COMMENTARY

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

Disclosures

January 07, 2015

In This Article

Basic Science Advances and Clinical Observations

Engineering In Vitro Human Hepatic Organoids

A central challenge in drug development is the divergence between results obtained from animal studies and from human trials. Thus, reliable in vitro human organoid models that can capture the complexity of their in vivo counterparts are crucial to gain mechanistic insights into human physiology and enable effective drug development across patient populations.

To reach this goal, Ebrahimkhani and colleagues[26] used genetic engineering and controlled heterotypic cell/cell interaction to generate human hepatic organoids. Through genetically engineering human induced pluripotent stem cells (iPS) cells, they developed a novel approach for generating and codifferentiating human iPSC-derived progenitors that results in stepwise development of complex, organ-like tissues. Within 16 days, they obtained vascularized hepatic-like tissue that contains hepatoblasts, cholangiocytes, hemogenic endothelium, stellate-like cells, and hematopoietic progenitors.

In addition, the generated hepatic environment induced and supported fetal hematopoiesis, as occurs naturally in the fetal liver. By recapitulating embryonic morphogenetic processes, they could drive complex hepatic tissue from human iPSCs, using autologous cell sources and generating stromal cells that codevelop with the parenchymal cells. This novel integrated approach paves a path toward engineering human organoid systems for a range of applications relevant to human health.

The Commensal Microbiota Is Hepatoprotective and Suppresses Liver Fibrosis

Translocation of bacteria and their products across the intestinal barrier is common in patients with liver disease, and there is strong evidence that experimental liver fibrosis depends on bacterial translocation.

Mazagova and colleagues[27] defined the role of the microbiota in liver fibrosis using conventional and germ-free mice. Chronic liver injury was induced by administration of thioacetamide, and increased fibrosis was observed only in the germ-free mice. This is the first study describing a beneficial role of the commensal microflora in maintaining liver homeostasis and suppressing liver fibrosis.

Salivary Microbiome in Patients With Cirrhosis

Gut microbiota changes are seen in patients with cirrhosis and hepatic encephalopathy. Can these changes be readily assessed in clinical practice?

Bajaj and colleagues[28] evaluated the oral microbiome in cirrhosis in comparison with the stool microbiome using 16S rRNA pyrosequencing to obtain relative abundance of microbiota. Dysbiosis, represented by reduction in commensal, autochthonous bacterial abundance, was also present in saliva in addition to stool and worsened with progressive disease and hepatic encephalopathy in patients with cirrhosis. This could represent a global mucosal/immune interface change in cirrhosis. Furthermore, oral microbiome analysis could be an easier alternative to stool to analyze dysbiosis in cirrhosis.

Steroids or Pentoxifylline for Alcoholic Hepatitis?

The short-term mortality rate in patients with severe alcoholic hepatitis exceeds 30%. Prednisolone and pentoxifylline are both currently recommended for treatment, but uncertainty persists about their benefit.

A multicenter, double-blind, randomized trial[29] designed to evaluate the therapeutic benefit of prednisolone (40 mg daily for 4 weeks) and pentoxifylline (400 mg three times daily for 4 weeks) concluded that prednisolone reduces the risk for mortality at 28 days by approximately 39%. However, this benefit was not sustained. The investigators also indicated that because pentoxifylline had no impact on disease progression, it should no longer be used for the treatment of severe alcoholic hepatitis.

Apolipoprotein AV Deficiency Exacerbates Alcohol-Induced Liver Injury

Almost all heavy drinkers will develop fatty liver, but only 20%-40% develop more severe forms of liver injury. The underlying mechanisms contributing to disease progression remain elusive. Although there are an increasing number of animal models of alcoholic liver injury, none depicts the complex metabolic profile and the typical histologic pattern.

Because apolipoprotein (apo) AV is synthesized exclusively in the liver, Wang and colleagues[30] hypothesized that it plays a critical role in regulating hepatic lipid metabolism. They demonstrated that ethanol interacts with apoAV to disrupt hepatic lipid homeostasis, leading to lipotoxic hepatocellular injury. After ethanol feeding, apoAV knockout mice displayed rapid development of liver steatosis, subsequently evolving from simple steatosis to alcoholic liver injury and then to liver fibrosis. This model closely recapitulates many characteristics of the pathogenic processes and histologic patterns of severe alcoholic liver injury, and these innovative studies elucidate a critical role of apoAV in the pathogenesis of alcoholic liver disease.

Terlipressin Plus Albumin Reverses Hepatorenal Syndrome

Boyer and colleagues[31] described the efficacy and safety of terlipressin plus albumin vs albumin alone for the treatment of hepatorenal syndrome (HRS-1), defined as rapidly deteriorating renal function (serum creatinine [SCr] ≥ 2.5 mg/dL and actual or projected doubling of SCr within 2 weeks) without improvement in renal function (< 20% reduction in SCr and SCr ≥ 2.5 mg/dL) 48 hours after both diuretic withdrawal and albumin-fluid challenge in adults with cirrhosis and ascites. Patients were randomly assigned to receive terlipressin (1 mg intravenously every 6 hours) or placebo; both groups received albumin. A higher percentage of patients in the terlipressin group achieved HRS reversal (24%) compared with the placebo group (15%). All patients in the terlipressin group whose renal function improved were alive without dialysis at day 90 vs 46% in the placebo group.

In a related observation, cirrhosis and septic shock led to changes in the hemodynamics and microcirculation. Because terlipressin improves microcirculation, reverses HRS-1, and prevents variceal bleeding when used as a vasopressor, Choudhury and colleagues[32] hoped to compare the efficacy and safety of monotherapy with terlipressin or noradrenaline in 78 patients with cirrhosis with septic shock. Terlipressin as a vasopressor was noninferior to noradrenaline, with greater hemodynamic stability, early survival benefit, improved urine output, reduced variceal bleeding, and lower incidence of nosocomial spontaneous bacterial peritonitis as well as nonfatal and reversible adverse effects. Terlipressin is recommended in patients with decompensated cirrhosis presenting with septic shock.

Acetaminophen Therapeutic Misadventure

The development of the so-called acetaminophen therapeutic misadventure (ATM) was evaluated in a large prospective study.[33] All patients (n = 271) admitted with severe acetaminophen-related hepatitis were divided into a group with acute hepatitis related to acetaminophen overdose and a group with acetaminophen use at a therapeutic dose (≤ 6 g/day), termed "ATM." Therapeutic misadventure occurs after several days of acetaminophen intake at a dosage < 6 g/day and was mainly observed in chronic alcohol consumers and rarely after prolonged starvation.

Acetaminophen intake was 16 g in patients with acetaminophen overdose vs 3 g in those with ATM, and in 70% of patients with ATM, the acetaminophen intake was below the daily 4-g dose typically considered safe. One-month survival was 85% in patients with ATM and 93% in those with acetaminophen overdose. This study is a useful reminder to clinicians that repeated intake and prescription of acetaminophen must be carefully monitored in patients with risk factors for ATM.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....