Onset Of End-stage Liver Disease Research Articles

S3221 Adult Onset Progressive Familial Intrahepatic Cholestasis: A Rare Presentation

Introduction: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive childhood genetic disorders that disrupt intrahepatic biliary secretion. PFIC accounts for 10 to 15% of children's cholestatic diseases and liver transplantation. Although all patients will require liver transplantation at a certain point, early diagnosis and intervention can delay complications and transplantation. Case Description/Methods: A 41-year-old male presented with cryptogenic cirrhosis and a MELD score of 35 for transplantation evaluation. He had a childhood history of abnormal liver enzymes with a mixed pattern and cholecystectomy due to recurrent gallstones. Prior liver biopsy showed autoimmune features; however, there was no significant response to the conventional therapy with prednisone and azathioprine. However, a re-evaluation of his liver biopsy favored biliary disease: subsequent MRCP with normal bile ducts. Given the insidious onset of his cirrhosis without an identifiable etiology and the suggestion of biliary cause, PFIC was considered during pre-transplantation workup. Genetic testing for ABCB4 confirmed PFIC type 3; subsequently, he underwent liver transplantation with an unremarkable post-operative course. Discussion: This case highlights the impact of exploring a diagnosis of PFIC in adults referred for liver transplantation with long-standing cholestatic liver disease and negative initial workup. While currently, liver transplantation is the primary treatment option for end-stage liver disease from PFIC, advances in gene therapy have led to potentially curative treatments. As such, improved provider awareness and having a lower threshold for diagnostic testing may lead to an earlier diagnosis which is critical for optimal management, delaying the onset of end-stage liver disease, and offering to screen for family members.

Case report: progressive familial intrahepatic cholestasis type 3 with compound heterozygous ABCB4 variants diagnosed 15\u2009years after liver transplantation

BackgroundProgressive familial intrahepatic cholestasis (PFIC) type 3 is an autosomal recessive disorder arising from mutations in the ATP-binding cassette subfamily B member 4 (ABCB4) gene. This gene encodes multidrug resistance protein-3 (MDR3) that acts as a hepatocanalicular floppase that transports phosphatidylcholine from the inner to the outer canalicular membrane. In the absence of phosphatidylcholine, the detergent activity of bile salts is amplified and this leads to cholangiopathy, bile duct loss and biliary cirrhosis. Patients usually present in infancy or childhood and often progress to end-stage liver disease before adulthood.Case presentationWe report a 32-year-old female who required cadaveric liver transplantation at the age of 17 for cryptogenic cirrhosis. When the patient developed chronic ductopenia in the allograft 15 years later, we hypothesized that the patient’s original disease was due to a deficiency of a biliary transport protein and the ductopenia could be explained by an autoimmune response to neoantigen that was not previously encountered by the immune system. We therefore performed genetic analyses and immunohistochemistry of the native liver, which led to a diagnosis of PFIC3. However, there was no evidence of humoral immune response to the MDR3 and therefore, we assumed that the ductopenia observed in the allograft was likely due to chronic rejection rather than autoimmune disease in the allograft.ConclusionsTeenage patients referred for liver transplantation with cryptogenic liver disease should undergo work up for PFIC3. An accurate diagnosis of PFIC 3 is key for optimal management, therapeutic intervention, and avoidance of complications before the onset of end-stage liver disease.

Biliary fibrosis drives liver repopulation and phenotype transition of transplanted hepatocytes

