Hepatocyte Dropout Research Articles

Selpercatinib-induced hepatotoxicity: A rare case report

Abstract Introduction/Objective Selpercatinib (Retevmo) is a highly selective rearranged during transfection (RET) kinase inhibitor indicated for treatment of solid tumors with RET gene mutation or fusion, such as medullary thyroid carcinoma or non-small cell lung carcinoma. Among selpercatinib’s side effects, severe hepatotoxicity was only seen in 3% of the patients. Here we report a case of selpercatinib-induced hepatotoxicity, which has not been well characterized before. Methods/Case Report The patient was a 56-year-old female who had medullary thyroid carcinoma with RET M918T mutation (pT3aN1b) status post total thyroidectomy. Recurrence occurred and selpercatinib treatment was initiated. Then the patient complained of mouth sores, tongue sensitivity, and lower extremity cramping. The dosage was reduced to half. The magnetic resonance imaging on day 67 of selpercatinib treatment showed heterogeneous enhancement in the right hepatic lobe, compatible with parenchymal liver disease/hepatitis, trace perihepatic ascites, and mild splenomegaly. On day 71, liver function abnormalities were detected (ALK 315 IU/L, ALT 745 IU/L, AST 899 IU/L, total bilirubin 7.7 mg/dL). Workups including autoimmune hepatitis serology, viral hepatitis, or other infections were all negative. She had no history of other drug use. On day 72, a liver biopsy was performed that demonstrated mild to moderate portal lymphocyte-predominant mixed inflammation with interface activity. The lobules showed marked inflammation with hepatocyte disorganization, acidophil bodies, hepatocyte dropout, and rare lipogranulomas. Bile duct injury and patchy canalicular cholestasis were also noted. Trichrome stain showed focal bridging fibrosis. Overall, the histologic findings were acute and chronic hepatitis pattern injury, favor selpercatinib-induced hepatotoxicity. Selpercatinib was discontinued. All liver enzymes gradually returned to normal levels on day 169. Results (if a Case Study enter NA) NA Conclusion Our study suggests that screening patients for abnormal liver function tests prior to and monitoring periodically during selpercatinib treatment is necessary. Based on the severity of hepatotoxicity, withholding, reducing the dose, or permanently discontinuing selpercatinib is recommended.

Successful living-donor liver transplantation for sustained liver failure even after resolution of infiltrative massive hepatic invasion of stage 4S neuroblastoma: a case report

BackgroundNeuroblastoma is the most common extracranial solid tumor in childhood. Stage 4S neuroblastoma is a unique subset of neuroblastoma characterized by a favorable course and potentially low malignancy with a high rate of spontaneous tumor regression. However, recent reports have shown that there is a subgroup of patients with stage 4S neuroblastoma characterized by MYCN amplification, chromosomal aberrations, age of < 2 months at diagnosis, and significantly poorer outcomes.Case presentationA 1-month-old male infant with a huge abdominal tumor was transferred to our hospital and diagnosed with stage 4S neuroblastoma. The patient showed respiratory distress due to abdominal compartment syndrome secondary to massive hepatic invasion, and he required a silo operation and mechanical ventilation. After chemotherapy using carboplatin and etoposide, the infiltrative massive hepatic invasion was resolved and the abdominal compartment syndrome gradually improved; however, liver dysfunction as evidenced by hyperbilirubinemia, coagulopathy, and hyperammonemia continued. At the age of 3 months, living-donor liver transplantation was performed for treatment of sustained liver failure using a reduced lateral segment graft from the patient’s father. Post-transplant liver function recovered immediately. Examination of the explanted liver demonstrated that the majority of liver tissue had been replaced by fibroblastic cells after massive hepatocyte dropout. There were only small areas of residual neuroblastoma cells in the liver specimen. The patient was discharged from the hospital 5 months after transplantation with home intermittent respiratory support. At the time of this writing (23 months after liver transplantation), he was in good condition with no signs of recurrence of neuroblastoma.ConclusionsWe have herein presented a case of successful pediatric living-donor liver transplantation for sustained liver failure even after resolution of infiltrative massive hepatic invasion of stage 4S neuroblastoma. Our case clearly shows that liver transplantation can be added as an appropriate extended treatment option for liver failure after resolution of stage 4S neuroblastoma.

Unique Morphologic Findings in the Liver After Stereotactic Radiation for Cholangiocarcinoma.

Newer radiotherapy techniques, such as stereotactic body radiation, have been increasingly used as part of the treatment of cholangiocarcinomas, particularly as a bridge to liver transplantation. Although conformal, these high-dose therapies result in tissue injury in the peritumoral liver tissue. This retrospective study characterized the morphologic changes in the liver after stereotactic body radiation in a series of liver explant specimens with perihilar cholangiocarcinoma. The morphologic changes in the irradiated zone were compared against the nonirradiated background liver parenchyma to control for chemotherapy-related changes. Of the 21 cases studied, 16 patients (76.2%) had underlying primary sclerosing cholangitis, and 13 patients (61.9%) had advanced liver fibrosis. The average duration between completion of radiotherapy and liver transplantation was 33.4 weeks (range: 6.29 to 67.7). Twelve patients (57.1%) had no residual tumor in the liver. The most frequent histologic changes in the peritumoral irradiated liver tissue were sinusoidal congestion (100%), sinusoidal edematous stroma (100%), and hepatocellular atrophy (100%), followed by partial/complete occlusion of central veins (76.2%), sinusoidal cellular infiltrates (76.2%), and hepatocyte dropout (66.7%). The findings in the radiated areas were more extensive than in the background liver ( P <0.01). Sinusoidal edematous stroma was striking and dominated the histologic findings in some cases. Over time, there was less sinusoidal congestion but more hepatocyte dropout (r s =-0.54, P =0.012 and r s =0.64, P =0.002, respectively). Uncommon findings, such as foam cell arteriopathy in the liver hilum, were also observed. In summary, postradiation liver specimens have distinctive morphologic findings.

