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Cholangiopathy After Severe COVID-19: Clinical Features and Prognostic Implications

Faruqui, Saamia; Okoli, Fidelis C; Olsen, Sonja K; Feldman, David M; Kalia, Harmit S; Park, James S; Stanca, Carmen M; Figueroa Diaz, Viviana; Yuan, Sarah; Dagher, Nabil N; Sarkar, Suparna A; Theise, Neil D; Kim, Sooah; Shanbhogue, Krishna; Jacobson, Ira M
INTRODUCTION/BACKGROUND:Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 virus, is a predominantly respiratory tract infection with the capacity to affect multiple organ systems. Abnormal liver tests, mainly transaminase elevations, have been reported in hospitalized patients. We describe a syndrome of cholangiopathy in patients recovering from severe COVID-19 characterized by marked elevation in serum alkaline phosphatase (ALP) accompanied by evidence of bile duct injury on imaging. METHODS:We conducted a retrospective study of COVID-19 patients admitted to our institution from March 1, 2020, to August 15, 2020, on whom the hepatology service was consulted for abnormal liver tests. Bile duct injury was identified by abnormal liver tests with serum ALP > 3x upper limit of normal and abnormal findings on magnetic resonance cholangiopacreatography. Clinical, laboratory, radiological, and histological findings were recorded in a Research Electronic Data Capture database. RESULTS:Twelve patients were identified, 11 men and 1 woman, with a mean age of 58 years. Mean time from COVID-19 diagnosis to diagnosis of cholangiopathy was 118 days. Peak median serum alanine aminotransferase was 661 U/L and peak median serum ALP was 1855 U/L. Marked elevations of erythrocyte sedimentation rate, C-reactive protein, and D-dimers were common. Magnetic resonance cholangiopacreatography findings included beading of intrahepatic ducts (11/12, 92%), bile duct wall thickening with enhancement (7/12, 58%), and peribiliary diffusion high signal (10/12, 83%). Liver biopsy in 4 patients showed acute and/or chronic large duct obstruction without clear bile duct loss. Progressive biliary tract damage has been demonstrated radiographically. Five patients were referred for consideration of liver transplantation after experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis. One patient underwent successful living donor liver transplantation. DISCUSSION/CONCLUSIONS:Cholangiopathy is a late complication of severe COVID-19 with the potential for progressive biliary injury and liver failure. Further studies are required to understand pathogenesis, natural history, and therapeutic interventions.
PMID: 33993134
ISSN: 1572-0241
CID: 4876442

Efficacy of GKT831 in patients with primary biliary cholangitis and inadequate response to ursodeoxycholic acid: Interim efficacy results of a phase 2 clinical trial [Meeting Abstract]

Dalekos, G; Invernizzi, P; Nevens, F; Hans, V V; Zigmond, E; Andrade, R J; Ari, Z B; Heneghan, M; Huang, J; Harrison, S; Minuk, G; JornPD, S; Moreno, C; Vierling, J; Vincent, C; Bowlus, C; Lurie, Y; Muratori, L; Niro, G; Hirschfield, G; Post, A; Zeuzem, S; Welzel, T; Ch'ng, C L; Levy, C; Miller, M; Albillos, A; Collier, J D; Corless, L; Dieterich, D; Kremer, A E; Papatheodoridis, G; Romeo, D; Silveira, M; Bernstein, D; Cohen-Naftaly, M; Floreani, A; Borg, B; Carey, E; Hollywood, C; Maliakkal, B; Marzioni, M; Rabinovitz, M; Rupp, C; Sheridan, D; Stanca, C; Swain, M G; Veitsman, E; Dourakis, P S; Wiese, P
[Figure Presented] Background and aims: GKT831 is a potent inhibitor of the nicotinamide adenine dinucleotide phosphate oxidases 1 and 4 (NOX1/4). NOX1/4 produce reactive oxygen species and modulate intracellular signaling pathways through oxidation of target proteins. In response to cellular stress including cholestatic injury to cholangiocytes and hepatocytes, NOX1/4 coordinate the activation of multiple inflammatory and fibrogenic pathways. GKT831 has shown marked anti-inflammatory and anti-fibrotic activity in multiple models of advanced cholestatic diseases. We are conducting a 24-week, randomized, double blind, placebo controlled trial to assess the safety and efficacy of GKT831 in patients with primary biliary cholangitis (PBC) and inadequate response to ursodeoxycholic acid (UDCA).
Method(s): PBC patients on a stable dose of UDCA and with alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (GGT) levels >= 1.5 times the upper limit of normal (ULN), and normal bilirubin were randomized to GKT831 400 mg once a day (QD), 400 mg twice a day (BID), or placebo. All subjects continued UDCA treatment during the treatment period. A predefined interim efficacy analysis was conducted when 92 patients completed 6 weeks of treatment.
Result(s): 111 patients with high baseline disease activity were randomized (female = 91%, mean ALp = 312 IU/L, mean GGT = 225 IU/L). Changes in the primary efficacy end point GGT, a marker of liver and bile duct injury, were-7%, -12%, and-23% in the placebo, 400 mg OD and 400 mg BID groups, respectively (p < 0.01 for 400 mg BID vs placebo). GKT831 achieved even greater GGT reductions (29% for GKT831 400 mg BID vs 8% for placebo, p < 0.01) in patients with higher baseline GGT (>= 2.5 x ULN, n = 68), suggesting that GKT831 may also benefit patients with more advanced disease. Changes in ALP were-2%, -8% and -17% in the placebo, 400 mg OD, and 400 mg BID groups, respectively (p < 0.001 for 400 mg BID vs placebo). Although patients had low baseline levels of liver transaminases and high sensitivity C-reactive protein, dose dependent reductions were achieved. Total and conjugated bilirubin remained unchanged.
Conclusion(s): GKT831 achieved rapid, dose and time dependent reductions in markers of cholestatic bile duct and liver injury. These reductions in disease activity were highly significant for both ALP and GGT in the 400 mg BID group at week 6. Quality of life and markers of liver fibrosis will be assessed at week 24.
Copyright
EMBASE:2001821469
ISSN: 1600-0641
CID: 3915082

