Lobular Hepatitis Research Articles

A histopathological analysis of extrapulmonary lesions in fatal coronavirus disease (COVID-19)

IntroductionThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents diverse clinical manifestations and multi-organ involvement. This study aimed to evaluate the extra-pulmonary histopathological patterns underpinning COVID-19-induced lesions in cardiac, hepatic, renal, brainstem, and splenic tissues. Materials and methodsThe research involved conventional forensic autopsies conducted between April 2020 and April 2021 on individuals with confirmed SARS-CoV-2 infection in Cluj-Napoca, Romania. Tissues were processed and stained for histological examination. Differences in patients with and without diffuse alveolar damage (DAD) were evaluated. ResultsIn our study of 79 COVID-19 autopsies conducted on unvaccinated patients besides lung involvement, the patients had histological changes in at least two out of five (brain, heart, liver, kidney, and spleen) organs. Notable findings include hepatitis observed in 46.8 % of cases, 21.5 % with lobular hepatitis, and 41.8 % with liver steatosis. Additionally, 69.6 % exhibited acute tubular necrosis, and 55.7 % had varying degrees of splenic lymphocyte depletion. Almost 41 % of cases had pericardial effusion, 36.7 % myocarditis, 24.1 % myocardial infarction, and 12.7 % of cases had encephalitis. Acute tubular necrosis (78.6 %) was the most frequent histopathological finding observed in patients with DAD. Myocarditis was described in 45.9 % of the patients without DAD. DiscussionThe autopsy findings in our cohort of COVID-19 victims align with international scientific literature. Distinguishing viral-induced myocarditis, encephalitis, hepatitis, or systemic inflammatory syndrome remains challenging. ConclusionPost-mortem analysis identified lesions associated with SARS-CoV-2 in multiple organs, highlighting the systemic nature of the virus and emphasizing the need for continued research into organ-specific damage and long-term sequelae of COVID-19.

The etiology and differential diagnosis of "autoimmune hepatitis-like liver disease" in children: a single-center retrospective study.

Children with autoimmune hepatitis (AIH) often present with symptoms similar to those of other liver diseases. This study consists of a comparison between the clinical and histological characteristics of AIH and those of other four AIH-like liver diseases [i.e., drug-induced liver injury (DILI), gene deficiency, infectious liver disease and other etiology of liver disease], as well as an evaluation of the AIH scoring system's diagnostic performance. All children with AIH-like liver disease at our center from January 2013 to December 2022 were included. The clinical and histological characteristics of the AIH group were retrospectively analyzed and compared with those of the other four groups. A total of 208 children were included and divided into AIH group (18 patients), DILI group (38 patients), gene deficiency group (44 patients), infectious liver disease group (74 patients), and other etiology group (34 patients). The antinuclear antibodies (ANA) ≥ 1:320 rate was significantly higher in the AIH compared to the other four groups after multiple testing correction (p < 0.0125), while patients with positive antibodies to liver-kidney microsomal-1 (anti-LKM1, n = 3) and smooth muscle antibodies (SMA, n = 2) were only observed in the AIH group. The positive rates of antibodies to liver cytosol type1 (anti-LC1) and Ro52 were higher than those in the other four groups. The serum immunoglobulin G (IgG) and globulin levels, as well as the proportions of portal lymphoplasmacytic infiltration, lobular hepatitis with more than moderate interface hepatitis, and lobular hepatitis with lymphoplasmacytic infiltration, were significantly higher in the AIH group than in the other four groups after multiple testing correction (p < 0.0125). The cirrhosis rate in the AIH group was higher than that in the DILI and infectious liver disease groups (p < 0.0125). Both the simplified (AUC > 0.73) and the revised systems (AUC > 0.93) for AIH have good diagnostic performance, with the latter being superior (p < 0.05). Positive autoantibodies (ANA ≥ 1:320 or anti-LKM1 positive, or accompanied by SMA, anti-LC1 or Ro-52 positive) and elevated serum IgG or globulin levels contribute to early recognition of AIH. The presence of lobular hepatitis with more than moderate interface hepatitis and lymphoplasmacytic infiltration contribute to the diagnosis of AIH.

Liver manifestation of patients with celiac disease: A single center experience

ObjectivesCharacterize the clinicopathologic features of liver biopsies from patients with celiac disease (CD). MethodsSingle center, retrospective search for liver biopsies from patients with CD. Results36 unique patients were included, median age of 46 years (range: 2–75), including 5 pediatric patients, with an overall female predominance (25, 69 %) but in in children a male predominance was seen (p = 0.023). Most cases (75 %) had an underlying condition including autoimmune hepatitis (AIH) (11 %), AIH/primary biliary cholangitis (PBC) overlap (3 %) and PBC (3 %). The median body mass index was 28, with 4 (11 %) underweight and 22 (61 %) overweight/obese patients. The most common histologic pattern was steatosis (18, 50 %), considered severe in 5 (14 %) and in 7 (19 %) regarded as steatohepatitis. The other histologic patterns included a nonspecific portal and/or lobular inflammation (“celiac hepatitis”) in 9 cases (25 %), autoimmune hepatitis (3, 8 %), chronic cholestatic pattern (3, 8 %), chronic hepatitis (1, 3 %), acute lobular hepatitis (1, 3 %) and stablished cirrhosis (1, 3 %). Additionally, 2 of the cases with steatosis show cirrhosis. ConclusionsThe biopsy findings from patients with CD are heterogenous and in most represent a concomitant underlying disease, particularly metabolic dysfunction-associated steatotic liver disease. Additionally, CD injury should remain in the differential diagnosis in liver biopsies with a nonspecific portal and/or lobular inflammation.

