 6 months until the present admission to our center. Upon admission, he was noted to be minimally responsive to verbal stimuli and had just experienced hematochezia after he had received a lactulose enema in the emergency department. Head computed tomography in the emergency department was negative for a contributory pathology. His ammonia level was 349 lg N/dL. Flexible sigmoidoscopy was performed and demonstrated friable mucosa in the setting of a supratherapeutic international normalized ratio of 3.5 on warfarin for portal vein thrombosis, and there was no active hemorrhaging. He
continued to have persistent, covert hepatic encephalopathy despite lactulose, rifaximin, zinc, and appropriate nutrition and hydration. The features of hepatic encephalopathy were slowed and slurred speech, word-finding and verbal-formulation problems, mild irritability, difficulty in comprehending complex explanations and plans, and executive dysfunction. Physical examinations by multiple physicians from the hepatology, nephrology, and neurology divisions demonstrated a consistent absence of asterixis. After the exclusion of a large spontaneous portosystemic shunt with intravenous contrast–enhanced computed tomography scanning, therapy with the Molecular Adsorbent Recirculating System (MARS; Gambro) was pursued. MARS is Food and Drug Administration– approved for the treatment of hepatic encephalopathy (typically deep-grade overt hepatic encephalopathy), but it has not been reported for use in covert hepatic encephalopathy.1-4 Neuropsychometric testing performed 1 day before the initiation of MARS revealed cognitive impairment with significant slowing, inefficiency, and executive dysfunction consistent with his known hepatic encephalopathy. The executive dysfunction was apparent in his severely impaired performance on the ReyOsterrieth Complex Figure Test and in set-shifting errors on the Trail Making Test. His Grooved Pegboard speed was markedly slow bilaterally, and there was marked slowing on the Symbol Digit Modalities Test. His phonetic verbal fluency was slow and well below the baseline. He was fully oriented, but his memory was mildly below the baseline in verbal (Hopkins Verbal Learning Test) and nonverbal modalities (Benton Visual Retention Test). The MARS treatment was performed via a Mahurkar right internal jugular temporary dialysis catheter for 3 consecutive days (7 hours per treatment). His graft function was stable when MARS was started with the following liver biochemistries and synthetic function markers: total bilirubin, 1.1 mg/dL; direct bilirubin,
The study protocol received a prior approval by the institutional review board. Address reprint requests to Michael D. Leise, M.D., William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail: [email protected] DOI 10.1002/lt.23883 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION. DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
2 LETTER TO THE EDITORS
0.5 mg/dL; aminotransferases, normal; international normalized ratio, 1.4; and albumin, 3.4 g/dL. The lactulose dose and frequency were decreased during the MARS treatment. A clinical benefit was noted on day 2 by the attending physician and was more evident in the clarity of his conversation noted by family members on day 3. His calorie intake also improved after he had begun MARS with a mean intake of 1723 kcal before MARS (3 days) and a mean intake of 2661 kcal (3 days) after MARS. The MARS treatment was well tolerated with no complications. Neuropsychometric testing performed 1.5 days after the completion of the MARS treatment demonstrated significantly improved executive functions. This was seen in marked improvements on the Rey-Osterrieth Complex Figure Test, on which he improved from very impaired (1st percentile) to normal (60th percentile), and in his error-free set-shifting performance on part B of the Trail Making Test. His semantic fluency and word-list delayed recall improved by 1 standard deviation with no improvement in word-list recognition. His psychomotor speed remained significantly slowed (Grooved Pegboard and Symbol Digit Modalities Test). In conclusion, this is the first known report of the use of MARS for persistent covert hepatic encephalopathy refractory to medical therapy. The expense of central-line placement and MARS therapy makes this option problematic for the masses. However, there may be a role for select patients with refractory covert hepatic encephalopathy who gain enough benefit from MARS to participate in physical rehabilitation or a chemical dependency/psychiatric assessment in order to make liver transplantation viable. This patient had dramatic clinical improvements along with neuropsychometric test improvements, and this allowed participation in physical therapy, which had been previously impossible. Subsequently, the patient underwent a second cycle of MARS (3 sessions
LIVER TRANSPLANTATION, Month 2014
for 7 hours each), was dismissed to home to participate in outpatient rehabilitation, and was able to meet peroral calorie requirements. On the basis of this encouraging case report, the further evaluation of MARS for select patients with covert hepatic encephalopathy refractory to medical therapy is warranted. Michael D. Leise, M.D.1 Nelson Leung, M.D.2 Ziad El-Zoghby, M.D.2 Humberto C. Gonzalez Gonzalez, M.D.1 Jane H. Cerhan, Ph.D.3 Scott L. Nyberg, M.D., Ph.D.1 1 William J. von Liebig Center for Transplantation and Clinical Regeneration, 2Division of Nephrology and Hypertension, and 3Department of Psychiatry and Psychology Mayo Clinic Rochester, MN
REFERENCES 1. Ba~ nares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M, et al.; for RELIEF Study Group. Extracorporeal albumin dialysis with the Molecular Adsorbent Recirculating System in acute-on-chronic liver failure: the RELIEF trial. Hepatology 2013;57:1153-1162. 2. Hassanein TI, Tofteng F, Brown RS Jr, McGuire B, Lynch P, Mehta R, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology 2007;46:1853-1862. 3. Par es A, Deulofeu R, Cisneros L, Escorsell A, Salmer on JM, Caballerıa J, Mas A. Albumin dialysis improves hepatic encephalopathy and decreases circulating phenolic aromatic amino acids in patients with alcoholic hepatitis and severe liver failure. Crit Care 2009;13:R8. 4. Leise MD, Poterucha JJ, Kamath PS, Kim WR. Management of hepatic encephalopathy in the hospital. Mayo Clin Proc 2014;89:241-253.
