Novel and Emerging Therapies
Emerging therapies for cirrhosis mostly target the pathways that initiate hepatic fibrosis (Rockey 2013).
PPAR-γ is a nuclear receptor that is predominantly found in liver and adipose tissue. It becomes active when it senses fatty acids (and some anti-diabetic drugs) within cells, and responds in turn by activating genes that regulate lipid metabolism and fat cell growth (Zhang, Kong 2013). While it is a target for medications that restore insulin sensitivity in diabetics and promote fatty acid metabolism in high cholesterol, PPAR-γ also plays an important role in liver repair. During liver damage, specialized storage cells in the liver called hepatic stellate cells become active, multiplying and producing large amounts of fibrous matrix, which is a central event in hepatic fibrogenesis and cirrhosis. PPAR-γ inhibits this fibrosis, making it an attractive target for anti-fibrotic therapies (Zhang, Kong 2013; Deng 2012). Thiazolidinediones, originally developed as anti-diabetic drugs, activate PPAR-γ and have shown mixed results for hepatic fibrosis in animal investigations and early clinical trials; multiple larger trials of several candidates (pioglitazone [Actos], Rosiglitazone [Avandia], GFT505) for use in the treatment of fibrosis from NASH are underway or have recently been completed (Schuppan 2013).
Ursodeoxycholic acid (UDCA; Ursodiol), a natural constituent of bile, is the only approved pharmacological treatment for primary biliary cirrhosis, a disease that can cause liver cirrhosis (Corpechot 2000; Intercept Pharmaceuticals 2014). However, UDCA has broader pharmaceutical applications that are rarely appreciated or even understood. It is a promising therapy that deserves, and is indeed the subject of, further trials for chronic liver disease.
In a long-term (1-2 year) placebo-controlled trial evaluating UDCA (with or without vitamin E) in patients with NASH, those who received UDCA and vitamin E experienced a statistically significant reduction in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as significant improvements in liver tissue structure including steatosis, cellular injury, and inflammation (Dufour 2006). A two-week, double-blind, crossover study compared UDCA to placebo for 10 cirrhotic patients with indigestion and excess fat in their stools. During the trial, both groups ate an identical controlled diet. The treatment reduced indigestion symptoms common in cirrhosis; lowered the amount of fat in the stool, a sign of improved fat digestion; and significantly reduced AST levels in the blood (Salvioli 1990). Another uncontrolled trial using UDCA significantly lowered ALT in cirrhotic patients during a 15-month trial (Buongiorno 1994). In an uncontrolled trial that followed 100 patients over more than five years, UDCA was used as a hepatic anti-inflammatory in an attempt to prevent progression from early hepatitis C-associated cirrhosis to hepatocellular carcinoma. Subjects not taking UDCA had two and a half times the risk of developing hepatocellular carcinoma as did those taking placebo (Tarao 2005).
By inhibiting the pro-inflammatory mediator tumor necrosis factor-alpha (TNF-α), pentoxifylline may attenuate liver inflammation, one of the initiators of liver fibrosis (Jaurigue 2014). In an animal model of cirrhosis, it prevented the development of hepatopulmonary syndrome; it also decreased the risk of hepatorenal syndrome in cirrhosis patients in several studies (Sztrymf 2004; Parker 2013). A systematic review of pentoxifylline trials has shown conflicting data on survival of patients with chronic liver diseases (Jaurigue 2014). Pentoxifylline has also shown mixed results on reducing liver fibrosis in patients with hepatitis C infection or NASH, with several trials underway or recently completed (Schuppan 2013).
Current evidence points to pentoxifylline as an effective therapy to reduce the risk of severe hepatorenal syndrome in alcoholic hepatitis, but without apparent improvement in overall survival. It is recommended by several major gastroenterology organizations as a second-line therapy for severe alcoholic hepatitis for those in whom corticosteroids are contraindicated (Jaurigue 2014).
Angiotensin II Receptor Blockers
The renin-angiotensin system, which is central to the regulation of blood volume and pressure, has long been a therapeutic target for the treatment of hypertension and congestive heart failure (Li 2004; Volpe 2002). It may also represent a target for novel anti-fibrotic drugs. During chronic liver injury, overproduction of the hypertensive hormone angiotensin II can stimulate the activation of hepatic stellate cells and their overproduction of fibrous tissue in the liver (Kim 2012). Angiotensin II receptor blockers (ARBs) may block this interaction. Several ARBs (losartan [Cozaar], telmisartan [Micardis], olmesartan [Benicar], candesartan [Atacand], and valsartan [Diovan]) have been shown to reduce fibrosis in multiple animal studies and human trials of NASH and NAFLD (Georgescu 2008). A trial of a combination of candesartan and UDCA (a prescription isolated and concentrated bile acid) versus UDCA alone reduced measures of fibrosis in subjects with compensated alcoholic liver fibrosis (Kim 2012). Of the several available ARBs, telmisartan appears most intriguing because in addition to having demonstrated beneficial effects in various animal cirrhosis or fibrosis models (Tamaki 2013; Mende 2013; Jin 2007), it also activates an important modulator of metabolic activity called PPAR-gamma (Benson 2004). The PPAR-gamma signaling pathway is important for optimal mitochondrial function and the formation of new mitochondria, and this pathway appears to be downregulated among people with insulin resistance compared to healthy individuals (Patti 2003; Din 2014). Moreover, PPAR-gamma and associated metabolic pathways are thought to mediate some of the beneficial effects of caloric restriction and help promote cellular stress resistance and longevity; thus, agents that activate PPAR-gamma, like telmisartan, have gained the attention of longevity researchers as potential anti-aging interventions (Corton 2005; Scalera 2008).
