Top Highlights in Hepatology: The Liver Meeting 2014

The Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD)

William F. Balistreri, MD


January 07, 2015

In This Article

Intrahepatic Cholestasis: Diagnosis and Management

Hereditary forms of cholestasis comprise a series of partially defined autosomal dominant and recessive disorders. The nature and biological basis of many of these disorders has been partially deciphered. For example, the genetic basis of various forms of progressive familial intrahepatic cholestasis (PFIC) is now well understood. Others remain enigmatic. Next-generation sequencing, which allows high-throughput sequencing of multiple genes, should lower the cost and time of molecular analyses and aid in identifying new genes in these disorders.

Barbu and colleagues[17] assessed the feasibility and input of a next-generation sequencing strategy for screening of the genes implicated in the recessive disorders PFIC types 1, 2, and 3 (ATP8B1, ABCB11, and ABCB4, respectively) and Dubin-Johnson syndrome (ABCC2). They also screened for candidate genes encoding transporters (ABCG5, ABCG8, SLC4A2) or bile acid receptors (NR1H4, GPBAR1).The results obtained in a small study population highlight the frequent combination of variations in genes previously known to be involved in these disorders with other genes, mainly GPBAR1 and ABCG5.

Beneficial Effects of 4-Phenylbutylate Therapy

Hayashi and colleagues[18] previously provided experimental and clinical evidence suggesting that 4-phenylbutylate (4PB) had therapeutic potency for patients with PFIC through induction of BSEP expression at the hepatocanalicular membrane. In this study, 4PB was administered orally in gradually increasing dosages (200, 350, and 500 mg/kg/day) for 4-6 months. Aspartate aminotransferase, ALT, and total and direct bilirubin levels were markedly improved after administration of 4PB at the dosage of 500 mg/kg/day in patients with PFIC type 2. Histologic improvement and partial restoration of BSEP expression at the canalicular membrane were also confirmed in liver specimens from patients with PFIC type 2.

The investigators suggest that 4PB therapy may be an effective strategy for patients with PFIC type 1 who have intractable pruritus and for those with PFIC type 2 who retain transport activity of BSEP.

Thrombospondin-2 as a Candidate Modifier of Liver Disease Severity in Alagille Syndrome

Alagille syndrome is an autosomal dominant, multisystem disorder characterized by bile duct paucity, cholestasis, cardiac disease, and other features. This disorder is primarily caused by mutations in the JAG1 gene, which encodes a ligand in the Notch signaling pathway. Liver disease severity in Alagille syndrome is highly variable, even within families carrying the same JAG1 mutation. The factors that influence liver disease severity in Alagille syndrome are unknown.

Loomes and colleagues,[19] hypothesizing that genetic modifiers may contribute to the variable expressivity, carried out a genome-wide association study (GWAS) comparing patients with mild (n = 103) vs severe (n = 73) liver disease. GWAS identified a single nucleotide polymorphism upstream of thrombospondin-2 (THBS2) that correlated with liver disease severity in Alagille syndrome. THBS2 is known to augment JAG1/Notch interactions, and THBS2 is expressed in mouse bile ducts. Therefore, THBS2 is the first plausible candidate to be a genetic modifier of liver disease severity in patients with Alagille syndrome. Further studies will be required to determine the effect of the single nucleotide polymorphism on THBS2 expression and function.

Hepatocyte-Targeted RNA Interference-Based Treatment for Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin (AAT) deficiency causes pulmonary disease in adults and liver disease in children and adults. Wild-type AAT is a 52-kDa circulating glycoprotein produced primarily in liver hepatocytes. The PiZ mutation results in improper AAT processing and impairs its secretion by hepatocytes.

Wooddell and colleagues[20] reported initial results of an RNA interference (RNAi)-based therapeutic designed to reduce Z-AAT aggregates in liver and proposed that this strategy will prevent the progression and development of AAT deficiency-associated liver disease in individuals with PiZ mutations. They demonstrated dramatic and long-lasting reduction of AAT after coinjection of chol-UNA and MLP (CDM-NAG) in the PiZ mouse model and in cynomolgus monkeys. Repeat dosing prevented or reversed the accumulation of Z-AAT aggregates in the PiZ mouse. This RNAi therapeutic holds promise for the treatment of patients with AAT deficiency-associated liver disease.


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