THE NOX1/4 INHIBITOR GKT831 ACHIEVES CLINICALLY MEANINGFUL REDUCTIONS IN LIVER STIFFNESS, ATTENUATES CHOLESTASIS, AND IMPROVES QUALITY OF LIFE IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS [Meeting Abstract]

Huang, Jonathan C.; Invernizzi, Pietro; Dalekos, George N.; Nevens, Frederik; Van Vlierberghe, Hans; Zigmond, Ehud; Andrade, Raul J.; Ben-Ari, Ziv; Heneghan, Michael A.; Harrison, Stephen A.; Minuk, Gerald Y.; Schattenberg, Joern; Moreno, Christophe; Vierling, John M.; Vincent, Catherine; Bowlus, Christopher L.; Lurie, Yoav; Muratori, Luigi; Niro, Grazia; Hirschfield, Gideon; Post, Anthony B.; Zeuzen, Stefan; Welzel, Tania; Ch\Ng, Chinlye; Levy, Cynthia; Miller, Michael H.; Collier, Jane D.; Corless, Lynsey; Dieterich, Douglas T.; Kremer, Andreas; Papatheodoridis, George V.; Romeo, David P.; Silveira, Marina G.; Bernstein, David Eric; Naftaly-Cohen, Michal; Floreani, Annarosa; Borg, Brian; Carey, Elizabeth J.; Hollywood, Coral; Maliakkal, Benedict J.; Marzioni, Marco; Rabinovitz, Mordechai; Rupp, Christian; Sheridan, David A.; Stanca, Carmen M.; Swain, Mark Gordon; Veitsman, Ella; Ntourakis, Spyridon P.; Wiesel, Philippe
ISI:000488653502430
ISSN: 0270-9139
CID: 4155752

PHARMACOKINETICS OF SELADELPAR IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS, WITH OR WITHOUT CIRRHOSIS [Meeting Abstract]

Mao, Lily; Bowlus, Christopher L.; Levy, Cynthia; Odin, Joseph; Stanca, Carmen M.; Trivedi, Palak; Varga, Monika; Bergheanu, Sandrin; Yang, Ke; Steinberg, Alexandra; Rossi, Stephen; Boudes, Pol
ISI:000488653503016
ISSN: 0270-9139
CID: 4155762

Effect of Seladelpar on Pruritus in Primary Biliary Cholangitis: 26-Week Analysis of an Ongoing International, Randomized, Dose Ranging Phase 2 Study [Meeting Abstract]

Kremer, Andreas; Bowlus, Christopher L.; Neff, Guy W.; Aspinall, Richard; Galambos, Michael R.; Goel, Aparna; Hirschfield, Gideon; Mayo, Marlyn J.; Swain, Mark Gordon; Borg, Brian; Doerffel, Yvonne; Gordon, Stuart C.; Harrison, Stephen A.; Jones, David; Thuluvath, Paul J.; Levy, Cynthia; Sheridan, David A.; Stanca, Carmen M.; Bacon, Bruce R.; Berg, Christoph; Hassanein, Tarek I.; Odin, Joseph; Shiffman, Mitchell L.; Thorburn, Douglas; Vierling, John M.; Bernstein, David; Buggisch, Peter; Corless, Lynsey; Landis, Charles S.; Peyton, Adam L.; Shah, Hemant A.; Woerns, Marcus-Alexander; Gitlin, Norman; Steinberg, Alexandra; Bergheanu, Sandrin; Amato, Gianni; Choi, Yun-Jung; Rosenbusch, Scott; Varga, Monika; McWherter, Charles; Boudes, Pol
ISI:000451622600027
ISSN: 0270-9139
CID: 3545142