Current research focuses on developing alternative strategies to restore decreased liver mass prior to the onset of end-stage liver disease. Cell engraftment/repopulation requires regeneration in normal liver, but we have shown that severe liver injury stimulates repopulation without partial hepatectomy (PH). We have now investigated whether a less severe injury, secondary biliary fibrosis, would drive engraftment/repopulation of ectopically transplanted mature hepatocytes. Ductular proliferation and progressive fibrosis in dipeptidyl-peptidase IV (DPPIV)(-) F344 rats was induced by common bile duct ligation (BDL). Purified DPPIV(+)/green fluorescent protein (GFP)(+) hepatocytes were infused without PH into the spleen of BDL rats and compared to rats without BDL. Within one week, transplanted hepatocytes were detected in hepatic portal areas and at the periphery of expanding portal regions. DPPIV(+)/GFP(+) repopulating cell clusters of different sizes were observed in BDL rats but not untreated normal recipients. Surprisingly, some engrafted hepatocytes formed CK-19/claudin-7 expressing epithelial cells resembling cholangiocytes within repopulating clusters. In addition, substantial numbers of hepatocytes engrafted at the intrasplenic injection site assembled into multicellular groups. These also showed biliary "transdifferentiation" in the majority of intrasplenic injection sites of rats that received BDL but not in untreated recipients. PCR array analysis showed upregulation of osteopontin (SPP1). Cell culture studies demonstrated increased Itgβ4, HNF1β, HNF6, Sox-9, and CK-19 mRNA expression in hepatocytes incubated with osteopontin, suggesting that this secreted protein promotes dedifferentiation of hepatocytes. Our studies show that biliary fibrosis stimulates liver repopulation by ectopically transplanted hepatocytes and also stimulates hepatocyte transition towards a biliary epithelial phenotype.

Intracellular processing of alpha1-antitrypsin.

α(1)-Antitrypsin (AAT) secreted from hepatocytes is an inhibitor of neutrophil elastase. Its normal circulating concentration functions to maintain the elasticity of the lung by preventing the hydrolytic destruction of elastin fibers. Severely diminished circulating concentrations of AAT, resulting from the impaired secretion of genetic variants that exhibit distinct polypeptide folding defects, can function as an etiologic agent for the development of chronic obstructive pulmonary disease. In addition, the inappropriate accumulation of structurally aberrant AAT within the hepatocyte endoplasmic reticulum can contribute to the etiology of liver disease. This article focuses on the discovery and characterization of a biosynthetic quality control system that contributes to the secretion of AAT by first facilitating its proper structural maturation, and then by orchestrating the selective elimination of those molecules that fail to attain structural maturation. Mechanistic elucidation of these interconnected quality control events recently led to the identification of an underlying genetic modifier capable of accelerating the onset of end-stage liver disease by impairing the efficiency of an initial step in the protein disposal process.

Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency.

Inappropriate accumulation of the misfolded Z variant of alpha1-antitrypsin in the hepatocyte endoplasmic reticulum (ER) is a risk factor for the development of end-stage liver disease. However, the genetic and environmental factors that contribute to its etiology are poorly understood. ER mannosidase I (ERManI) is a quality control factor that plays a critical role in the sorting and targeting of misfolded glycoproteins for proteasome-mediated degradation. In this study, we tested whether genetic variations in the human ERManI gene influence the age at onset of end-stage liver disease in patients homozygous for the Z allele (ZZ). We sequenced all 13 exons in a group of unrelated Caucasian ZZ transplant recipients with different age at onset of the end-stage liver disease. Homozygosity for the minor A allele at 2484G/A (refSNP ID number rs4567) in the 3'-untranslated region was prevalent in the infant ZZ patients. Functional studies indicated that rs4567(A), but not rs4567(G), suppresses ERManI translation under ER stress conditions. These findings suggest that the identified single-nucleotide polymorphism can accelerate the onset of the end-stage liver disease associated with alpha1-antitrypsin deficiency and underscore the contribution of biosynthetic quality control as a modifier of genetic disease.

Growth, nutritional status, body composition, and energy expenditure in prepubertal children with Alagille syndrome

Objectives: To describe the patterns of growth, nutritional status, body composition, and resting energy expenditure (REE) in prepubertal children with Alagille syndrome (AGS) before the onset of end-stage liver disease. Study design: Thirteen prepubertal subjects with AGS (8 male; mean age, 6.8 ± 2.8 years) were evaluated for growth parameters, body composition by skinfolds and by dual-energy x-ray absorptiometry, and REE by indirect calorimetry. The children with AGS were compared with a healthy, age-matched reference group of 37 prepubertal children. Results: Compared with healthy children, children with AGS had significantly reduced ( P < .05) growth (weight, weight z score, height, height z score), nutritional status (midarm circumference, triceps skinfold, and midarm muscle area), and body composition (fat mass and fat-free mass). Subscapular thickness, percent body fat, and REE were not different. The AGS subgroup (n = 4) with REE greater than 110% predicted value had a reduced percent body fat ( P < .02). Conclusions: Growth and body composition abnormalities are common in prepubertal children with AGS. (J Pediatr 1999;134:172-7)