Successful Orthotopic Liver Transplantation Research Articles

Successful Orthotopic Liver Transplantation in Mice Utilizing Microcomputed Tomography Angiography.

Microcomputed tomography (microCT) angiography is an invaluable resource to researchers. New advances in this technology have allowed for high-quality images to be obtained of micro-vasculature and are high-fidelity tools in the field of organ transplantation. In this model of orthotopic liver transplantation (OLT) in mice, microCT affords the opportunity to evaluate allograft anastomosis in real time and has the added benefit of not having to sacrifice study animals. The choice of contrast, as well as image acquisition settings, create a high-definition image, which gives researchers invaluable information. This allows for evaluation of the technical aspects of the procedure as well as potentially evaluating different therapeutics over an extended duration of time. In this protocol, we detail an OLT model in mice in a stepwise fashion and finally describe a microCT protocol that can give high-quality images, which aid researchers in in-depth analysis of solid organ transplantation. We provide a step-by-step guide for liver transplantation in a mouse, as well as briefly discuss a protocol for evaluating the patency of the graft through microCT angiography.

Autoimunní hepatitida po očkování proti covidu-19

Summary: In this case report, we present a 61-year-old patient admitted to the hospital because of tiredness and jaundice less than three weeks after vaccination against SARS-CoV-2 with the first dose of the Comirnaty vaccine (Pfizer/BioNTech). Based on the patient’s medical history, laboratory data, imaging methods and liver bio­psy, we dia­gnosed autoimmune hepatitis. The patient developed acute liver failure, and his liver function did not improve after corticosteroid administration. Therefore, the patient was enrolled in the waiting list and underwent a successful orthotopic liver transplantation. Key words: autoimmune hepatitis – COVID-19 – vaccination – liver failure

The needle in the haystack: deciphering diagnostic data in a case of acute on chronic liver failure

The needle in the haystack: deciphering diagnostic data in a case of acute on chronic liver failure

Reverse Takotsubo Stress Cardiomyopathy During Liver Transplantation

Reverse Takotsubo Stress Cardiomyopathy During Liver Transplantation

Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review.

Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant-free survival, extrahepatic manifestations may cause relevant morbidity. We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited. Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver-associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT. The spectrum of extrahepatic manifestations in PFIC highlights essential, non-redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health-related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.

Electroconvulsive Therapy in a Patient With a Liver Transplant.

Depression is common in patients after liver transplantation and, when severe, can threaten both viability of the graft and the patient's life. Electroconvulsive therapy (ECT) is a safe and highly effective therapy for severe depression, but there have been very few reports of its use in liver transplant recipients. We describe a patient who had undergone a successful orthotopic liver transplant 26 years previously, who developed severe major depression. The patient tolerated an index course of ECT well and responded robustly. There were no complications pertinent to the graft or otherwise. Liver transplantation is not a contraindication to ECT, and clinicians should not hesitate to proceed when necessary.

Repeat SARS-CoV-2 testing after recovery. Is a pretransplant PCR necessary?

The emergence of SARS-CoV-2 and the clinical syndrome of COVID19 resulted in a major decrease in transplant volumes during the first months of the pandemic followed by a change in practice, with strict screening and SARS-CoV-2 PCR testing prior to transplant. Protocols required a negative SARS-CoV-2 PCR prior to proceeding with transplantation. Many transplants were delayed nationwide due to persistent positive PCRs in asymptomatic patients, sometimes for months (1).

Successful Liver Transplantation in a Patient With Acute COVID-19 Infection and Acute Liver Failure: A Case Report.

Current liver transplantation societies recommend recipients with active coronavirus disease 2019 (COVID-19) be deferred from transplantation for at least 2 wks, have symptom resolution and at least 1 negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test.1 This approach does not address patients who require urgent transplantation and will otherwise die from liver failure. We report a successful orthotopic liver transplant (OLT) in a patient with active COVID-19 infection. This is only the second to be reported worldwide and the first in Canada.