S2958 Do Not Trust the Internet: Acute Liver Failure Secondary to DILI From Online Hormones Versus Stimulant Use in a Transgender Patient

Introduction: Approximately half of acute liver failure cases in the United States are from drug-induced liver injury (DILI), a process modulated by the interplay between host, environment, and agent. Here, we present a case of DILI from unsupervised feminizing hormones versus stimulant use. Case Description/Methods: A 27 year old transgender (M to F) woman with history of anxiety, depression, and attention deficit hyperactivity disorder (ADHD) presented with 3 weeks of jaundice, abdominal discomfort, acholic stools, and memory issues after consuming several drugs purchased from international websites. Due to severe anxiety, she did not seek endocrinology evaluation for hormone guidance, instead ordering estrogen and anti-androgen therapy to transition on her own. She had been on estradiol for 5 years and cyproterone acetate intermittently for 4 years, restarted 9 months prior with N-methyl cyclazodone for ADHD. All 3 agents were discontinued at the onset of jaundice, but she then began copious water and laxative intake—“to flush the bilirubin out of [her] body”—along with that of milk thistle and delta-8 THC extract. Pertinent labs included AST 485, ALT 668, T. Bili 52.8, AP 140, INR 3, and K of 2.3. Chronic liver disease workup was negative. Biopsy revealed severe hepatocyte dropout with associated marked cholestasis and mixed portal inflammatory cell infiltrate including eosinophils, features consistent with DILI (Figure). Hospital course involved hematemesis, spontaneous bacterial peritonitis, Ogilvie’s syndrome, acute tubular necrosis requiring continuous renal replacement therapy, paraphimosis, and, ultimately, acute liver failure. Given severely compromised hepatic function with transplant the only option for viable recovery, patient was listed as category 1a with a MELD score of 37. She underwent orthotopic liver transplantation complicated by hemorrhage from a vein near the porta hepatis, which was repaired. She was started on tacrolimus, mycophenolate, prednisone, fluconazole, valganciclovir, and bactrim with recommendations to defer hormone replacement therapy for 1 year post-transplant. Discussion: Those with gender dysphoria may turn to the internet to relieve the distress caused by mismatch between biological sex and gender identity. Unfortunately, the online market is rife with unregulated information and products. In consuming such, physician supervision is imperative, and lack thereof lead our self-medicating patient to incur multiorgan insult, notably dire hepatic dysfunction requiring transplant.Figure 1.: Patient’s histopathology with hematoxylin and eosin staining (A) versus trichrome staining (B) demonstrating severe hepatocyte dropout with inflammatory cell infiltrate.

S3014 Hepatotoxic Effects of Whey Protein Supplementation

Introduction: Currently, more than 50% of Americans take dietary supplements. Whey is a commonly used protein supplement that is often viewed as safe, with only rare reports of drug-induced liver injury (DILI). Here, we report an unusual case of severe liver injury following whey protein consumption. Case Description/Methods: A 40-year-old female with obesity and well-controlled hypothyroidism presented with 3 days of nausea and painless jaundice. Her only home medication was levothyroxine. Two months prior, she began drinking whey protein shakes (each containing 20 grams of protein) twice daily to aid with weight loss. She denied use of alcohol, recreational drugs, herbal supplements, and recent medication changes. On physical exam, she was alert and oriented x4, with jaundice and scleral icterus present. Lab work was significant for ALT 2,502, AST 1,434, total bilirubin 11.0, INR 1.42, and platelets 217,000. Acetaminophen and salicylate levels were unremarkable. Her whey protein supplementation was immediately stopped and a workup for transaminitis was initiated. RUQ ultrasound was unremarkable. Evaluation for other causes of acute liver injury, including viral hepatitis (A, B, C, E), EBV, CMV, HIV, hemochromatosis, Wilson’s disease, and autoimmune hepatitis was unremarkable. A liver biopsy was performed, with pathology showing diffuse ballooning degeneration of hepatic parenchyma, numerous acidophil bodies, and dominant pericentral hepatocyte drop-out. A diagnosis of DILI (with predominant hepatocellular injury) was made. Following discontinuation of whey protein supplementation, the patient’s labs and clinical symptoms improved, and she was discharged home on hospital day 8. Discussion: This case highlights a rare occurrence of DILI secondary to whey protein consumption and emphasizes the importance of taking a thorough history when working up liver injury. Furthermore, in the treatment of DILI, we recommend cessation of all possible offending agents that were recently started, including supplements that are reputably marketed to be safe for consumption.

Centrizonal hepatocyte dropout in allograft liver biopsies: a clinicopathological study.

Centrizonal hepatocyte dropout has been described in diverse liver pathologies, including viral hepatitis, venous outflow obstruction, and allograft cellular rejection. However, its clinical significance remains uncertain. We designed a clinicopathological study of 206 allograft liver biopsies with centrizonal hepatocyte dropout. Centrizonal hepatocyte dropout was associated most frequently with cellular rejection (n = 62), asymptomatic/protocol biopsies (n = 56), immediate post-transplantation biopsies (n = 21), biliary obstruction (n = 14), and viral hepatitis (n = 13). The differential diagnosis is informed by timing post-transplantation, biliary imaging and laboratory test results. 'Cholestatic' and 'hepatocytic' laboratory patterns were associated with biliary obstruction and cellular rejection, respectively. A mixed pattern peaking after biopsy was observed in viral hepatitis cases. In the context of cellular rejection, dropout was not associated with the time interval to normalisation of serum alanine aminotransferase (ALT), but was associated with shorter transplant-free survival (hazard ratio 4, P = 0.01) than that of histological severity-matched controls. In time zero allograft biopsies, time to ALT normalisation was prolonged (median, 15 versus 11 days, P = 0.002) in allografts with centrizonal dropout, with no effect on retransplant-free survival. Centrizonal hepatocyte dropout has low clinicopathological diagnostic specificity. However, it correlates with adverse clinical outcomes in allograft cellular rejection and time zero biopsies.

