Gestational Alloimmune Liver Disease: A Case Study

Gestational alloimmune liver disease (GALD) is initiated by maternal antibodies that attack fetal hepatocytes. The fetal immune response to the antibodies causes liver damage. The incidence of GALD is four per 100,000 live births in the United States. Frequently, liver injury leads to fetal loss or neonatal demise; nonetheless, the presentation of GALD has a wide range of severity. Survival rates have increased from 20 to 80 percent changes in treatment and understanding of GALD. Current treatment is focused on supportive care with intravenous immunoglobulin (IVIG) and exchange transfusions. Mortality risk is positively associated with the timing of diagnosis. Although there has been an increase in understanding this disease, the discovery of the specific alloantigen is still needed. Relevant embryology, pathophysiology, clinical manifestations, diagnosis, medical treatment, and prognosis are discussed to aid health care professionals in the early identification and treatment for the neonate and family unit.

Human fetal liver cultures support multiple cell lineages that can engraft immunodeficient mice

During prenatal development the liver is composed of multiple cell types with unique properties compared to their adult counterparts. We aimed to establish multilineage cultures of human fetal liver cells that could maintain stem cell and progenitor populations found in the developing liver. An aim of this study was to test if maturation of fetal hepatocytes in short-term cultures supported by epidermal growth factor and oncostatin M can improve their ability to engraft immunodeficient mice. Fetal liver cultures supported a mixture of albumin + cytokertin-19 + hepatoblasts, hepatocytes, cholangiocytes, CD14 ++ CD32 + liver sinusoidal endothelial cells (LSECs) and CD34 + CD133 + haematopoietic stem cells. Transplantation of cultured cells into uPA-NOG or TK-NOG mice yielded long-term engraftment of hepatocytes, abundant LSEC engraftment and multilineage haematopoiesis. Haematopoietic engraftment included reconstitution of B-, T- and NK-lymphocytes. Colonies of polarized human hepatocytes were observed surrounded by human LSECs in contact with human CD45 + blood cells in the liver sinusoids. Thus, fetal liver cultures support multiple cell lineages including LSECs and haematopoietic stem cells while also promoting the ability of fetal hepatocytes to engraft adult mouse livers. Fetal liver cultures and liver-humanized mice created from these cultures can provide useful model systems to study liver development, function and disease.

Metabolism of six CYP probe substrates in fetal hepatocytes

<p class="ADMETabstracttext">Cytochrome P-450 (CYP) are the most common drug metabolizing enzymes and are abundantly expressed in liver apart from kidney, lungs, intestine, brain etc. Their expression levels change with physiological conditions and disease states. The expression of these CYPs is less in human foetus and neonates compared to adults, which results in lower clearance of xenobiotics in infants and neonates compared to adults. Hepatocytes are the cells which are largely used to study these CYPs. We have isolated hepatocytes from aborted foetus to study the metabolism of six probe substrates: phenacetin, diclofenac, S-mephenytoin, dextromethorphan, nifedipine and testosterone. The results obtained show the expression of various CYPs (CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4) in human foetus and their involvement in metabolism of CYP probe substrates.</p>

Regulation of liver development: implications for liver biology across the lifespan

The liver serves a spectrum of essential metabolic and synthetic functions that are required for the transition from fetal to postnatal life. Processes essential to the attainment of adequate liver mass and function during fetal life include cell lineage specification early in development, enzymic and other functional modes of differentiation throughout gestation, and ongoing cell proliferation to achieve adequate liver mass. Available data in laboratory rodents indicate that the signaling networks governing these processes in the fetus differ from those that can sustain liver function and mass in the adult. More specifically, fetal hepatocytes may develop independent of key mitogenic signaling pathways, including those involving the Erk mitogen-activated protein kinases MAPK1/3 and the mechanistic target of rapamycin (mTOR). In addition, the fetal liver is subject to environmental influences that, through epigenetic mechanisms, can have sustained effects on function and, by extension, contribute to the developmental origin of adult metabolic disease. Finally, the mitogen-independent phenotype of rat fetal hepatocytes in late gestation makes these cells suitable for cell-based therapy of liver injury. In the aggregate, studies on the mechanisms governing fetal liver development have implications not only for the perinatal metabolic transition but also for the prevention and treatment of liver disorders throughout the lifespan.