Clinical and pathological characteristics of immune-mediated liver injury caused by immune checkpoint inhibitors

Objective: Cancer immunotherapy can lead to various side effects, termed immune-related adverse events (irAE). This study summarized and analyzed the clinical and pathological characteristics of immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI). Methods: This is a retrospective case series study involving 11 patients diagnosed with ILICI at the Peking Union Medical College Hospital from November 2019 to November 2021. Patient demographic information and clinical data, including gender, age, ILICI onset, clinical and radiological manifestations, pathological features, treatment, and resumption of ICI were retrospectively collected and analyzed. Results: The patients were primarily males (9/11) with a median age of 65 (range: 32-73) years. ICI mainly resulted in either partial remission (4/11) or stable disease (3/11). ILICI occurred after a median of two cycles of anti-programmed cell death-1 (PD-1) therapy, with a median time from the initial and last anti-PD-1 therapy to ILICI onset of 57 days and 17 days, respectively. ILICI was mostly severe (3/11) or very severe (6/11). While the clinical and radiological manifestations were non-specific, the pathological features were active lobular hepatitis and portal inflammation, with prominent CD8+T lymphocyte infiltration. The basic treatment was hepatoprotective drugs (10/11). Glucocorticoids were used as the primary therapy (9/11) but were ineffective in 4 of 9 cases. Of these, 3 of 9 cases received combined treatment with mycophenolate mofetil (MMF), only one of whom achieved remission. By the end of the study, 2 of 11 cases had resumed ICI and neither had experienced an ILICI relapse. Conclusion: The ILICI patients in this study had a corresponding history of ICI treatment and pathological features. The main treatment included hepatoprotective drugs and glucocorticoids. Immunosuppressive drugs were added for some cases but had poor efficacy.

Fulminant hepatitis due to spontaneous reactivation of virus B in an immunocompetent patient.

We present the case of a 52-year-old woman with a history of HBeAg-negative chronic hepatitis B virus (HBV) infection, viral load (VL) Z+<20,000U.l/ml with no evidence of liver fibrosis and, therefore, untreated. She presented to the emergency department with jaundice, epigastric pain, nausea, and vomiting. On admission, blood analysis revealed ALT 3982U/l, AST 3221U/l, Gamma-GT 80U/l, alkaline phosphatase 252U/l, LDH 960U/l, bilirrubin12.5mg/dl; no elevation of acute phase reactants, 141,000 platelets and coagulopathy with a prothrombin activity of 29%. Abdominal ultrasound showed no relevant findings. The serological profile revealed AgHBs+, anti-HBe+ y anti-HBc IgM+ and VL VHB>100 mills. Ul/ml, the remaining serology was negative and other causes of liver disease were ruled out. With the diagnosis of severe acute hepatitis (SAH) due to HBV reactivation (HBVR) treatment with entecavir was initiated. Given the analytical evolution (Table 1) and the appearance of encephalopathy grade I-II/IV, an urgent liver transplant was performed. The histological result of the explant was conclusive with intense interphase and lobular hepatitis with extensive areas of massive necrosis in both lobes, without hepatic fibrosis compatible with fulminant hepatitis (FH).