Liver histology in short telomere syndrome: A case report and review of the literature

Abstract Introduction/Objective Short telomere syndrome (STS) is a genetically inherited syndrome resulting in premature telomere shortening. STS encompasses a spectrum of clinical manifestations, including dyskeratosis congenita, premature hair graying, bone marrow failure, immunodeficiency, pulmonary fibrosis and liver disease. Liver histopathologic features in STS patients have not been well characterized. Methods/Case Report A 46-year-old man presented for dyspnea and cryptogenic cirrhosis. He had a complicated medical history significant for immune thrombocytopenic purpura and splenectomy, recurrent respiratory tract infections, pneumonia, sepsis, primary immunodeficiency, pulmonary mucosa-associated lymphoid tissue lymphoma, and severe hepatopulmonary syndrome. He and his brother had gray hair in their late 20s. He also had a long history of intermittently elevated liver enzymes starting at age 33. A liver biopsy performed 12 years before showed chronic portal inflammation with hepatocellular damage without significant fibrosis. These clinical manifestations prompted an evaluation for a possible telomere biology disorder, which revealed the telomere length was critically short and fell at or below the first percentile for age, supportive of the diagnosis. The most recent liver biopsy showed marked portal lymphocytic inflammation with interface hepatitis, bile ductular reaction and frequent foci of lobular inflammation with focal hepatocyte dropout. Some hepatocytes around the portal tracts were swollen with feathery degeneration and occasional Mallory-Denk bodies. A Rhodanine stain highlighted copper granules in the periportal hepatocytes, suggesting chronic cholestasis. Trichrome and reticulin stains demonstrated portal/periportal/pericellular/perisinusoidal fibrosis and focal bridging fibrosis. Results (if a Case Study enter NA) NA Conclusion Partly due to the rarity of STS and the risk of bleeding associated with biopsies, liver histology was described in only few limited studies with small samples of STS patients, including inflammation, nodular regenerative hyperplasia, steatohepatitis, hemosiderosis, cholestasis, cirrhosis, and large cell change of hepatocytes. Our case and others suggest liver disease associated with STS demonstrates a spectrum of histopathology. Being aware of these histomorphologic features in STS is important for establishing the correct diagnosis.

S2668 Sorafenib-Induced Autoimmune Hepatitis: A Case Report,

Introduction: Drug-induced liver injury (DILI) with autoimmune hepatitis-like features (DIAIH) is a specific phenotype of DILI with clinical features indistinguishable from de-novo autoimmune hepatitis (AIH). We describe a case of DIAIH due to Sorafenib. Case Description/Methods: A 61-year-old man and teetotaller presented with 1-week history of jaundice and malaise. He was on Atorvastatin 40mg daily for 4 years for hyperlipidaemia. Sorafenib was recently initiated six weeks ago for recurrent sarcoma of the left thigh. Clinical examination was unremarkable apart from scleral icterus. Liver function test (LFT) showed severe hepatocellular (HC) injury (bilirubin 4.56 mg/dL, alkaline phosphatase 190 U/L, alanine transaminase 1004 U/L, aspartate transaminase 790 U/L peak INR 1.53). Viral hepatitis screening, AIH specific antibodies and abdominal imaging were unremarkable. Serum IgG was raised (18.6 g/L). Liver biopsy was supportive of DILI and AIH histological features were also noted (Fig.1a-f). Simplified AIH score was 6. Roussel Uclaf Causality Assessment Model (RUCAM) score was 9 for Sorafenib and 6 for Atorvastatin. Diagnosis of Sorafenib-induced AIH was made. His LFT improved spontaneously with normalization of LFT eight weeks after stopping Sorafenib. Discussion: Sorafenib often causes idiosyncratic DILI with mild elevation of transaminases. However, it rarely causes severe DILI and has no known association with DIAIH, unlike Atorvastatin and immune checkpoint inhibitors (e.g Nivolumab and Atezolizumab). To our knowledge, this is the first case report of DIAIH due to Sorafenib. In patients with severe DILI or DILI with probable AIH based on AIH scoring, liver biopsy should be considered for evaluation. However, differentiating DIAIH from de-novo AIH is often challenging as both present with HC injury, may have positive AIH specific antibodies, raised serum IgG and share similar histological findings. The key distinguishing features are the history of drug exposure within a time frame and no requirement for long term immunosuppressant. DIAIH may resolve spontaneously after stopping culprit drug. Corticosteroids should be initiated in cases without improvement upon drug cessation. In DIAIH requiring corticosteroids, relapse is rare after stopping corticosteroids and long-term immunosuppression is rarely needed. In conclusion, DIAIH should be considered in patients who present with severe HC DILI. Differentiating DIAIH from AIH is crucial as the former rarely requires long term immunosuppression.Figure 1.: Liver biopsy specimen [a] H&E 200X: A portal tract, zone 1, showing moderate chronic inflammation with interface damage and rare bile droplets. [b] H&E 200X: Lobulitis characterized by aggregates of plasma cells, swollen hepatocytes and rosetting within liver parenchyma zone 2. [c] H&E 200X: Centrilobular region zone 3 showing hepatocyte drop-out, aggregates of plasma cells, rosetting and bile pigment. Reticulin [d, 40X] and Sirius Red [e, 40X] special stains show collapse with mild early young fibrosis without elastic fibers demonstrated on Orcein [f, 40X], consistent with subacute injury. Overall, the appearances are supportive of subacute DILI in association with features suggestive of AIH (i.e. interface damage, plasma cell aggregates and resetting).