Wilson’s Disease with Hepatogenous Diabetes: A Case Report

Introduction: Wilson’s disease (WD) is a hereditary autosomal recessive disorder caused by pathogenic variants within the ATP7B gene. Early diagnosis of WD is important but it can be difficult in pediatric clinical practice because of varied presentations. Fortunately, with the development of genetic testing, molecular analysis of the ATP7B gene is helpful in the early diagnosis of WD. Hepatogenous diabetes (HD) is defined as a state of impaired glucose regulation caused by chronic liver disease. Here we report a child with WD with HD. Case Presentation: A 4-year-old girl was admitted to our hospital with diarrhea for two months. On admission, urine glucose was 4+, fasting glucose was 2.6 mmol/L, and postprandial blood glucose was 7.2 mmol/L. Further clinical manifestations and laboratory tests showed coagulation dysfunction, hemolytic anemia, and cirrhosis. After admission, she developed hepatic encephalopathy. Significant abnormal glucose metabolism was later detected, but by then, hypoglycemic convulsions had taken place. The final diagnosis of WD was confirmed by detection of mutations in the ATP7B gene. Genetic sequencing revealed compound heterozygous mutations in ATP7B, including c.2975C>T, p.Pro992Leu and c.3809A>G, p.Asn1270Ser. On day 40 of admission, the patient underwent successful orthotopic liver transplantation. Her liver function, blood glucose levels, and coagulation test results returned to normal one month after the liver transplantation. The symptom of diarrhea was also relieved after surgery. Her abnormal glucose level in hospital was considered to be HD. Conclusions: Blood glucose levels must be carefully monitored in Wilson’s disease. Moreover, genetic sequencing provides an accurate and minimally invasive diagnostic tool for WD.

Acute fatty liver of pregnancy leading to a delayed hepatic failure necessitating liver transplantation: A case report

Acute fatty liver of pregnancy (AFLP) is a potentially fatal metabolic disorder in pregnant patients that requires urgent delivery and aggressive medical and aesthetic management of maternal complications associated with acute liver failure. A 41-year-old female (79 kg) G1P0 at 31 weeks gestation presented with nausea, vomiting, pruritus, and jaundice. A diagnosis of severe liver dysfunction secondary to AFLP was made. We proceeded with urgent delivery under general anaesthesia. The patient had an uncomplicated caesarean section and gave birth to female infant with Apgar scores of 7 and 8. The patient remained stable for the following 2 weeks, however, given the lack of further recovery of hepatic function, a transjugular liver biopsy was performed, revealing persistent AFLP. She received N-acetylcysteine infusion and 4 cycles of plasma exchange with no improvement. Over the next few days her mental status worsened and her liver functions further deteriorated. She was listed for a deceased liver donor transplant and underwent successful orthotopic liver transplantation. She was discharged on post-operative day (POD) 14 of liver transplant.

2399 West Nile Encephalitis in a Post-Liver Transplant Patient

INTRODUCTION: West Nile Virus (WNV) is a neurotropic flavivirus that is transmitted from animals to humans by the bite of the Aedes, Anaphales, or Culex mosquito, with disease incidence peaking in the late summer and early fall. It is the leading cause of arboviral illness in the U.S. While many infected with WNV are asymptomatic, 25% of patients develop fever, and less than 1% of patients will develop neurologic symptoms. Age over 75-years old and immunosuppressed state are risk factors for developing neuroinvasive disease. CASE DESCRIPTION/METHODS: A 65-year old woman with a history of HCV cirrhosis complicated by HCC status post successful orthotopic liver transplantation (OLT) in 2016 compliant with tacrolimus and everolimus immunosuppression (ISP) presented with painless jaundice and acute transaminemia. Liver biopsy revealed severe acute cellular rejection (ACR), so steroids and thymoglobulin were started. Tacrolimus was increased and everolimus was changed to mycophenolate mofetil. Clinically, she appeared well and her LFTs responded to treatment. Suddenly, she developed fever to 103º associated with bilateral hand tremors. Infectious workup was obtained, and she was started on broad-spectrum antibiotics. Initially, symptoms were attributed to changes in ISP and treatment of ACR. However, she developed progressively worsening dyskinesia and encephalopathy eventually requiring intubation. Given initial negative infectious workup, lumbar puncture was obtained; see Table 1. HSV, VZV, and Lyme PCR as well as VDRL in the CSF were negative. Given clinical symptoms, positive WNV IgM in the CSF, and MRI Brain concerning for WNV neuroinvasive disease, patient was treated with IVIG for 5 days. WNV IgG became positive as well on repeat lumbar puncture 2 weeks later. Patient’s encephalopathy improved, and she was able to be extubated. DISCUSSION: There may be a delay in diagnosis and treatment of WNV encephalitis in post-liver transplant patients as neurologic symptoms may be attributed to ISP or as in this patient, to the treatment of acute cellular rejection. West Nile encephalitis must remain on the differential diagnosis when neurologic symptoms are present in a post-liver transplant patient, especially in endemic areas during the summer and fall months. A change in this patient’s ISP for the treatment of ACR may have caused the development of a more severe, neuroinvasive response to WNV infection and ISP management in such patients should be studied further.