As a word of caution, it is worth noting that the combination of an ARB with an angiotensin converting enzyme (ACE) inhibitor caused severe hepatic encephalopathy in a patient with cirrhosis, portal hypertension, and kidney disease in one case study, which reversed when the combination was discontinued (Oertelt-Prigione 2010).
Lysyl Oxidase Inhibitors
Lysyl oxidase is an enzyme responsible for cross-linking collagen fibrils, one of the final steps in the maturation of the fibrous matrix produced during liver fibrosis. Additionally, lysyl oxidase is also thought to inhibit the breakdown of fibrous matrix, preventing the reversal of fibrosis. A humanized antibody (simtuzumab) against LOXL2 (one of the lysyl oxidase enzymes) is the subject of two trials for liver fibrosis at the time of this writing (Schuppan 2013).
Liver transplant remains the only definitive cure for end-stage, fibrotic liver disease. Given the shortage of donor livers, stem cell therapy may prove a useful alternative for replenishing hepatocytes, reducing inflammation, and reversing liver fibrosis in patients with cirrhosis or liver failure. Several human trials have investigated the use of mesenchymal (connective tissue), bone marrow-derived, or hematopoietic (blood-derived) stem cells in patients with liver failure or cirrhosis, and have revealed improvements in liver function, liver volume, and MELD or Child-Pugh score (Zhang, Wang 2013); several more trials are underway (Schuppan 2013).
Liver dialysis has similarities to kidney dialysis; aiming to filter blood through an external device to provide short-term support to the liver (extracorporeal liver support therapy) (Stange 2011). Since many blood toxins are tightly bound to albumin molecules in circulation, liver dialysis devices must selectively separate these toxins from the albumin, while preserving albumin levels in the blood. The use of this therapy is more prevalent outside the United States, though multiple reviews have reached varying conclusions about its degree of improvement to mortality and avoidance of liver transplant. Its primary indication is as a “bridge to transplant” – a palliative treatment that can be used while waiting for a liver transplant (Nevens 2012; Zheng 2013; Krisper 2011). Several different methodologies are in use: molecular adsorbent recirculating system (MARS); Prometheus dialysis; plasma exchange combined with hemodialysis (PE/HD); and single-pass albumin dialysis (SPAD) (Schaefer 2013).
Metformin Continuation in Diabetics with Cirrhosis
The prevalence of diabetes in patients with cirrhosis – reported at 37% – is five times higher than in those without cirrhosis. Moreover, cirrhotic patients who have diabetes are at increased risk of liver-related complications and death compared to those without diabetes (Zhang 2014).
Metformin, one of the most widely prescribed anti-diabetic drugs worldwide (Chen 2013), has been associated with reduced risk of several forms of cancer, including liver cancer, in diabetics (Thakkar 2013; Zhang, Li 2013). Since patients with cirrhosis have an increased risk of hepatocellular carcinoma, these findings raise the intriguing possibility that use of metformin in cirrhosis patients who have diabetes may provide protection against liver cancer in this at-risk population. On the other hand, the impact of liver impairment on the metabolism of metformin has not been extensively investigated, and some clinicians discontinue metformin in diabetics upon diagnosis of cirrhosis, citing concerns over increased risk of lactic acidosis (Scheen 2014; Zhang 2014). However, a 2014 study suggests that the benefits of metformin use in diabetics with cirrhosis may outweigh the risks (Zhang 2014).
Researchers analyzed data on 250 diabetics diagnosed with cirrhosis between 2000 and 2010. One hundred seventy-two of these subjects continued taking metformin after being diagnosed with cirrhosis, while 78 discontinued the drug. The median survival time for those who continued metformin was 11.8 years, whereas those who stopped using metformin survived for a median of 5.6 years. The study authors noted that “Continuation of metformin after cirrhosis diagnosis reduced the risk of death by 57%.” Importantly, they also highlighted the fact that “No patients developed metformin-associated lactic acidosis during follow-up.” Based upon their findings, the researchers concluded that “ Metformin should therefore be continued in diabetic patients with cirrhosis if there is no specific contraindication” (Zhang 2014).