S2792 Marked Elevation in Serum Aminotransferases in Immune-Mediated Necrotizing Myopathy

Introduction: This is an elderly female diagnosed with immune-mediated necrotizing myopathy with marked elevations in serum aminotransaminases. Case Description/Methods: A 71 year old female was admitted for progressive proximal muscle weakness and lower extremity myalgia with an initial creatinine kinase (CK) of 10,520U/L concerning for rhabdomyolysis. Gastroenterology was consulted given an elevation in liver-associated enzymes in a hepatocellular injury pattern (AST 552U/L and ALT 653U/L) thought to be due to muscle breakdown. After a few days of intravenous fluids, the myalgias continued and her CK remained elevated. Rheumatology was consulted and an MRI of the extremities was pursued revealing T2 hyper-intensity and enhancement in multiple muscle segments concerning for an inflammatory myopathy. A muscle biopsy was obtained along the right thigh confirming an inflammatory change with necrotic muscle fibers. Furthermore, an anti-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) returned strongly positive ( >200U). Her atorvastatin 10mg PO qHS was discontinued. Chronic liver disease serologic evaluation resulted in a positive anti-smooth muscle antibody (ASMA) and an immunoglobulin G (IgG) level of 1218mg/dL. Given the concern for a concomitant autoimmune hepatitis, an EUS-guided liver biopsy was pursued which showed centrilobular hepatocyte drop-out with associated moderate mixed inflammation, increased iron deposition (2+ out of 4), with patchy mild fibrous portal expansion with rare periportal fibrosis without features consistent with autoimmune hepatitis and were thought to be due to the underlying immune-mediated necrotizing myopathy (IMNM). She was diagnosed with anti-HMGCR myopathy and was started on a course of prednisone. After 1 month of corticosteroid therapy and one week of azathioprine, her LAEs remained elevated (AST 577U/L and ALT 645U/L) and she continued to be symptomatic with worsening weakness. Rheumatology will be initiating a course of intravenous immunoglobulin G (IVIG) given the failure to respond to corticosteroid and thiopurine combination therapy. Discussion: This is a rare example of markedly elevated liver enzymes in a hepatocellular injury pattern of greater than 20 times the upper limit of normal mimicking autoimmune hepatitis in association with IMNM refractory to corticosteroid and thiopurine combination therapy. Salvage therapy with intravenous immunoglobulin G (IVIG) will be started by rheumatology. Liver enzyme levels are expected to downtrend with improvement in CK.Figure 1.: The top of the image illustrates centrilobular hepatocyte drop-out with associated inflammation including plasma cells and ceroid laden macrophages. Contrast these changes with the normal portal tract in the bottom portion of the image. (400X magnification).

Clinicopathologic Characteristics of Centrilobular Injury in Pediatric Liver Transplantation.

Centrilobular injury (CLI) is defined as the presence of perivenular mononuclear inflammation, hepatocyte dropout, and extravasated erythrocytes. In pediatric liver allografts, CLI has been associated with advanced fibrosis and chronic rejection (CR). We sought to better characterize the clinicopathologic features of CLI in the setting of T cell-mediated rejection (TCMR) and its association with complement component 4d (C4d) deposition. A total of 206 posttransplant pediatric patients (491 allograft liver biopsies) were available from 2000 to 2018, of which 63 patients (102 biopsies) showed evidence of TCMR and were included in the study. Of the patients, 35 (55.6%) had CLI on their initial episode of TCMR; those patients with CLI were significantly associated with the type of immunosuppression treatment (P=0.03), severity of TCMR (P<0.001), higher gamma-glutamyltransferase (P=0.01), and advanced fibrosis (P=0.03). There was a trend to shorter time interval from transplantation to presentation of CLI compared with those without CLI (P=0.06). No difference was observed in graft or overall survival in the patients with CLI. In 20 patients with CLI, additional biopsies were available; in 45% of these patients, CLI was a persistent/recurrent finding. C4d deposition was noted in 12% of all biopsies (6 patients) with CLI. No significant correlation was noted in C4d deposition and CLI, CR, or graft/overall survival. In conclusion, CLI, although not significantly associated with worse graft survival, was significantly associated with severe TCMR and degree of fibrosis, which highlights the importance of active clinical management and follow-up for these patients.