LBODP039 Glycogenic Hepatopathy- An Underrecognized Complication Of Diabetes

Abstract Introduction Glycogenic hepatopathy (GH) is an infrequently described complication of predominantly type 1 diabetes characterized by liver dysfunction and hepatomegaly. This condition is different from the more common nonalcoholic fatty liver disease (NAFLD) which is clinically indistinguishable. Liver biopsy is currently the only way to differentiate the two conditions. We present a 19 year old female with persistent transaminasemia secondary to glycogenic hepatopathy associated with poorly controlled type 1 diabetes. Case Description A 19 year old female was admitted with DKA secondary to facial cellulitis. She had a past history of poorly controlled type 1 DM since age 9, proteinuria, and transaminasemia since age 14. Initial labs showed elevated plasma glucose 365 mg/dL, bicarbonate 15 mEq/L, anion gap 22, positive betahydroxybutyrate, AST 208 mmol/L, ALT 136 mmol/L, and HbA1c 12. 0%. She was successfully resuscitated from DKA. Repeat liver function tests showed further elevation of AST 819 mmol/L and ALT 346 mmol/L. Ultrasound of liver showed increased echotexture reported as steatosis. Further history revealed significant financial difficulty due to which patient was using different kinds of basal and bolus insulins interchangeably. She would sometimes use bolus insulin to cover for lack of basal insulin. Prior gastroenterology workup showed ANA positivity in a speckled pattern but was otherwise unrevealing for infective, autoimmune, or alcoholic hepatitis. Liver biopsy was therefore recommended by inpatient gastroenterology. Liver biopsy revealed spotty mild lobular hepatitis and focal portal fibrosis consistent with glycogenic hepatopathy. Features of autoimmune hepatitis were not seen in liver biopsy. Discussion Glycogen hepatopathy seems to represent an acquired form of glycogen storage disorder. Pathophysiology is suspected to be a combination of hyperglycemia and hyperinsulinemia leading to increased glycogen accumulation in hepatocytes while glycogenolysis is suppressed. This mechanism seems to correlate with our patient who reported use of large doses of short acting insulin followed by glucose administration to counteract hypoglycemia. Abnormal glucagon activity or enzymes deficiencies in glycogenolysis pathway (as reported with congenital glycogenstorage disorders) have not been elucidated. Recent data has also questioned reversibility and long term safety as liver biopsies of patients with glycogenic hepatopathy have demonstrated varying degrees of fibrosis. Newer MRI protocols seem to be able to distinguish GH from NAFLD, and this is important as these are pathophysiologically distinct and will have different management strategies. This case highlights glycogenic hepatopathy as an underrecognized complication of diabetes that will require improved recognition and further investigation to evaluate long term consequences. Presentation: No date and time listed

Histological and serological features of acute liver injury after SARS-CoV-2 vaccination

Liver injury with autoimmune features after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is increasingly reported. We investigated a large international cohort of individuals with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features. Individuals without known pre-existing liver diseases and transaminase levels ≥5x the upper limit of normal within 3 months after any anti-SARS-CoV-2 vaccine, and available liver biopsy were included. Fifty-nine patients were recruited; 35 females; median age 54 years. They were exposed to various combinations of mRNA, vectorial, inactivated and protein-based vaccines. Liver histology showed predominantly lobular hepatitis in 45 (76%), predominantly portal hepatitis in 10 (17%), and other patterns in four (7%) cases; seven had fibrosis Ishak stage ≥3, associated with more severe interface hepatitis. Autoimmune serology, centrally tested in 31 cases, showed anti-antinuclear antibody in 23 (74%), anti-smooth muscle antibody in 19 (61%), anti-gastric parietal cells in eight (26%), anti-liver kidney microsomal antibody in four (13%), and anti-mitochondrial antibody in four (13%) cases. Ninety-one percent were treated with steroids ± azathioprine. Serum transaminase levels improved in all cases and were normal in 24/58 (41%) after 3 months, and in 30/46 (65%) after 6 months. One patient required liver transplantation. Of 15 patients re-exposed to SARS-CoV-2 vaccines, three relapsed. Acute liver injury arising after SARS-CoV-2 vaccination is frequently associated with lobular hepatitis and positive autoantibodies. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. A close follow-up is warranted to assess the long-term outcomes of this condition. Cases of liver injury after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have been published. We investigated a large international cohort of individuals with acute hepatitis after SARS-CoV-2 vaccination, focusing on liver biopsy findings and autoantibodies: liver biopsy frequently shows inflammation of the lobule, which is typical of recent injury, and autoantibodies are frequently positive. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. Close follow-up is warranted to assess the long-term outcome of this condition.

S2939 Ashwagandha Toxicity: A Rare Case of Drug Induced Liver Injury (DILI)

Introduction: The pursuance of natural and herbal remedies by many has brought with it further knowledge of the many causes of Drug Induced Liver Injury (DILI). Many of these "natural" over-the-counter (OTC) supplements may not be benign due to the lack of scientific analysis and unregulated production. Ashwagandha is a supplement used for memory enhancement, management of anxiety, and general increase in vitality. We present a case of Ashwagandha DILI in a healthy 36-year-old man. Case Description/Methods: A 36-year-old male presented to our institution with 1 week of fatigue, jaundice, nausea and subjective fevers. Upon presentation he was hemodynamically stable and afebrile. Physical exam was notable for jaundice without other stigmata of liver disease or mental status changes. He was found to have acute liver injury with lab chemistries remarkable for AST= 1482 U/L, ALT= 1375 U/L, Tbili= 22.3 mg/dL, alkaline phosphatase= 202 U/L and an INR of 1.6. He denied alcohol and drug use, recent travel or sick contacts. Medications list was notable for cetirizine, diphenhydramine (both taken as needed), OTC testosterone supplements, OTC apple cider vinegar gummies BID and OTC ashwagandha gummies BID. Workup was negative for autoimmune, infectious, metabolic, obstructive and vascular causes of liver injury. Acetaminophen level and urine drug screen were negative. Trans-jugular liver biopsy revealed evidence of acute portal and lobular hepatitis and cholestasis, suggestive of DILI. Patient's liver enzymes continued to downtrend (AST=929, ALT=765, Tbili=22.5) after withdrawal of his supplements and was discharged (Figure). Discussion: Ashwagandha causing DILI has been infrequently reported in the literature. One case series of 5 patients in Iceland and a single case in Japan reported that ashwagandha is an uncommon culprit linked to acute liver injury. None of the reported cases necessitated liver transplant. Average time to resolution and normalization of LFTs was 3.5 months and R values usually ranged in the mixed range (R value 2-5). The case series also revealed that ashwagandha's toxicity could be dose dependent, as higher peaks in LFT's were tied to recent increases in ashwagandha dosing. Although ashwagandha has been a rarely reported cause of DILI, a thorough history of medication and OTC supplements in patients with undifferentiated acute liver injury may yield more cases. Further study and reporting of DILI in the ever-growing supplement market appears to be required to minimize potential injury.Figure 1.: Tranjugular Liver Biopsy Findings.

