Significant Improvement of Survival by Intrasplenic Hepatocyte Transplantation in Totally Hepatectomized Rats

The effect of intrasplenic hepatocyte transplantation (HTX) was studied in an experimental model of acute liver failure in rats with chronic liver atrophy. Rats underwent a portacaval shunt operation on Day -14 to induce liver atrophy, and underwent total hepatectomy on Day 0 as a start of acute liver failure. Intrasplenic hepatocyte or sham transplantation was performed on Day -7, -3, or -1 (n = 4 to 6 per group). During the period following hepatectomy, mean arterial blood pressure was maintained above 80 mm Hg and hypoglycaemia was prevented. Severity of hepatic encephalopathy was assessed by clinical grading and EEG spectral analysis, together with determination of blood ammonia and plasma amino acid concentrations, and “survival” time. Histological examination of the spleen and lungs was performed after sacrifice. Intrasplenic hepatocyte transplantation resulted in a significant improvement in clinical grading in all transplanted groups (p < 0.05), whereas a significant improvement in EEG left index was seen only in the group with transplantation on Day -1 (p < 0.05). In contrast to hepatocyte transplantation 1 day before total hepatectomy, rats with hepatocyte transplantation 3 and 7 days before total hepatectomy showed a significant 3- and 2-fold increase in “survival” time compared to sham transplanted controls: HTX at Day -1: 7.5 ± 0.3 h vs. 5.9 ± 0.6 h (p > 0.05), HTX at Day -3:19.7 ± 3.7 h vs. 6.5 ± 0.3 h (p < 0.05), and HTX at Day -7: 13.8 ± 3.2 h vs. 6.3 ± 0.3 h (p < 0.05). Furthermore, rats with hepatocyte transplantation on Day -3 and -7 showed significantly lower blood ammonia concentrations after total hepatectomy (p < 0.0001). Histological examination of the spleens after sacrifice showed clusters of hepatocytes in the red pulp. Hepatocytes present in the spleen for 3 and 7 days showed bile accumulation and spots of beginning necrosis. The present data show that in a hard model of complete liver failure in portacaval shunted rats, intrasplenic hepatocyte transplantation is able to prolong “survival” time significantly 2- to 3-fold. The relevance of this observation for human application is discussed.

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A study of Acute Liver Failure in adults in a tertiary care hospital

The Journal of Medical Research ◽

10.31254/jmr.2019.5601 ◽

2019 ◽

Vol 5 (6) ◽

pp. 204-207

Author(s):

Dr. Mohini Singh ◽

◽

Dr. Srilakshmi Sathiyaseelan ◽

Devarasetty Shashank ◽

Dr. S.R. Ramakrishnan ◽

...

Keyword(s):