15. Incidence, Significance and Outcome of Ischemia-reperfusion Injury in 1113 Living Donor Liver Transplants

Background and Aims: Ischaemia–reperfusion injury (IRI) after liver transplant is a dynamic process that involves two interrelated phases of local ischaemic insult and inflammation-mediated reperfusion injury and has an impact on morbidity and mortality. Majority of data on IRI comes from the deceased donor liver transplantation setting. Our aim was to analyse the incidence, risk factors and outcomes of IRI in our living donor liver transplantation (LDLT) series. Methods: A retrospective analysis of prospectively collected data of patients undergoing LDLT from January 2013–November 2017 was performed. Among those who developed graft dysfunction in the early post-transplant period (3 months), analysis of patients with histopathology proven IRI (hepatocyte dropout, microvesicular steatosis and cholestasis in zone 3) was performed. Results: Among 1113 patients undergoing LDLT, 7 (6.28%) had IRI (49 males; 21 females, mean age 46.79±9.6 years). IRI was diagnosed at 14.23±13.62 days post-transplantation. Etiology of chronic liver disease was alcohol in 17, cryptogenic in 17, hepatitis C in 12, hepatitis B in 9 and others in 15. Mean MELD and CTP scores were 17.84±7.06 and 9.48±2.12 respectively. The overall mortality rate among patients with IRI was high (37.14%). Patients who did not survive had lower graft-recipient weight ratio (GRWR) (0.87±0.16 vs 0.97±0.19; p = 0.025), longer anhepatic phase (217.2±126.19 vs 166.37±52.49 min; p = 0.023), longer warm ischemia time (55.75±24.01 vs 46.07±12.14 min; p = 0.033), higher serum bilirubin (9.32±4.63 vs 5.76±4.8 mg/dl; p = 0.003), lower haemoglobin (8.65±1.4 vs 9.44±1.39 g/dl; p = 0.025), higher serum creatinine (1.18±0.58 vs 0.7±0.23 mg/dl; p < 0.0001) and longer hospitalisation time (27.88±15.16 vs 19±8.68 days; p = 0.002). Non-survivors also had higher incidence of Cytomegalovirus (CMV) infection (65% vs 41%; p = 0.047) and sepsis (77% vs 54%; p = 0.061) (Table 1). On univariate analysis, length of hospitalisation, GRWR, anhepatic phase, haemoglobin, serum bilirubin, serum creatinine and CMV infection were significant factors predicting mortality. Serum creatinine remained significant on multivariate analysis. Conclusions: IRI adversely affects survival and should be considered in the differential diagnosis of early graft dysfunction in the LDLT setting.Tabled 1Table 1: Comparison between survivors and non survivors of IRISurvivors (n = 44)Non survivors (n = 26)p valueChild-Turcotte-Pugh score9.34 ± 2.369.73 ± 1.610.427MELD score17.41 ± 7.0918.61 ± 7.110.520Graft-Recipient Weight Ratio0.97 ± 0.190.87 ± 0.160.025Anhepatic phase (minutes)166.37 ± 52.49217.2 ± 126.190.023Cold Ischemia Time (minutes)113.98 ± 39.44127 ± 55.710.272Warm Ischemia Time (minutes)46.07 ± 12.1455.75 ± 24.010.033Small for size6 (13.63%)4 (15.38%)0.975Cytomegalovirus infection18 (41%)17 (65%)0.047Hospital Days19 ± 8.6827.88 ± 15.160.002 Open table in a new tab The authors have none to declare.

HIV and Autoimmune Hepatitis: A Case Series and Literature Review

Liver disease is the leading cause of non-AIDS related morbidity and mortality in human immunodeficiency virus (HIV) infected patients. There are many causes of liver disease in these patients, most commonly co-infection with viral hepatitis or alcoholic liver disease. A far less commonly described entity is autoimmune hepatitis (AIH) in HIV patients. The relationship between HIV and autoimmune diseases is well-described in a few conditions such as systemic lupus erythematosus and diffuse infiltrative lymphocytosis syndrome; however, patients with HIV who subsequently develop autoimmune hepatitis (AIH) has rarely been described in the existing literature. Managing these coexisting morbidities requires careful monitoring, as treating AIH requires the further immunosuppression of an HIV-infected individual. Herein, we present two patients who were diagnosed with and treated for AIH while receiving concurrent highly active anti-retroviral therapy. This case series provides treatment outcome data for a situation that has heretofore been rarely reported.Figure: A. Liver biopsy from case patient #1. On left, fibrous septum containing a dense lymphoplasmacytic inflammatory infiltrate with prominent interface and lobular activity. 100x; hematoxylin and eosin. On right, dense plasma cell-rich infiltrate and an area of hepatocyte drop-out at the interface. 400x; hematoxylin and eosin. Biopsy is compatible with autoimmune hepatitis. B. Liver biopsy from case patient #2. On left, dense portal lymphoplasmacytic inflammation with prominent interface and lobular activity. 100x; hematoxylin and eosin. On right, lobular lymphoplasmacytic inflammation with hepatocyte rosette formation. 400x; hematoxylin and eosin. Biopsy is typical for autoimmune hepatitis.Figure: A timeline that plots patient liver function tests in relationship to initiation of autoimmune hepatitis (AIH) targeted therapy. Both patients were started on prednisone. Patient CD4 counts (cells/mL) are also shown.Table: Table. A review of the existing literature on patients with HIV who developed AIH. CD4 count is in cells/microliter and viral load is in copies/microliter