2289 Clostridioides difficile-Associated Hemolytic Uremic Syndrome After Orthotopic Liver Transplantation

INTRODUCTION: Clostridium Difficile infection (CDI) has previously been reported as a rare cause of possible Hemolytic Uremic Syndrome (HUS) in both adults and children. We present a unique case of CDI related HUS in a patient post orthotopic liver transplantation (OLT). CASE DESCRIPTION/METHODS: A 40-year-old African American male presented with acute decompensation of alcoholic cirrhosis. After evaluation, the patient underwent successful OLT. Post-transplant course was complicated by post-operative bleeding requiring multiple exploratory laparotomies. Patient developed new-onset acute renal failure post transplantation requiring hemodialysis and prolonged courses of antibiotics. On post op day 15, patient developed diarrhea and tested positive for CDI. Physical examination was significant for jaundice, multiple ecchymoses, and a large abdominal wound without signs of excessive erythema. Laboratory data at that time showed hemoglobin drop to 5 g/dL from 8.7 g/dL, thrombocytopenia with a drop in platelets from 282 × 103/uL to 15 × 103/uL, and blood smear consistent with presence of schistocytes raising the concern for a hemolytic process. Lactate dehydrogenase (LDH) was greater than 6450 U/L, haptoglobin was less than 6 mg/dL, and reticulocytes were elevated at 8.06%. ADAMSTS-13 resulted at 26% with a negative ADMASTS-13 antibody screen suggestive against thrombotic thrombocytopenic purpura. Serotonin release assay antibodies and heparin induced thrombocytopenia antibodies were not present. A diagnosis HUS secondary to CDI was made, and the patient was started on treatment for severe CDI with oral vancomycin, vancomycin enemas, and intravenous metronidazole. The patient also underwent emergent plasma exchange receiving 4 treatments, blood transfusions, and prednisone therapy (1 mg/kg). The patient had improvement in his hemoglobin and platelets following therapy and eventual resolution of diarrhea. His mental status as well returned to baseline. Patient’s hospital course was later complicated by aright hemicolectomy, end ileostomy secondary to toxic megacolon, and pathology was consistent with pseudomembranous colitis.His renal function did not recover and he was declared end-stage renal disease. DISCUSSION: CDI related HUS is exceedingly rare. The pathogenesis of CDI related HUS has not been well defined. To our knowledge, this is the first case of CDI related HUS in a patient post OLT. It is important for gastroenterologists and hepatologists to be aware that although rare, CDI is a possible cause of HUS.