S2935 Autoimmune Hepatitis After COVID-19 Vaccine: An Unusual Complication

Introduction: Vaccination against SARS-Cov2 has represented a major milestone in our ability to ameliorate the COVID-19 pandemic. The vaccines are generally safe and effective, but some adverse events have been reported, including recent reports of autoimmune-like hepatitis. This case report presents a rare diagnosis of autoimmune hepatitis after administration of an mRNA COVID-19 vaccine. Case Description/Methods: An 18-year-old man with no medical history presented after receiving the Pfizer COVID-19 vaccine in April 2021, and second dose in May 20221. In June of 2021, about two weeks after the second dose, the patient was found with AST 120 u/L, ALT 181 u/L, Platelets 90. See Table 1 for further lab values. Per family, prior liver chemistries were normal. Initial serological workup was completed, including viral hepatitis (Hepatitis A, B, C, E), CMV IgG and IgM, EBV IgG and IgM, ceruloplasmin, alpha-1-antitrypsin, iron studies, all of which were unremarkable. Patient was also found to have ANA titer 1:640, positive anti-smooth-muscle antibody of 1:640, IgG level of 1,845, and positive antibody to soluble liver antigen of 2.321. Abdominal MRI was completed with findings of splenomegaly 20 cm, radiographic evidence of advanced hepatic fibrosis Patient underwent a liver biopsy with foci of interface and lobular hepatitis, areas of bridging necrosis, and scarring and focal nodularity concerning for transition to cirrhosis. Given these findings and it's timing close to administration of COVID-19 vaccine, the patient was diagnosed with autoimmune hepatitis associated with the vaccine. Patient was started on steroids in November 2021, and later, azathioprine, with improvement of liver enzymes. Discussion: Autoimmune hepatitis is a rare complication of COVID-19 vaccines, reported in few case reports in the literature. The pathophysiology remains unclear but is hypothesized to be related to molecular mimicry. The mRNA vaccines developed against COVID-19 leads to the production of the spike protein, and its antibodies. Antibodies to the spike protein have high affinity toward other human tissue proteins, which can lead to autoimmune tissue injury. In most reports, patients improved after treatment with steroids, though two have been reported to have passed away of liver failure. No liver transplants have yet been reported. Given the serious implications of this disease and the number of vaccines against COVID-19 given world-wide, further research is needed to better understand this entity and its pathophysiology. Table 1. - Lab Values 6/6/2021 11/15/2021 12/2/2021 1/12/2022 2/11/2022 4/18/2022 5/30/2022 AST U/L 120 323 31 35 48 37 50 ALT U/L 181 519 87 58 74 44 48 ALK P U/L 265 292 165 101 109 116 124 PLATELET COUNT 90 86 93 82 96 111 98

S3272 A Potential New Use for Tocilizumab: A Case of Refractory Checkpoint Inhibitor Hepatitis

Introduction: Immune checkpoint inhibitors (CPI) are becoming increasingly common treatment options for several types of cancers. While their use in cancer treatment is very promising, these medications are not without side effects. Specifically, these drugs are commonly associated with hepatic adverse events, including auto-immune hepatitis (AIH). In fact, in one study, AIH was found in approximately 5% of people treated with a CPI. While we know that CPI hepatitis is a potential outcome of treatment with CPIs, we have yet to establish the best treatment options for this adverse event. Based on expert opinion, the recommended course of treatment involves high dose steroids and immunomodulators if needed. There is not, however, much literature on management of CPI hepatitis that is refractory to the typical treatments, though use of tocilizumab has shown some success previously in treatment of immune-related adverse events secondary to CPIs . Case Description/Methods: A 35 y.o. female with recurrent right renal cell carcinoma, status-post resection with nephrectomy, on palliative treatment with nivolumab/ipilimumab, presented to the hospital for further evaluation of elevated liver function tests (LFT) and an abdominal MRI concerning for hepatitis. At time of admission, she was on her 3rd week of steroids, started with concern for drug-induced autoimmune hepatitis due to her checkpoint inhibitor (CPI) treatment. At admission, she was started on IV steroids and mycophenolic acid. LFTs and bilirubin continued to rise despite several days of this treatment and she was given a dose of rituximab. Liver biopsy was obtained which was consistent with CPI induced hepatitis. LFTs and bilirubin continued to rise and tocilizumab was given. 4 days after that treatment, AST and ALT were nearly half their pretreatment values and bilirubin began downtrending. At this point, the patient was stable enough for discharge with very close follow up (Figure). Discussion: Studies from 2019 reveal that 43.68% of all people with cancer in the United States are eligible for CPI therapy. This number translates to 7.9 million patients who are potentially eligible for CPI therapy. With the incidence of severe CPI hepatitis suspected to be up to 20% of all people taking CPIs, this equates to 1.58 million people of whom could be affected. More studies need to be done to address treatment for refractory auto-immune CPI hepatitis, and to better understand the underlying pathogenesis in this rapidly growing population.Figure 1.: Liver biopsy with significant lobular hepatitis, loss of zone 3 hepatocytes, acidophil bodies, and Kupffer cell hyperplasia consistant with checkpoint inhibitor auto-immune hepatitis.