Budd-Chiari Syndrome and Portal Vein Thrombosis in Crohnʼs Disease

Introduction: Untreated Crohn's disease (CD) is a prothrombotic state associated with venous thromboembolism and can present with portal vein thrombosis, deep venous thrombosis and pulmonary embolism (PE). There are a handful reported cases of CD presenting as hepatic vein thrombosis or Budd-Chiari syndrome. Case description: A 27 year old male presented with hematochezia, abdominal pain, anasarca with ascites, fatigue and hepatomegaly. A year prior to presentation he developed hematochezia and was seen at a different hospital where he underwent colonoscopy that was suggestive of inflammatory bowel disease but was lost to follow up and remained untreated and continued to have intermittent hematochezia and abdominal pain. On admission his Hb was 5.7 g/dL with elevated ALT (83 U/L) and AST (81 U/L) and albumin of 2.1 g/dL. Stool studies were negative for C difficile toxins, ova & parasites, enteric cultures but positive for leukocytes. Colonoscopy was performed that showed terminal ileitis and pancolitis with rectal pseudopolyp formation. EGD demonstrated duodenal ulcerations and inflammation of pylorus which on biopsy showed non-necrotizing granuloma formation that was consistent with a diagnosis of CD (Figure 1). His hypoalbuminemia was suspected to be due to protein-losing enteropathy from active enterocolitis.Figure 1Paracentesis of the ascitic fluid showed a serum:ascites albumin gradient of >1.4 which suggested portal hypertension. CT scan of abdomen demonstrated hepatomegaly with thrombi in the inferior vena cava, portal vein and right hepatic vein (Figure 2). Liver biopsy showed extensive perivenular sinusoidal dilation, areas of hepatocyte atrophy and drop-out, and mild centrizonal fibrosis (Budd-Chiari syndrome; Figure 3). He was then anti-coagulated with heparin drip and transitioned to apixiban. His anasarca improved with diuretics and CD was treated with prednisone and mesalamine at the time of discharge. Discussion: Active CD is a prothrombotic state that can lead to Budd-Chiari syndrome and subsequent hepatocyte injury as a result of venous congestion. Protein losing enteropathy can develop as a result of untreated CD leading to anasarca and loss of procoagulant factors which further increases the risk of venous thrombosis. Early recognition of thrombotic complications of CD and initiation of anticoagulation is recommended to prevent hepatocyte injury from venous congestion or fatal complications like development of PE.Figure 2Figure 3

Death due to acute fatty liver in pregnancy

Introduction: Acute fatty liver of pregnancy (AFLP) results due to disordered metabolism of fatty acids by mitochondria in the mother, caused by deficiency ofdehydrogenase enzyme. This is a rare instance of a foetus causing metabolic disease in the mother. The ‘working diagnosis’ of the clinicians was HELLP syndrome. The exact cause of death was made clear only after the postmortem examination. Case report : 24 year old primi with 34 weeks of gestation admitted for blood pressure monitoring. She developed jaundice, high blood pressure with proteinurea, marginally elevated liver enzymes, low platelets which warranted termination of pregnancy. Despite the termination of pregnancy, she developed renal failure and hepatic encephalopathy and died on the eleventh day after delivery. Post mortem histopathology of liver revealed that the architecture was not altered and micro-vesicular fat infiltrations in centrilobular and mid zones. Hepatocytes were swollen but inflammation was not evident. Other tissues did not show any fat infiltration. HELLP syndrome was excluded due to absence of macro-vesicular fat infiltration in modest quantities throughout the liver lobules. There were no lobular disarray with hepatocyte dropout, reticulin collapse and portal tract inflammation to suggest viral hepatitis. There were no evidence of drug induced, toxic or viral induced micro-vesicular steatosis. Reye’s syndrome is characterized by uniform micro-vesicular fatty change in the liver and other tissues such as skeletal muscles, kidney and heart. Conclusion: Having excluded all other possibilities, the cause of death was ascertained as AFLP and this emphasizes the value of correct histopathological diagnosis . Medico-Legal Journal of Sri Lanka 2013; 1(2) : 42-45

Atypical Acute Liver Failure in Acute Myeloid Leukemia

Gastroent Question: A 65-yearold white womanwith therapy-related acute myeloid leukemia was admitted to the intensive care unit with altered mental status 33 days after completing induction chemotherapy with azacitadine, high-dose cytarabine, and mitoxantrone. She had a history of breast cancer treated 12 years prior with 4 cycles of cyclophosphamide and doxorubicin, local radiation therapy, and tamoxifen, as well as mantle cell lymphoma treated 6 years prior with bendamustine, rituximab, and radiation therapy to a lytic lesion of the L1 vertebrae. On physical examination, she was afebrile, normotensive (133/89 mmHg), but obtunded. She had scleral icterus as well as mild abdominal distension with minimal ascites. There were no recent additions to her medication list; the only potentially hepatotoxic agent present was prophylactic posaconazole, which had been discontinued several days prior. Her laboratory studies revealed neutropenia (absolute neutrophil count, 90 K/mL) and evidence of acute hepatic dysfunction (aspartate aminotransferase [AST], 4,891 U/L; alanine aminotransferase [ALT], 2,070 U/L; International Normalized Ratio [INR], 3.3). The total bilirubin (TB) was 5.4 mg/dL, alkaline phosphatase (AP) 90 U/L, and serum ammonia 61 mg/dL. There was no serologic evidence of acute varicella zoster or hepatitis A, B, C, D, or E infections. Furthermore, polymerase chain reaction assays for herpes simplex virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, and adenovirus were all negative. Thick and thin blood smears ruled out a transfusion-related trypanosomiasis infection; a urine toxicology screen was unremarkable, and a serum acetaminophen level was <3.0 mg/mL. Abdominal ultrasound revealed hepatomegaly (18.7 cm), ascites, a large right pleural effusion and patent hepatic vasculature. A liver biopsy had been deferred given her coagulopathy and persistent thrombocytopenia (<10 K/mL). Thus, the etiology of her acute hepatic dysfunction remained unknown. Thirteen days later, despite improvements in coagulopathy (INR 1.5), aminotransferases (AST, 68 U/L; ALT, 36 U/L) and mental status, she continued to have worsening cholestasis (TB,16.6 mg/dL; conjugated, 12.6 mg/dL; AP, 175 U/L, which peaked at 492 U/L days later). Thus, a liver biopsy was finally obtained (Figure A, B). What was the elusive etiology of this patient’s acute liver failure? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