Downstaging of Hepatocellular Carcinoma Outside Milan Criteria Using SBRT

Orthotopic liver transplantation (OLT) offers the potential for cure in patients (pts) with hepatocellular carcinoma (HCC) who meet Milan criteria. Many pts are outside of Milan at diagnosis or after subsequent progression. Prior studies have shown that downstaging with local therapies can facilitate successful OLT leading to prolonged disease free survival. Stereotactic body radiotherapy (SBRT) is an established local therapy for HCC, though data for this specific indication is limited. From a survey of a large single institution database, the present study therefore reports on outcomes of patients treated with SBRT with the intention of downstaging to facilitate OLT. We surveyed our IRB-approved prospective liver SBRT data registry for pts not meeting Milan criteria and treated with the intention of downstaging. The primary outcome was undergoing OLT. Overall survival (OS) and progression-free survival (PFS) were estimated with Kaplan Meier methods. Time to transplant, as well as local, liver, and extrahepatic failure, were estimated with cumulative incidence functions. 14 pts treated between 2010 and 2018 met criteria for analysis. Median follow up was 27 months and 7 pts were alive at time of analysis. Most were male (n=11), and median age was 60. Median KPS was 80 (range 60-90). 5 pts were Child-Pugh (CP) A, 3 CP B, and 6 CP C. Median size of the largest single lesion was 4.2 cm (1.8 - 6.8 cm). The most common reason for not meeting Milan criteria was multiple lesions larger than 3 cm (n=8). Median AFP at time of SBRT was 40 (3 - 3255). 11 pts (79%) had undergone prior liver directed therapy. Pts were treated a median of 6.5 months after diagnosis. Median dose was 40 Gy, and median number of fractions was 5. There were no local failures. 11 pts (79%) were successfully downstaged to within Milan Criteria after SBRT. 5 pts (36%) had subsequent disease progression within the liver, 2 of whom were successfully salvaged and proceeded to transplant. 2 pts became ineligible for OLT due to extrahepatic failure. In total, 7 pts (50%) underwent OLT at a median 3.6 months after SBRT. Percent necrosis was reported for 5 pts, 4 (80%) of whom had greater than 67%. 2 pts (29%) had recurrence after OLT, one with metastases to lung and the other with solitary recurrence in the transplanted liver. Median OS was 33.0 months for all pts, 14.5 months in pts not undergoing OLT, and not reached for those who did undergo OLT. No pts developed radiation induced liver disease. SBRT provides excellent local control and high rates of radiographic downstaging, however progression within the liver is common. Despite this significant risk, a sizeable number of patients are able to proceed to transplant and achieve prolonged survival. SBRT should be considered for patients requiring downstaging to meet transplant criteria.

Intraoperative TOE guided management of newly diagnosed severe tricuspid regurgitation and pulmonary hypertension during orthotopic liver transplantation: a case report demonstrating the importance of reversibility as a favorable prognostic factor

BackgroundTricuspid regurgitation (TR) and pulmonary hypertension (PHT) are highly dynamic cardiovascular lesions that may progress rapidly, particularly in the orthotopic liver transplantation (OLT) waitlist population. Severe TR and PHT are associated with poor outcomes in these patients, however it is rare for the two to be newly diagnosed intraoperatively at the time of OLT. Without preoperative information on pulmonary vascular and right heart function, the potential for reversibility of severe TR and PHT is unclear, making the decision to proceed to transplant fraught with difficulty.Case presentationWe present a case of successful orthotopic liver transplantation (OLT) in a 48 year old female with severe (PHT) (mean pulmonary arterial pressure > 55 mmHg) and severe TR diagnosed post induction of anaesthesia. The degree of TR was associated with systemic venous pressures of > 100 mmHg resulting in massive haemorrhage during surgery and difficulty in distinguishing venous from arterial placement of vascular access devices. Intraoperative transoesophageal echocardiography (TOE) proved crucial in diagnosing functional TR due to tricuspid annular and right ventricular (RV) dilatation, and dynamically monitoring response to treatment. In response to positioning, judicious volatile anaesthesia administration, pulmonary vasodilator therapy and permissive hypovolemia during surgery we noted substantial improvement of the TR and pulmonary arterial pressures, confirming the reversibility of the TR and associated PHT.ConclusionTR and PHT are co-dependent, dynamic, load sensitive right heart conditions that are interdependent with chronic liver disease, and may progress rapidly in patients waitlisted for OLT. Use of intraoperative TOE and pulmonary artery catheterisation on the day of surgery will detect previously undiagnosed severe TR and PHT, enable rapid assessment of the cause and the potential for reversibility. These dynamic monitors permit real-time assessment of the response to interventions or events affecting right ventricular (RV) preload and afterload, providing critical information for prognosis and management. Furthermore, we suggest that TR and PHT should be specifically sought when waitlisted OLT patients present with hepatic decompensation.