How should endocrinologists diagnose and treat non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) was first described in 1980 in a report from the Mayo Clinic that described the characteristics of non-alcoholic steatohepatitis in 20 patients.1 A liver biopsy showed “the presence of striking fatty changes with evidence of lobular hepatitis, focal necroses with mixed inflammatory infiltrates; and evidence of fibrosis in most specimens”.1 Most of the patients had moderate obesity, and many had type 2 diabetes and cholelithiasis.1 The report concluded “currently, we know of no effective therapy”.

Consensus recommendations for histological criteria of autoimmune hepatitis from the International AIH Pathology Group: Results of a workshop on AIH histology hosted by the European Reference Network on Hepatological Diseases and the European Society of Pathology: Results of a workshop on AIH histology hosted by the European Reference Network on Hepatological Diseases and the European Society of Pathology.

Diagnostic histological criteria for autoimmune hepatitis (AIH) have not been clearly established. Previously published criteria focused mainly on chronic AIH, in which inflammatory changes mainly occur in portal/periportal regions and may not be applicable to acute presentation of AIH, in which inflammatory changes are typically predominantly lobular in location. International consensus criteria for the diagnosis and assessment of disease severity in both acute and chronic AIH are thus urgently needed. Seventeen expert liver pathologists convened at an international workshop and subsequently used a modified Delphi panel approach to establish consensus criteria for the histopathological diagnosis of AIH. The consensus view is that liver biopsy should remain standard for diagnosing AIH. AIH is considered likely, if there is a predominantly portal lymphoplasmacytic hepatitis with more than mild interface activity and/or more than mild lobular hepatitis in the absence of histological features suggestive of another liver disease. AIH is also considered likely if there is predominantly lobular hepatitis with or without centrilobular necroinflammation and at least one of the following features: portal lymphoplasmacytic hepatitis, interface hepatitis or portal-based fibrosis, in the absence of histological features suggestive of another liver disease. Emperipolesis and hepatocellular rosettes are not regarded as being specific for AIH. The criteria proposed in this consensus statement provide a uniform approach to the histological diagnosis of AIH, which is relevant for patients with an acute as well as a chronic presentation and to more accurately reflect the current understanding of liver pathology in AIH.