Efficacy and Safety of Seladelpar, a Selective Peroxisome Proliferator-Activated Receptor Delta Agonist, in Primary Biliary Cholangitis: 52-Week Analysis of an Ongoing International, Randomized, Dose Ranging Phase 2 Study [Meeting Abstract]

Bowlus, Christopher L.; Neff, Guy W.; Aspinall, Richard; Galambos, Michael R.; Goel, Aparna; Hirschfield, Gideon; Kremer, Andreas; Mayo, Marlyn J.; Swain, Mark Gordon; Borg, Brian; Doerffel, Yvonne; Gordon, Stuart C.; Harrison, Stephen A.; Jones, David; Thuluvath, Paul J.; Levy, Cynthia; Sheridan, David A.; Stanca, Carmen M.; Bacon, Bruce R.; Berg, Christoph; Hassanein, Tarek I.; Odin, Joseph; Shiffman, Mitchell L.; Thorburn, Douglas; Vierling, John M.; Bernstein, David; Buggisch, Peter; Corless, Lynsey; Landis, Charles S.; Peyton, Adam L.; Shah, Hemant A.; Woerns, Marcus-Alexander; Gitlin, Norman; Steinberg, Alexandra; Bergheanu, Sandrin; Amato, Gianni; Choi, Yun-Jung; Rosenbusch, Scott; Varga, Monika; McWherter, Charles; Boudes, Pol
ISI:000451622600004
ISSN: 0270-9139
CID: 3545152

The Dynamic and Clinical Significance of Autoantibodies and Immunoglobulins in Liver Transplant Recipients

Stanca, Carmen M; Aloman, Costica; Fiel, Maria Isabel; Raja, Kaiser; Uskudar, Oguz; Florman, Sander; Schiano, Thomas D
Little is known about autoantibody pattern in liver transplantation (LT). The aim of the study is to examine autoantibodies and immunoglobulins in patients with end-stage liver disease before and after LT. Patients with LT who underwent post-LT biopsies between 10/2008- 8/2011 were enrolled. Autoantibodies were assessed at the time of LT and liver biopsy. Demographics, serum immunoglobulins, autoantibodies, liver histology (explant, post-LT biopsies) were analyzed. Two hundred and twenty patients (M/F 143/77; age at LT 54 (19-73)) were included; autoantibodies and immunoglobulins were evaluated in 76 patients. Length of follow-up from LT was 285 (30-1462) days. Sixty-one percent of patients had HCV; 83% developed recurrent HCV. A significant decrease in IgG, IgA, IgM (p<0.001 each), anti-cardiolipin antibodies IgG and IgM (p=0.02), and beta-2 microglobulin (p=0.004) was observed post-LT. HCV patients had higher IgG (p=0.005), rheumatoid factor (p=0.044) before LT; elevated IgM was associated with increased inflammation in the explant (p=0.007). Lower IgG levels and ASMA were present before LT in a higher percentage in patients who would develop recurrent HCV (p=0.004, p=0.077, respectively). In conclusion, autoantibodies change significantly after LT and have a different pattern in HCV. Some immunological markers are associated with HCV recurrence and advanced inflammation on explant
PMID: 26700965
ISSN: 1399-0012
CID: 1933562

Factors associated with persistent thrombocytopenia after liver transplantation

Stanca, C M; Fiel, M I; Aledort, L; Cohen, E; del Rio Martin, J; Schiano, T D
BACKGROUND: Thrombocytopenia typically resolves with resolution of portal hypertension after liver transplantation (LT) but persists in some patients. Identifying risk factors associated with persistent post- LT thrombocytopenia may provide important information about its pathogenesis. METHODS: Cirrhotic adults with platelet levels of <150,000 mu/L at the time of LT and followed at least 1 year were studied. A retrospective analysis of lab values, radiologic spleen index (SI), and donor data using nonparametric methods was performed to characterize patients having persistent thrombocytopenia, defined as persistently low platelet levels at 3 and 12 months after LT. RESULTS: One hundred patients were studied: mean age 55 y (range 23-75 y); platelet count at LT 62,000/microL (range 14,000- 148,000/microL; mean total bilirubin 2.6 mg/dL; mean Mayo end-stage liver disease score 29; SI 1,476 (range 347-4,843 mL; normal 120-480 mL). Platelet count at 3 and 12 months after LT correlated with SI (r = -0.41 and -0.54; P < .001). Fifty-seven patients had persistent thrombocytopenia. Compared with patients whose platelet levels normalized by month 3 or 12, they had higher SI and lower platelet count before LT (P < .001). The SI and platelet levels at the time of LT were independent predictive factors for platelet levels at 3 and 12 months after LT (P < .001). CONCLUSIONS: High SI and low platelet count at the time of LT are associated with persistent thrombocytopenia after LT. They are also independent predictive factors of platelet levels at 3 and 12 months after LT. This suggests that patients may have persistent thrombocytopenia after LT owing to persistence of some degree of hypersplenism and incomplete resolution of splenomegaly.
PMID: 20620520
ISSN: 1873-2623
CID: 2215262