Orthotopic Liver Transplantation for Treatment of Sinusoidal Obstruction Syndrome: A Case Report

We here report the case of successful orthotopic liver transplantation (LT) following acute liver failure (ALF) related to sinusoidal obstruction syndrome (SOS). This syndrome is one of the main causes of death early after bone marrow transplantation (BMT); LT seems to be an effective treatment of the most severe forms of SOS but no official recommendation exist about this subject. With this clinical case we would like to show that after careful patient selection and appropriate timing, LT for treatment of severe SOS is safe and effective.

Peri-operative management of swine orthotopic liver transplantation

Objective To summarize the peri-operative management experience of swine orthotopic liver transplantation. Methods From September 2013 to August 2016, 62 liver transplantations (LT) were performed with 124 Bama mini-pigs, including 30 cases of standard LT, 10 cases of split LT, 11 cases of donation after cardiac death (DCD) LT, 5 cases of extracorporeal membrane oxygenation (ECMO) repaired DCD LT and 6 cases of normothermic machine perfusion (NMP) repaired DCD LT. Results For all of the 124 pigs, 3 underwent tracheotomy after failed tracheal intubation. Anhepatic time was (22.3±2.6) min (range 18-26 min), similar among the 62 different type LTs. Mean arterial pressure could be mainted ≥ 50 mmHg (1 mmHg=0.133 kPa) through rapid colloid solution infusion without administration of any vasoactive substances.5 receipts of split LTs died during the operation because of bleeding. 14 cases died after operation. 3 were of standard LT, all in the very beginning period when we first build this animal model, 1 died of abdominal bleeding, the other 2 died of bile leak induced severe infection.11 cases from the DCD LT died of model related hepatic failure. Post-operative 5-day survival rates of standard, split, DCD, ECMO-repaired DCD, NMP-repaired DCD were 90%, 50%, 0%, 100%, 100%, respectively. Conclusion Precise peri-operative management is essential for successful swine orthotopic liver transplantation. Skilled trachea intubation and tracheotomy procedure, accurate liquid management, well-practiced animal model are the key points, and anhepatic period should be shortened as much as possible. Key words: Pig; Liver transplantation; Peri-operative management

Technique for orthotopic liver transplantation in cynomolgus monkeys (Macaca fascicularis).

PurposeRecent studies investigating new strategies to modulate the immune system have utilized animal models of liver transplantation (LT). However, the anhepatic phase (AHP) remains a crucial problem in LT. The aim of the present study is to introduce a technique for successful orthotopic LT in cynomolgus monkeys using an early-reperfusion strategy.MethodsOrthotopicallo-LT was performed with seven donor/recipient pairs of cynomolgus monkeys.ResultsIn 2 recipients, liver allografts were perfused after suprahepatic inferior vena cava (SHIVC), portal vein (PV), and infrahepatic inferior vena cava (IHIVC) anastomosis. To reduce the time of AHP in five recipients, liver allografts ware perfused after SHIVC and PV anastomosis while the IHIVC was not anastomosed. In the latter strategy, the AHP was reduced from 46 minutes to 31 minutes and a 24-hour survival rate of 80% was achieved.ConclusionOur results indicate that an early-reperfusion strategy can be successfully used to establish a LT model in cynomolgus monkeys with a consistently high rate of animal survival.