Successful Liver Transplantation From a SARS-CoV-2 Positive Donor to a Positive Recipient: Potential Role of Monoclonal Antibodies.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic initially resulted in a decline in organ transplantation, including a 35.9% decrease in the United States.1 Although there are many factors contributing to this, potential donors who tested positive for SARS-CoV-2 have been largely excluded from donation. Simultaneously, there was uncertainty about safety of transplanting a recipient with coronavirus disease 2019 (COVID-19). Although there are emerging reports of liver transplantation from SARS-CoV-2-infected deceased donors,2 optimal risk mitigation strategies are unclear. Herein, we report a case of liver transplantation from a SARS-CoV-2 positive deceased donor to a SARS-CoV-2 positive recipient who was managed with anti spike monoclonal antibodies. This report did not require review board approval. Our patient was a 33 y-old female with adult-onset Still’s disease, treated previously with canakinumab, admitted for severe acute-on-chronic liver failure of unclear etiology. She had experienced several months of relapsing elevations in liver biochemistries attributed to lobular hepatitis of unclear etiology. She developed jaundice with progressive encephalopathy over 3 wk, culminating in a clinical scenario consistent with subacute liver failure, with a calculated Model for End-stage Liver Disease-Sodium score of 35. Concurrently, multiple household contacts developed mild upper respiratory symptoms and were diagnosed with COVID-19. She had not undergone SARS-CoV-2 vaccination. Upon admission, the patient was jaundiced, encephalopathic, and coagulopathic, although normoxic, and her chest radiograph did not show infiltrates. Urgent evaluation for liver transplantation was initiated. Nasopharyngeal SARS-CoV-2 polymerase chain reaction was positive (cycle threshold N 33.0, open reading frame 27.6; ARIES SARS-CoV-2 assay, Luminex Corp), and serum SARS-CoV-2 nucleocapsid antibody was negative. Because of high-risk comorbidities and likely impending transplantation, she received casirivimab and imdevimab on hospital day 1. She received an organ offer for liver transplantation on hospital day 4. The donor was incidentally found to have a positive SARS-CoV-2 polymerase chain reaction on routine donor screening without evidence of clinical disease. The donor had died from trauma, and the liver was normal. After shared decision-making, she proceeded with orthotopic liver transplantation and received a 5-d course of remdesivir after transplantation. She received induction immunosuppression with methylprednisolone and maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone. She did receive augmented prophylactic anticoagulation with enoxaparin 30 mg twice per day; however, this was complicated by perihepatic hematoma requiring reoperation for evacuation and hemostasis on posttransplant day 8. She experienced no thrombotic complications. She was dismissed from the hospital 11 d following transplantation and remained in isolation for 20 d posttransplantation. She did not develop respiratory symptoms or abnormal lung imaging in 30 d of follow-up. There is currently little experience transplanting a SARS-CoV-2 positive donor to a SARS-CoV-2 positive recipient.3 We utilized anti spike monoclonal antibodies to mitigate the risk of progression to severe infection while awaiting transplantation. This treatment has been associated with good outcomes in solid organ transplantation4 and has been utilized as postexposure prophylaxis.5 We propose anti spike monoclonal antibodies may have a role in mitigating the risks of SARS-CoV-2 donor-derived infection and progression to severe disease posttransplantation. Our case highlights that donor SARS-CoV-2 positivity does not necessarily preclude nonlung organ transplantation, and risks of transmission must be balanced with the risk of death while remaining on the transplant waitlist. SARS-CoV-2-directed monoclonal antibody therapy and/or preemptive remdesivir administration may have roles in this setting; however, additional studies on strategies to mitigate donor-derived COVID-19 are necessary.

S2616 Here’s the Tea — A Case of Drug-Induced Autoimmune Hepatitis and Salvage Therapy With Plasmapheresis

Introduction: Drug-induced liver injury (DILI) is a staple in the differential for acute hepatitis, though discerning agents as potentiating underlying autoimmune hepatitis (AIH) is challenging. Here, we present an unusual case of drug-induced AIH. Case Description/Methods: A 64 year old male with history of hypertension, tobacco use, and remote heavy alcohol use presented with 5 days of progressive jaundice, fatigue, acholic stools, and dark urine after consuming herbal teas made from fermented prickly pear as well as jujube/chili mix. Notable labs include AST 1677, ALT 1669, AP 196, T. Bili 16.8, and Globulin 3.9. Besides elevated IgG and IgA, chronic liver disease workup was negative. Biopsy finalized as moderate to severe plasma rich portal and lobular hepatitis with portal fibrosis. Patient was treated with Prednisone for seronegative drug-induced AIH with decline in transaminases. Interestingly, he had a monoclonal gammopathy on SPEP, which was unexpected given polyclonal hypergammaglobulinemia is typically seen with AIH. Immunofixation electrophoresis revealed elevated kappa/lambda ratio with negative bone survey and bone marrow biopsy leading to MGUS diagnosis. Three months later, he was readmitted with similar complaints and worsened liver dysfunction. Prednisone had been rapidly tapered within days of discharge due to PCP concerns, yet the patient had demonstrated improvement in transaminases until reengaging in moringa, ginseng, and turmeric herbal teas. Biopsy revealed progression to severe portal and lobular hepatitis with numerous plasma cells and stage 3/4 patchy bridging fibrosis. Serologies were now positive for AMA and ASMA, both 1:160. Patient was started on Methylprednisolone and Azathioprine, given normal TPMT, with labs essentially unchanged for 1 week. He then underwent a 5 day course of plasmapheresis (PLEX) as salvage therapy with downtrend in transaminases before discharge with Prednisone, Azathioprine, Tacrolimus, and Ursodiol. Discussion: Phenotypically, AIH and DILI are challenging to differentiate. Also difficult to determine is when drugs contribute to or reveal an underlying AIH, as we suspect occurred here. Drug-induced AIH has high relapse frequency post-corticosteroid withdrawal, especially when rechallenged, and this patient was given strict instructions not to consume herbal teas given concerns for disease progression. While PLEX is not a standard treatment for AIH, there are some studies indicating benefit, as seen with our patient who has been doing well since discharge.