Intranasal desmopressin versus blood transfusion in cirrhotic patients with coagulopathy undergoing dental extraction: a randomized controlled trial

Stanca, Carmen M; Montazem, Andre H; Lawal, Adeyemi; Zhang, Jin X; Schiano, Thomas D
PURPOSE: Cirrhotic patients waiting for liver transplantation who need dental extractions are given fresh frozen plasma and/or platelets to correct coagulopathy. This is costly and may be associated with transfusion reactions and fluid overload. We evaluated the efficacy of intranasal desmopressin as an alternative to transfusion to correct the coagulopathy of cirrhotic patients undergoing dental extraction. PATIENTS AND METHODS: Cirrhotic patients with platelet counts of 30,000 to 50,000/microL and/or international normalized ratio (INR) 2.0 to 3.0 were enrolled in a prospective, controlled, randomized clinical trial. Blood transfusion (fresh frozen plasma 10 mL/kg and/or 1 unit of single donor platelets, respectively) or intranasal desmopressin (300 microg) were given before dental extraction. A standard oral and maxillofacial surgical treatment protocol was performed by the same surgeon. Patients were followed for postextraction bleeding and side-effects over the next 24 to 48 hours. RESULTS: No significant differences were noted between the 2 groups in gender, age, INR, platelet count, creatinine, total bilirubin, ALT, albumin, MELD score, or number of teeth removed (median 3 vs 4). The number of teeth removed ranged between 1 and 31 in the desmopressin group and 1 and 22 in the transfusion group. No patients in desmopressin group required rescue blood transfusion after extraction. One patient in the transfusion group had bleeding after the procedure and required an additional transfusion. Another patient experienced an allergic reaction at the end of transfusion, which was effectively treated with diphenhydramine. Treatment associated average costs were lower for desmopressin ($700/patient) compared with transfusion ($1,173/patient). CONCLUSIONS: Intranasal desmopressin was as effective as blood transfusion in achieving hemostasis in cirrhotic patients with moderate coagulopathy undergoing dental extraction. Intranasal desmopressin was much more convenient, less expensive, and well tolerated.
PMID: 20006168
ISSN: 1531-5053
CID: 1933572

Recurrence of primary biliary cirrhosis and development of autoimmune hepatitis after liver transplant: A blind histologic study

Hytiroglou, Prodromos; Gutierrez, Julio A; Freni, Maria; Odin, Joseph A; Stanca, Carmen M; Merati, Sukma; Schiano, Thomas D; Branch, Andrea D; Thung, Swan N
Aim: This long-term study aimed to evaluate recurrence and evolution of primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT). Methods: We reviewed 'blindly' allograft biopsy specimens of women who underwent transplantation for PBC (n = 84), and women who received a transplant for chronic hepatitis C virus infection (CHCV ) (n = 108). All needle liver biopsy specimens obtained more than 6 months post-OLT were examined, including 83 specimens from 44 PBC patients and 152 specimens from 58 CHCV patients. Results: Granulomatous destructive cholangitis was found in five biopsies from four PBC patients (P = 0.0048). Non-necrotizing epithelioid cell granulomas were present in four biopsies from four PBC patients, and in two biopsies from one CHCV patient. Piecemeal necrosis (P = 0.0002), lobular necroinflammatory activity (P < 0.0001), steatosis (P < 0.0001) and fibrosis (P < 0.0001) were more prevalent in CHCV patients than PBC patients. Four PBC patients developed histologic evidence of autoimmune hepatitis (AIH), at a mean time of 3.66 years post-OLT. One of these patients had histologic features of AIH/PBC overlap syndrome. All four patients developed bridging fibrosis (n = 2) or cirrhosis (n = 2). No other PBC patient had evidence of cirrhosis after OLT. Conclusions: Histologic findings indicative of recurrent PBC were present in 15.9% of the PBC patients undergoing biopsy in this series. However, this group of patients did not suffer significant bile duct loss or fibrosis, as compared to the control group, suggesting that recurrent PBC is a mild or slowly progressive disease. Histologic evidence of AIH was observed in allograft biopsies of some PBC patients
PMCID:3127546
PMID: 19207586
ISSN: 1386-6346
CID: 96916