An Unexpected Cause of an Infiltrative Liver Mass

Question: A 73-year-old man with history of obesity, diabetes, and recently diagnosed cryptogenic cirrhosis is admitted to the hospital for progressively worsening ascites and altered mental status. He had been living in El Salvador for the past 6 years and had recently returned to the United States. The patient denies significant alcohol use but had a history of obesity throughout his adult life, with a body mass index of >40 kg/m2. The patient’s home medications included Furosemide, spironolactone, and metformin. He reported frequent ingestion of the herb Chipilin (Crotalaria longirostrata). Physical examination revealed icteric sclera, moderate abdominal distention without tenderness, and asterixis. Laboratory studies demonstrated an alanine aminotransferase of 100 U/L, aspartate aminotransferase of 139 U/L, alkaline phosphatase of 138 U/L, total bilirubin of 16.0 mg/dL, albumin of 3.1 g/dL, platelet count of 99,000/UL, and International Normalized Ratio of 2.6. Hepatitis B and C serologies were negative and alpha-fetoprotein level was normal. Magnetic resonance imaging revealed hepatomegaly with a nodular liver contour and without fatty infiltration of the liver. Additionally, diffuse, heterogeneous signal intensity was seen primarily in the right hepatic lobe, with heterogeneous enhancement and washout pattern, suggestive of an infiltrative malignancy (Figure A). The hepatic veins and portal veins were patent (Figure B). A targeted, computed tomography–guided liver biopsy was performed (Figure C, D). Based on the clinical scenario, imaging, and pathologic findings, what is the diagnosis? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Liver biopsy demonstrated changes consistent with hepatic outflow obstruction, including partial central vein obstruction from organizing thrombi (Figure C) and sinusoidal congestion and dilatation with hepatocyte dropout in zone 3 (Figure D). The findings were consistent with sinusoidal obstructive syndrome (SOS). No evidence of malignancy was found on biopsy. The significant degree of hepatic congestion secondary to the venous outflow obstruction can lead to the infiltrative picture seen on imaging.1Mortelé K.J. Van Vlierberghe H. Wiesner W. et al.Hepatic veno-occlusive disease: MRI findings.Abdom Imaging. 2002; 27: 523-526Crossref PubMed Scopus (26) Google Scholar Once the patient was diagnosed with SOS, he was placed on anticoagulation. However, he developed acute renal failure during his hospital course, and per the patient and his family’s wishes, he decided not to undergo dialysis and instead undergo comfort measures only. He died shortly afterward. SOS is a form of acute hepatic injury secondary circulatory to obstruction at the sinusoidal level, often occurring concurrently with central vein obstruction. Associated clinical features include hyperbilirubinemia, ascites, weight gain, and hepatomegaly. Although most commonly seen as a complication from myeloablative conditioning regimens before hematopoietic stem cell transplantation, ingestion of food containing pyrrolizidine alkaloids may also lead to SOS. The patient’s family reported that the patient frequently ingested Chipilin (Crotalaria longirostrata), a plant containing pyrrolizidine alkaloids. Consumption of large amounts of this plant can cause acute SOS, and chronic ingestion of lower doses can lead to a subacute presentation of SOS.2DeLeve L.D. Shulman H.M. McDonald G.B. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease).Semin Liver Dis. 2002; 22: 27-42Crossref PubMed Scopus (550) Google Scholar

Rare Case of Rituximab-associated Hepatitis B Virus Reactivation with Co-existence of IgM Anti-Hepatitis A and IgM Anti-Hepatitis E Antibodies

Purpose: A 68-year-old Caucasian man was seen in the hospital for abnormal LFTs. He carried a diagnosis of HHV-8 related plasmablastic T-cell lymphoma. He had undergone treatment with cyclosporine, doxorubicin, vincristine, and prednisone, with initial remission of disease; however, he developed recurrence and was subsequently treated with rituximab 8 months prior to presentation. Before the initiation of chemotherapy, the patient underwent testing for hepatitis B (HBV), which demonstrated he was HBV surface antigen (HBsAg) negative, anti-HBV surface antibody (anti-HBS) positive, and IgM anti-HBV core antibody (anti-HBc IgM) negative. A total anti-HBV core antibody (anti-HBc total) was not checked prior to starting therapy. On the current admission, total bilirubin was 7.9 mg/dL with conjugated fraction of 4.7 mg/dL. AST was elevated to 830 U/L, ALT to 1591 U/L, and alkaline phosphatase to 189 U/L. Serum ANA was positive at a titer of <1:80 and anti-smooth muscle antibody was negative. Ceruloplasmin was noted at 44 mg/dL. Serologies demonstrated HBsAg to be positive, anti-HBs negative, anti-HBc total positive, anti-HBc IgM positive, HBeAg positive, and anti-HBe negative. HBV PCR found 5.81 Log IU viral particles. Furthermore, his hepatitis A virus (HAV) total antibody was positive, and the anti-HAV IgM antibody was reactive. His anti-hepatitis E virus (HEV) IgM antibody was also detected, and anti-HEV IgG was negative. Hepatitis D antibody was negative. Liver biopsy showed irregular hepatic plates with hepatocyte dropout, peri-portal inflammation, multiple apoptotic bodies, and ballooning degeneration. Stage one to two fibrosis was found. Tenofovir 300 mg daily was started for reactivated HBV, and his AST, ALT, and bilirubin declined to normal 16 weeks later. Acute hepatitis resulting from co-infection with multiple hepatotropic viruses may occur. In some instances, the mechanism by which they are contracted and risk factors for their exposure are shared. In the developing world, several case reports and series have described instances where patients presented with serologic evidence for acute infection from both HAV and HEV. These studies have generally been performed in the setting of sporadic cases with clinical syndromes of acute hepatitis. However, the use of serologic testing to establish diagnoses of acute HAV or HEV in these settings is problematic. Serologic tests were designed for cases in which the pretest probability and clinical suspicion for exposure to acute HEV or HAV were high (i.e., epidemic outbreaks or travel to endemic areas). Whether the presence of anti-HAV and HEV in the setting of such sporadic cases are indicative of true co-infection or represent false positive results remains debatable.

