Auxiliary transplantation for acute liver failure: Histopathological study of native liver regeneration

Abstract

Auxiliary liver transplantation (ALT) permits the serial assessment of regeneration in livers of patients with acute liver failure (ALF). Forty-nine ALF patients [32 adults (median age, 23 years; range, 16-40 years) and 17 children (median age, 12 years; range, 1-15 years)] underwent ALT between 1994 and 2004 at King's College Hospital. Twenty-four patients had seronegative liver failure, 15 had acetaminophen toxicity, 4 had hepatitis B virus (HBV) infection, 3 had drug-induced liver failure, 2 had autoimmune hepatitis, and 1 had mushroom poisoning. Nine patients without post-ALT native liver histology were excluded from review. All acetaminophen-induced, HBV, and drug-related patients had diffuse injury. Twelve seronegative patients and the autoimmune hepatitis patient had a map-like injury. On follow-up, 9 acetaminophen-induced patients, 9 seronegative patients, 2 drug-induced ALF patients, 3 HBV patients, and the autoimmune patient recovered to a near-normal native liver with inconsequential scarring. The hepatocyte proliferative rate in diffuse necrosis was 27.4% (range, 3.1%-69.4%) at hepatectomy and sharply decreased after 8 days post-ALT, being minimal months and years after ALT. In conclusion, in patients undergoing ALT for ALF with a diffuse pattern of liver injury-mainly acetaminophen toxicity-hepatocyte proliferation occurs in the native liver within a few days of transplantation. If the injury is map-like (most cases of seronegative ALF), regeneration seems to involve variable hepatocellular proliferation and potential ductular hepatopoiesis, but sequential assessment is difficult because of sampling variation. The likelihood of histological recovery appears to be minimal in livers with total hepatocyte loss at the time of ALT.

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

“…Moreover, evidence of hepatic DNA synthesis, albeit insufficient for completing liver regeneration, was similar to that in people with ALF. 20 In the NOD/SCID setting, deficiencies in DNA repair are driven by mutant catalytic subunit of DNA-dependent protein kinase (Prkdc), which is applicable to T and B lymphocytes with a propensity for lymphoma and thymoma. 21,22 By contrast, Prkdc mutation is of no consequence for liver cells.…”

“…40 By contrast, ALF induced by Rif-Phen-MCT in NOD/SCID mice was similar to the human condition, including extensive hepatic necrosis, liver test abnormalities, encephalopathy, high mortality rates, and the presence of some hepatocytes with DNA synthesis. 20 In the second part of this study, we addressed critical cell therapy mechanisms. The ability to rescue subjects with ALF by transplanting cells into the peritoneal cavity without reseeding of the liver will be of immense clinical significance in view of the simplicity of the former procedure.…”

Bridging Therapies and Liver Transplantation in Acute Liver Failure; 10 Years of MARS Experience from Finland

“…Auxiliary LT allows native liver recovery and eventual immunosuppression withdrawal with subsequent graft atrophy or removal. As liver regeneration potential is best in young patients with hyperacute ALF, auxiliary LT is generally considered for patients under 40 years old and paracetamol-induced ALF with limited extrahepatic organ dysfunction (23,25).…”

Spontaneous origin from human embryonic stem cells of liver cells displaying conjoint meso-endodermal phenotype with hepatic functions

“…The role of ataxia telangiectasia mutated (ATM) signaling pathways in oxidative stress, DNA damage and p21-dependent checkpoint controls has been defined in this model (Bandi et al, 2011). The ability of residual hepatocytes in this model to regenerate the liver reproduces the clinical situation in humans, where significant liver regenerative activity is observed, despite terminal ALF (Quaglia et al, 2008).…”