S2867 Turmeric-Induced Hepatitis

Introduction: Dietary supplementation use has been on an exponential rise for the past few years. Turmeric is one of the most used, with curcumin being its major active ingredient. Recently, cases of turmeric induced autoimmune hepatitis as well as herbal induced liver injury (HILI) have been documented. We present a case of turmeric induced hepatotoxicity in a 64-year-old female. Case Description/Methods: A 64-year-old female with a history of hypertension, presents with jaundice and abdominal discomfort. Vitals were normal. Exam showed scleral icterus with an unremarkable abdominal exam. Lab findings revealed a normal CBC, INR, and a negative blood alcohol level, a total bilirubin of 13.6 mg/dl with a direct bilirubin of 9.2 mg/dl, an ALP of 248 IUnits/L, a GGT of 616 Units/L, an AST of 2789 IUnits/L, and an ALT of 3296 IUnits/L. Hepatitis panel with HEV were negative. ANA, AMA, ASMA, tTg antibody, Ig levels, TSH, and T4 were all negative or within normal limits. Patient had a normal iron saturation, negative ceruloplasmin, Tylenol and ASA levels. COVID19 PCR test was negative. CT abdomen/pelvis was non-diagnostic. An EGD/EUS/ERCP showed a mildly thickened gallbladder wall. Liver biopsy showed portal and lobular hepatitis with spotty necrosis, without evidence of an autoimmune process, suggesting a drug induced liver injury. Patient then admitted to the use of turmeric in the past 3-4 weeks. Turmeric was discontinued and patient’s lab values normalized within 1 month. Discussion: Turmeric has been used for thousands of years as a spice, and has been linked to antioxidant, anti-inflammatory and anti-cancer effects. Clinical studies have popularized its use for patients with immune disorders such as autoimmune thyroiditis, and rheumatoid arthritis, despite the associated risk of autoimmune hepatitis in such patients. Curcumin is the major active ingredient in turmeric, however when taken alone, it has a poor bioavailability, with extensive 1st pass metabolism. Turmeric contains Piperine (a black pepper extract), that augments and increases curcumin doses up to 2000-fold by inhibiting hepatic drug-metabolizing enzymes. Multiple RCTs have studied the safety of curcumin showing minimal side effects. In 2013, HILI accounted for 20% of drug-induced liver injury cases. Liver enzymes resolve within 1 month of discontinuation. Due to turmeric’s possible increased risk for hepatotoxicity, clinicians should highlight this to their patients and make them aware of the potential risks that exist when using turmeric.Figure 1.: 400x H&E stain): The portal areas are expanded by predominantly lymphocytic inflammation with scattered eosinophils and rare plasma cells. Figure 2 (400 x PAS): There is spotty necrosis. There is no steatosis, ballooned hepatocytes, granulomas, or viropathic changes. Figure 3 (400x): The Reticulum stain shows a mild increase in portal/periportal fibrosis.Table 1.: RUCAM (Roussel Uclaf Causality Assessment Method) Score: Method for detecting drug-induced liver injury or herb-induced liver/hepatocellular injury (modified) ALT: Alanine Transaminase, AST: Aspartate Transaminase, EBV: Epstein-Barr Virus, HSV: Herpes Simplex Virus, VZV: Varicella-Zoster Virus, PSC: Primary Sclerosing Cholangitis.

S2900 Autoimmune Hepatitis Presenting as Hemophagocytic Lymphohistiocytosis

Introduction: Hemophagocytic Lymphohistiocytosis (HLH) is rare syndrome characterized by a systemic macrophagocytic process triggered by excessive cytokine and immune activation. We present a case of fulminant autoimmune hepatitis leading to HLH. Case Description/Methods: A 30 year old African American woman was admitted with nausea, vomiting, low grade fevers, and abdominal pain for 4 days. Home medications included 3 days of amoxicillin with acetaminophen 2 g daily for dental infection. She denied heavy alcohol use, illicit drug use, and herbal supplementation. Comprehensive laboratory investigation shown on Table 1. Hepatitis A, B, C, E , CMV, EBV, COVID-19, and pan cultures were negative. Hepatospleenomegaly present. After 3 days of IV NAC, aminotransfereases downtrended to a persistent 400-500's range, however total bilirubin and INR worsened despite Vitamin K administration. Due to clinical suspicion for autoimmune hepatitis, she was started on prednisone 60mg daily. Liver biopsy showed portal and lobular interface hepatitis with focally prominent plasma cells with periportal fibrosis as well as extensive histocyte/macrophage infiltration and activation. Additional labs showed: ferritin 4,014 mg/mL, fibrinogen 94 mg/dL, LDH 1100 U/L, normal triglycerides, elevated IL-2 receptor (6300), and normal NK cell activity. With concern for HLH, a bone marrow biopsy confirmed hypercellular bone marrow with active trilineage hematopoiesis and foci of hemophagocytocytosis. She later developed grade 2-3 hepatic encephalopathy requiring closer monitoring in ICU. Liver transplant evaluation was initiated, but fortunately her clinical status improved with continued steroid use. Azathioprine 50 mg was subsequently started with steroid taper. Her current hepatic function panel remains normal with azathioprine monotherapy. Discussion: HLH has a wide range of clinical presentations, making it difficult to diagnose promptly. The disease has a quick progression and carries a high mortality. HLH subtypes are classified into genetic and acquired etiologies. HLH can be triggered by infections, autoimmune processes, malignancy, and organ transplant with immunosuppressant use. She met 6 of 8 diagnostic criteria, based on the HLH 2004 trial. Although liver failure can be a manifestation of HLH, autoimmune hepatitis likely incited her macrophage activation syndrome. HLH should remain on the differential for patients with unexplained pancytopenia, hepatospleenomegaly, hyperferritinemia, and fevers. (Figure Presented).