A Heavy Price for Weight Loss Supplements: Herbalife Related Acute Hepatitis

Background: Obesity is an increasing global health problem creating a big market for weight loss supplements of controversial safety profile. Case Report: A 43-year-old woman with PMH of hypothyroidism and dyslipidemia presented with 2 week history of RUQ abdominal pain, nausea and jaundice. She reported taking “Herbalife” weight loss supplements for 12 weeks. Her medications included oral contraceptives and simvastatin. The patient denied alcohol or Tylenol use, any sick contacts, recent travel or unprotected sexual intercourse. She was afebrile with normal vitals. Her examination was benign except for significant icterus with RUQ tenderness but no asterixis or encephalopathy. Her labs revealed AST 1400, ALT 1000, T. bilirubin 20 with direct bilirubin 13, INR 1.5, Alk Phosphatase 125, Albumin 2.7. The work-up revealed no viral etiologies and negative toxicology screen. Anti-mmooth muscle antibody was positive with negative ANA and AMA. Liver vascular ultrasound showed patent hepatic vasculature with normal liver echotexture and no biliary dilation. Liver biopsy revealed marked lobular and portal inflammation and focal perivenular hepatocyte dropout; no definite evidence of fibrosis or cholestasis - consistent with drug/medication/herbal supplement-induced injury as well as autoimmune hepatitis. She was started on prednisone and N-acetyl cysteine with clinical improvement and AST/ALT decreasing to around 500. Discussion: Herbalife weight loss supplements are widely sold in many countries since 1980. There have been about 40 cases of acute liver injury since 2007 related to Herbalife reported from 5 different countries. The component responsible and the mechanism of liver damage is not clear but there is a report suggesting hepatotoxicity due to contamination with Bacillus subtilis. Our patient is an example of yet another Herbalife related liver injury based on the strong temporal relation between exposure and injury, negative evaluation of other causes of hepatic injury and improvement with discontinuation of the medication. The presence of anti-SMA can be confounding but we hypothesize that Herbalife may either contribute to development of autoimmune hepatitis or may make a subclinical autoimmune process more evident. The mainstay of treatment is discontinuation of Herbalife and empiric treatment with steroids and/or N-acetyl cysteine. The prognosis is variable with most patients improving but in some patients the disease progresses even after discontinuation of Herbalife and possible death. Our case report probably represents only the tip of the iceberg related to Herbalife induced liver damage. More research in the safety of these supplements is needed to prevent fatal outcomes.

Hepatic angiosarcoma mimicking sinusoidal obstruction syndrome/venoocclusive disease: a pathologic-radiologic correlation

We present a case of a 63-year-old man with liver dysfunction and biopsy findings of venoocclusive disease (VOD) who, at autopsy, was discovered to have multifocal hepatic angiosarcoma. After double lung transplantation, he initially presented with signs of liver failure and portal hypertension resulting in recurrent high-volume ascites. Clinically, VOD was considered, and tacrolimus was discontinued, due to its known association with VOD. This, however, did not result in clinical improvement, and computed tomography eventually revealed the development of multiple low-attenuating hepatic lesions over the course of several months. Biopsies of the masses and background liver demonstrated changes most consistent with VOD, characterized by sinusoidal congestion affecting the centrilobular areas with associated hepatocyte atrophy and dropout. A reticulin stain highlighted deposition of reticulin fibers within the sinusoids and central veins. Scattered sinusoidal atypical cells were identified; however, a definitive diagnosis of malignancy was not possible. He eventually passed away because of complications of liver disease. At autopsy, there were multiple firm, red-brown masses identified throughout both hepatic lobes. Upon histologic review, the masses were shown to be angiosarcoma. Away from the tumor, the liver also demonstrated features of VOD. It is likely that the histologic appearance of VOD in the background liver probably represents secondary changes due to injury to the hepatic sinusoids by the primary malignancy. We conclude that it is necessary to consider the possibility of unsampled vascular malignancy when hepatic masses are identified on imaging and histology is consistent with VOD.

Naproxen-induced liver injury

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to induce liver injury. Patterns of the injury usually range from mild elevations of liver enzymes to sometimes severe fulminant hepatic failure. Likewise, naproxen is a propionic acid derivative NSAID that was introduced in 1980 and has been available as an over-the-counter medication since 1994, but has rarely been reported to cause liver injury. We treated a 30-year-old woman with jaundice and intractable pruritus that developed shortly after taking naproxen. We reviewed the medical history and liver histopathology of the patient as well as all previously published case reports of naproxen-associated liver toxicity in the English language literature. The liver biochemical profile of the patient revealed a mixed cholestasis and hepatitis pattern. Consecutive liver biopsies demonstrated focal lobular inflammation, hepatocyte drop-out, and a progressive loss of the small interlobular bile ducts (ductopenia). The biopsy performed two years after onset of the disease showed partial recovery of a small number of bile ducts; however, 10 years passed before the biochemical profile returned to near normal. Naproxen-associated liver toxicity remains a rare entity, but should be considered in any patient presenting with cholestasis shortly after its use. Liver injury is most commonly seen in a mixed pattern characterized by cholestasis and hepatitis. The resulting liver damage may take years to resolve.