Cirrhosis - Emerging treatments

Antifibrotic agents

There are many antifibrotic agents being considered for therapeutic use in chronic liver disease, (e.g., silymarin, transforming growth factor [TGF]-beta antagonists, endothelin-receptor antagonists, ACE inhibitors, and relaxin). As it stands, there are no clinically approved therapies for liver fibrosis. Several are in phase 2 and 3 clinical trials, including drugs targeting the farnesoid X receptor, peroxisome proliferator-activated receptors (PPARs), and chemokine receptors.[177] Macitentan, an endothelin-receptor antagonist, may benefit patients with portopulmonary hypertension, but is not approved for this indication.[165]

Pentoxifylline

Pentoxifylline is a phosphodiesterase inhibitor with anti-inflammatory properties that lowers blood viscosity and improves erythrocyte flexibility. Pro-inflammatory cytokines, including tumour necrosis factor (TNF)-alpha and interleukin-6, are elevated in patients with cirrhosis in response to endotoxaemia. These cytokines lead to a pro-inflammatory, hyperdynamic state. Pentoxifylline has been shown not only to decrease levels of TNF-alpha but also to increase systemic vascular resistance, directly opposing splanchnic vasodilation without precipitating an increase in the pressure in the portal venous system. In one randomised placebo-controlled trial of patients with advanced cirrhosis, pentoxifylline reduced the risk of complications, including bacterial infections, renal insufficiency, hepatic encephalopathy, and gastrointestinal haemorrhage, compared with placebo.[178] It did not improve short-term mortality.[178] Pentoxifylline added to the standard care of volume expansion with albumin and vasoconstriction appeared to be safe in one small randomised controlled trial of patients with type-1 hepatorenal syndrome, but further large-scale prospective studies are needed to validate the efficacy of this treatment.[179]

Cyanoacrylate injection

Although a single study suggested that cyanoacrylate injection is more effective than propranolol in preventing first bleeding in patients with large type 2 gastro-oesophageal varices or isolated gastric varices, there were no differences in survival, and further research is necessary.[54]

Microbiome-targeted therapy

Dysregulation of the gut-liver axis contributes to the development of liver disease.[180] Studies have found that the gut microbiome may be affected in cirrhosis.[181][182] Modulating the gut microbiome using targeted therapies may slow liver deterioration, reduce hepatic venous pressure gradient, and reduce the inflammation of the liver.[180][183][184] Probiotics, prebiotics, synbiotics, or fecal microbiota transplantation may be used for the modulation.[180][181][182]

Mesenchymal stem cells (MSCs)

MSCs have been found to be promising for the treatment of patients with chronic liver disease.[185][186] One meta-analysis reported improved liver function and survival rates among patients with end-stage liver disease upon treatment with MSCs.[185] Another systematic review and meta-analysis reported that MSCs had a protective effect on complications of cirrhosis and the incidence of hepatocellular carcinoma, in addition to improving liver function.[187] Further trials are needed to establish the benefits of MSCs in patients with cirrhosis.