Long-term follow-up of portal vein thrombosis in an American Cocker Spaniel with lobular dissecting hepatitis: a case report

BackgroundLobular dissecting hepatitis (LDH) is a rare form of canine liver cirrhosis that may be accompanied by portal hypertension in American Cocker Spaniels. In human patients with liver cirrhosis, portal vein thrombosis (PVT) is a common complication. However, PVT has not been reported in dogs with LDH. Herein, we describe the long-term follow-up of PVT in an American Cocker Spaniel with LDH.Case presentationAn 8-year-old neutered male American Cocker Spaniel presented with a 1-month history of severe abdominal effusion. The dog was histopathologically diagnosed with LDH and treated with low-dose prednisolone on day 14. On day 115, computed tomography angiography (CTA) confirmed the presence of a thrombus in the portal vein. Therefore, the dog was subcutaneously administered with the anticoagulant dalteparin, and low-dose prednisolone was continued. As a follow-up for PVT, CTA examinations were performed on days 207, 515, 886, and 1168, and the dog’s antithrombin and D-dimer levels were measured. Following anticoagulant therapy, the dog was confirmed to have gradually increased antithrombin activity and decreased D-dimer concentrations. In addition, although the thrombus was confirmed to be in the same area of the portal vein system by CTA, atrophy and increased CT values due to organization were observed during the follow-up period. The dog’s condition remained stable without clinical signs until day 1112 when it developed hepatic encephalopathy. The dog died on day 1208. On postmortem examination, histopathologically, the liver showed marked bile duct hyperplasia and fibrosis with chronic thrombus in the portal vein.ConclusionsThis case demonstrated that low-dose glucocorticoid combined with dalteparin allowed long-term follow-up of PVT in an American Cocker Spaniel with LDH.

Histological Patterns of Hepatitis and Cholangitis

Histological Patterns of Hepatitis and Cholangitis

A case with hepatic immune-related adverse events caused by nivolumab exhibiting impaired accumulation of regulatory T cells

Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.

A205 PEMBROLIZUMAB ASSOCIATED SCLEROSING CHOLANGITIS RESPONDS TO COMBINATION OF STEROIDS AND MYCOPHENOLIC ACID: A CASE REPORT

Abstract Background Pembrolizumab is a check point inhibitor that targets programmed cell death receptor ligand 1 (PD-L1). However, check-point inhibitors are associated with its characteristic adverse event know as immune related adverse events that can affect a myriad of organ systems. In the hepatobiliary system, the most commonly described iRAE is hepatitis/hepatotoxicity and latest oncology guidelines offer recommendations on treatment and followup of immunotherapy related hepatitis (1). However, a more rare presentation of iRAE, that have only been described as case reports or case series, is secondary cholangitis. We report one of such a case. Aims Case report Methods Case report Results The patient is a 55 year-old Caucasian female know for lung adenocarcinoma presented to the emergency room on May 5th, 2020, having received her 8th cycle of pembrolizumab. Her blood works mildly elevated transaminitis; ALT 78 U/L, AST 11 U/L, alkaline phosphate of 130 U/L, and total bilirubin of 3.5 umol/L. MRI of the abdomen showed a normal appearing liver without focal parenchymal lesion, no biliary stones or obstructing masses, dilated common bile duct at 11 mm with small pericholecystic free fluid, and normal gall badder thickness of 2 mm. There was also notion of minimally prominent intrahepatic biliary radicles seen within the CBD. Etiology workup of cholestatic transaminitis was negative. A diagnosis of immunotherapy related sclerosing cholangitis was posed and the patient was treated with MMF and prednisone with good response. Conclusions Discussion This patient seems to have developed immunotherapy mediated cholangitis. Liver biopsy when performed in liver injury tend to show lobular hepatitis, with liver parenchyma infiltrated with lymphocytes and focal necrosis with acidophilic bodies. However, there seems to be another, less frequent pattern of injury described with pembrolizumab and associated with cholangiopathy, resembling primary biliary cholangitis. It is characterized with portal tracts enlarged with fibrosis and inflammatory cells infiltration; infiltrating cells are lymphocytes (2). Biliary epithelium with fibrosis with CD8+ T cells infiltration seem to be recurrently reported in case reports. (3, 4). Other cases have been describe in the literature. In many cases, steroid therapy was attempted, but response rates seem to be inconsistent. Nivolumab related cholangitis have been also been described and characterized by extra hepatic bile duct dilatation along with negative immunological markers such as ANA and IgG4 in patients with non-small cell lung cancer, and seems to respond only moderately to steroid therapy (6). Retrospective data of nivolumab related cholangiopathy seems to suggest that there is favourable response to the combination of MMF and steroid therapy (7). Funding Agencies None