Heterozygous Hemochromatosis (HH) and Heterozygous Alpha 1 Antitrypsin Deficiency (AAT) as a Cause of Cirrhosis Requiring Liver Transplant

Hereditary hemochromatosis (HH) is an autosomal recessive disease caused by mutations of HFE gene that increases iron absorption in the intestine. It is commonly found in Caucasians. Men have 24 times higher rate of iron overload compared to women. 85-90% of patients with homozygous HFE gene mutation C282Y will be affected. 10% of them will develop clinical symptoms or end organ damage like cirrhosis of liver. Role of heterozygous C282Y or H63D mutations in the development of cirrhosis is still questionable. Alpha 1-Antitrypsin (AAT) deficiency is usually characterized by impaired secretion of α-1 AT from liver cells.This disorder is usually inherited as autosomal co-dominant. AAT deficiency usually is associated with Pi ZZ, Pi SZ, or Pi Null haplotypes and can progress to liver cirrhosis. On the contrary, Pi MZ which is considered the most common heterozygous type often does not lead to liver disease. We are reporting a rare case of both heterozygous HH and AAT deficiency that developed cirrhosis requiring liver transplant. 57 yr old white male who received a liver transplant for end stage liver disease with complications of cirrhosis. Both his father and grandmother had liver disease. Patient was found to have elevated liver enzymes at age 17 during routine physical exam. Lab exam showed elevated iron saturation (83%) and elevated Ferritin (1061) with low α-1 AT. Genetic testing showed HFE heterozygous for C282Y wild type and heterozygous for alpha 1 antitrypsin deficiency MZ phenotype. MRI showed cirrhosis with evidence of portal hypertension. Liver biopsy showed cirrhotic liver with grade 2/4 intra hepatocyte iron deposition. Immunohistochemical stain and PAS- D stains were positive with presence of α-1 AT globule. As Ferritin level continued to rise, patient underwent multiple sessions of phlebotomy. In matter of few years he developed intractable ascites, hepatic encephalopathy, and hepatic hydrothorax. Transjugular intrahepatic portosystemic shunt was not performed due to high MELD score. After thorough workup patient underwent a successful orthotopic liver transplant. Conflicting evidence on the association of the two disorders and on the severity of the condition in patients in whom these disorders coexist have rised from reviewing small numbers of patients. Our case is the first reported case of cirrhosis developed from heterozygous HH C282Y wild type and heterozygous AAT deficiency Pi MZ type which required liver transplant.Figure: Hepatocellular siderosis (Iron stain).Figure: Alpha-1-antitrypsin globules within hepatocytes (Immunostain).Figure: Alpha-1-antitrypsin globules within hepatocytes (PASD stain).

Use of a pressure wire to evaluate right heart pressures in a pre-liver transplant recipient through a peripheral IV.

Use of a pressure wire to evaluate right heart pressures in a pre-liver transplant recipient through a peripheral IV.

Liver transplantation in transthyretin amyloidosis: issues and challenges.

Hereditary transthyretin amyloidosis (ATTR) is a rare worldwide autosomal dominant disease caused by the systemic deposition of an amyloidogenic variant of transthyretin (TTR), which is usually derived from a single amino acid substitution in the TTR gene. More than 100 mutations have been described, with V30M being the most prevalent. Each variant has a different involvement, although peripheral neuropathy and cardiomyopathy are the most common. Orthotopic liver transplantation (OLT) was implemented as the inaugural disease-modifying therapy because the liver produces the circulating unstable TTR. In this review, we focus on the results and long-term outcomes of OLT for ATTR after more than 2063 procedures and 23 years of experience. After successful OLT, neuropathy and organ impairment are not usually reversed, and in some cases, the disease progresses. The overall 5-year survival rate is approximately 100% for V30M patients and 59% for non-ATTR V30M patients. Cardiac-related death and septicemia are the main causes of mortality. Lower survival is related to malnutrition, a longer duration of disease, cardiomyopathy, and a later onset (particularly for males). Deposits, which are composed of a mixture of truncated and full-length TTR (type A) fibrils, have been associated with posttransplant myocardial dysfunction. A higher incidence of early hepatic artery thrombosis of the graft has also been documented for these patients. Liver-kidney/heart transplantation is an alternative for patients with advanced renal disease or heart failure. The sequential procedure, in which ATTR livers are reused in patients with liver disease, reveals that neuropathy in the recipient may appear as soon as 6 years after OLT, and ATTR deposits may appear even earlier. Long-term results of trials with amyloid protein stabilizers or disrupters, silencing RNA, and antisense oligonucleotides will highlight the value and limitations of liver transplantation.