Liver Function ◽

Liver Failure ◽

Acute Liver Failure ◽

Viral Hepatitis ◽

Tertiary Care Hospital ◽

Early Recognition ◽

Tertiary Care ◽

Care Hospital ◽

Arterial Blood ◽

Function Test

Acute liver failure (ALF) is a condition with rapid deterioration of liver function resulting in hepatic encephalopathy and/or coagulopathy in patients with previously normal liver. Acute liver failure (ALF) is an uncommon condition associated with high morbidity and mortality. The prognosis is poor for untreated cases of Acute liver failure, so early recognition and management of patients with acute liver failure is crucial. A cause for acute liver failure can be identified in 60 to 80 percent of patients. Identifying the underlying cause of the liver failure is important because it influences the approach to management and provides prognostic information. Aims and Objectives: The aim of our study is to identify the clinical features, etiology and outcome of acute liver failure in a tertiary care hospital. Materials and Methods: This study is an observational study where patients with Acute Liver Failure admitted in ICU in our institution after meeting the diagnostic criteria for Acute liver failure were included in the study. Details of history, relevant symptoms and baseline investigations included, complete blood count, blood glucose, renal function test, serum electrolytes, liver function test (LFT), prothrombin time, international normalized ratio (INR), lactate dehydrogenase (LDH), creatine kinase (CK)], arterial blood gas analysis, arterial lactate, arterial ammonia, amylase and lipase level and pregnancy test (if female) and ultrasonography (USG) abdomen were recorded, MRI brain and other investigations relevant to the admission diagnosis, co morbidities and aetiology if needed were recorded. All the patients received standard supportive treatment for ALF. Results: In this study of 57 patients, majority of the patients were from the age group 41 to 50 years (17 patients) and 31 to 40 years (13 patients). 36 patients were male and 21 patients were females. Jaundice and encephalopathy was observed in all 57 (100%) patients, 24 (42%) patients had INR >2.5, 27 (47%) patients had serum creatinine >1.2 mg/dl and 18 (31.5%) patients had serum ammonia levels >100 micromol/L. The lowest value for serum aminotranferase was observed in infections (other than viral hepatitis) and maximum value was observed in drugs leading to ALF.In 20 (35%) patients viral hepatitis was the cause for ALD, followed by drugs and toxins which was the cause of ALD in 18 (31.5%) patients. Infections other viral hepatitis as the aetiology for ALF was observed in 16 (28%) of patients. Ischemic hepatitis was observed in 1 and Wilson’s disease was noted in 2 patients. Total 6 (10.5%) patients out of 57 patients had died, 4 patients with hepatitis B infection, 1 patient with paracetamol over dosage and 1 patient with dengue fever had died. Conclusion: Viral hepatitis and drugs are the commonest cause for acute liver failure. The aetiology of ALF varies significantly worldwide. Determining the etiology of acute liver failure requires a combination of detailed history taking and investigations. A broad evaluation is required to identify a cause of the acute liver failure, as the prognosis is poor in untreated cases of acute liver failure, so early recognition and management of patients with acute liver failure is crucial.

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O45 THE NEW POSSIBILITY OF AUTOLOGOUS HEPATOCYTE TRANSPLANTATION TO PREVENT ACUTE LIVER FAILURE AFTER MASSIVE HEPATECTOMY

Journal of Hepatology ◽

10.1016/s0168-8278(14)60047-7 ◽

2014 ◽

Vol 60 (1) ◽

pp. S19

Author(s):

S. Kita ◽

K. Yasuchika ◽

T. Ishii ◽

H. Katayama ◽

T. Kawai ◽

...

Keyword(s):

Liver Failure ◽

Acute Liver Failure ◽

Hepatocyte Transplantation ◽

Massive Hepatectomy

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Mycophenolate Mofetil and Sirolimus in Hepatocyte Transplantation in an Experimental Model of Toxic Acute Liver Failure

Journal of Investigative Surgery ◽

10.3109/08941939.2013.879967 ◽

2014 ◽

Vol 27 (4) ◽

pp. 205-213 ◽

Cited By ~ 3

Author(s):

Ioannis Loukopoulos ◽

Ioannis Sfiniadakis ◽

Andrew Pillai ◽

Manousos Konstantoulakis ◽

Georgios Androulakis ◽

...

Keyword(s):

Mycophenolate Mofetil ◽

Liver Failure ◽

Acute Liver Failure ◽

Experimental Model ◽

Hepatocyte Transplantation

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Extracorporeal support and hepatocyte transplantation in acute liver failure and cirrhosis

Journal of Gastroenterology and Hepatology ◽

10.1046/j.1440-1746.1999.01945.x ◽

1999 ◽

Vol 14 (8) ◽

pp. 757-770 ◽

Cited By ~ 39

Author(s):

Stephen M Riordan ◽

Roger Williams

Keyword(s):

Liver Failure ◽

Acute Liver Failure ◽

Hepatocyte Transplantation ◽

Extracorporeal Support

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Hepatosplanchnic haemodynamics and renal blood flow and function in rats with liver failure

Gut ◽

10.1136/gut.43.2.272 ◽

1998 ◽

Vol 43 (2) ◽

pp. 272-279 ◽

Cited By ~ 20

Author(s):

P Javlé ◽

J Yates ◽

H G Kynaston ◽

K F Parsons ◽

S A Jenkins

Keyword(s):

Blood Flow ◽

Liver Function ◽

Liver Failure ◽

Acute Liver Failure ◽

Renal Blood Flow ◽

Portal Pressure ◽

Renal Haemodynamics ◽

Aminopyrine Breath Test ◽

Arterial Blood ◽

And Function

Background—Massive liver necrosis, characteristic of acute liver failure, may affect hepatosplanchnic haemodynamics, and contribute to the alterations in renal haemodynamics and function.Aims—To investigate the relation between hepatosplanchnic haemodynamics, including portal systemic shunting, and renal blood flow and function in rats with acute liver failure.Methods—Liver failure was induced in male Wistar rats by intraperitoneal injection of 1.1 g/kg ofd(+)-galactosamine hydrochloride. The parameters assessed included: systemic, hepatosplanchnic, and renal blood flow (57Co microsphere method); portal-systemic shunting and intrarenal shunting (consecutive intrasplenic, intraportal, or renal arterial injections of 99mTc methylene diphosphonate and99mTc albumin microspheres); arterial blood pressure and portal pressure; renal function; and liver function (liver function tests and 14C aminopyrine breath test).Results—Progressive liver dysfuntion was accompanied by the development of a hyperdynamic circulation, a highly significant decrease in renal blood flow and function, and an increase in intrarenal shunting 36, 42, and 48 hours after administration of d-galactosamine. The alterations in renal blood flow and function were accompanied by significant increases in portal pressure, portal venous inflow, and intrahepatic portal systemic shunting in galactosamine treated rats compared with controls. There was a significant correlation between changes in renal blood flow and changes in portal pressure, intrahepatic portal systemic shunting, and deterioration in liver function (r=0.8, p<0.0001).Conclusions—The results of this study suggest that both increased intrahepatic portal systemic shunting and hepatocyte impairment may contribute to alterations in renal haemodynamics and function.

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Experimental Models of Acute and Chronic Liver Failure in Nude Mice to Study Hepatocyte Transplantation

Cell Transplantation ◽

10.3727/000000005783983061 ◽

2005 ◽

Vol 14 (5) ◽

pp. 277-290 ◽

Cited By ~ 10

Author(s):

Arnaud Gandillet ◽

Isabelle Vidal ◽

Eliane Alexandre ◽

Maxime Audet ◽

Marie-Pierre Chenard-Neu ◽

...

Keyword(s):

Liver Failure ◽

Acute Liver Failure ◽

Partial Hepatectomy ◽

Nude Mice ◽

Survival Rates ◽

Experimental Models ◽

Chronic Liver ◽

Hepatocyte Transplantation ◽

Acute Injury ◽

Published Data

Although hepatocyte transplantation is a promising therapy for acute liver failure in human, there is still a lack of animal models suffering from hepatic injury in which the benefits of hepatocyte transplantation could be evaluated solely, without the bias caused by immunosuppression. As a consequence, the aim of the study was first to develop reproducible models of partial hepatectomy and of thioacetamide (TA)- or Jo2-induced acute liver failure in nude mice. Chronic liver disease was also investigated by repeated injections of sublethal doses of thioacetamide. Survival rates, routine histologic observations, alanin aminotransferase sera content, Ki67, and caspase 3 immunodetection were investigated both after 40% partial hepatectomy and after toxic-induced damages. Liver injuries were more severe and/or precocious in nude mice than in Balb/c mice for a given treatment with a maximum of acute injury obtained 24 h after single toxic injection, and were found to be transitory and reversible within 10 days. Toxics induced apoptosis followed by necrosis, confirming recent published data. Onset of fibrosis leading to reproducible chronic cirrhosis in nude mice correlated with increasing number of Ki67-positive cells, indicating that high levels of cell proliferation occurred. Chronic cirrhosis progressively reversed to fibrosis when the treatment ceased. Preliminary results demonstrated that engrafted xenogeneic hepatocytes could be detected in the host liver by anti-MHC class I immunohistochemistry. Fractions enriched in 2n or 4n hepatocytes by cell sorting using a flow cytometer were equivalent to the unpurified fraction in terms of engraftment in control nude mice or in nude mice subjected to PH. However, in mice suffering from liver injury 24 h after Jo2 or TA treatment, the engraftment of 2n hepatocytes was about twice that of an unpurified hepatocyte population or of a population enriched in 4n hepatocytes.

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