Liver cirrhosis is characterized by fibrosis of the liver secondary to chronic injury, which leads to an alteration in the normal lobular organization of the liver. Cirrhosis is a clinically significant affliction that has an impact on the morbidity and mortality of patients (1,2). Cirrhosis is typically classified as compensated or decompensated. In compensated cirrhosis, the liver can maintain its important functions and patients can remain asymptomatic for the first few years, until diagnosis (3). In decompensated cirrhosis, abnormal liver function test results are observed (including elevated serum transaminase) and patients develop notable health problems (including jaundice, bleeding varices in the esophagus, ascites and hepatic encephalopathy) (4). The median survival time of patients with compensated cirrhosis is <12 years. By contrast, in decompensated cirrhosis, the median survival time is 2-4 years, with a rate of transition of 5-7% each year (5). Liver cirrhosis is a notable health problem and its prevalence is difficult to estimate as patients often present in the advanced stages of disease; thus, the incidence of this disease may be underestimated. The incidence of liver cirrhosis in Europe is estimated to be 26 cases per 100,000 individuals; in Asia, its prevalence is 16-23 cases per 100,000 individuals (6,7). Liver cirrhosis affects both sexes, predominantly between the ages of 40 and 60 years old. The majority of patients die within 12 years (8), on average and, based on the Global Burden of Liver Disease 2023, >2 million individuals die annually from this disease, citing it as the 14th leading cause of death (9-11). In Mexico, liver cirrhosis is the sixth leading cause of mortality, with a case fatality rate of 34.2 per 100,000 individuals and an incidence of 3.7% (12-14).

There are multiple etiological causes of cirrhosis that vary geographically. For instance, in Western countries, alcoholism, metabolic-associated fatty liver disease, alcoholic liver disease and hepatitis C virus (HCV) infection are the most common causes (15). By contrast, chronic hepatitis B virus (HBV) infection is the primary cause of liver cirrhosis in the Asia-Pacific region (16). Other less common causes of liver cirrhosis include hemochromatosis (17), Wilson's disease (18), primary sclerosing cholangitis (19), primary biliary cirrhosis (20) and autoimmune-related cirrhosis (21). However, it is considered that ~60% of liver cirrhosis cases have an alcoholic origin (22,23), and that 24% have non-alcoholic origins (7,24). Chronic liver disease is a progressive deterioration of liver function characterized by inflammation leading to fibrosis, cirrhosis and hepatocarcinoma. Hepatic fibrosis is the formation of a fibrous scar that results from the accelerated production of extracellular matrix components for myofibroblasts and hepatic stellate cells (HSCs) (25,26). Furthermore, liver fibrosis results from chronic liver injuries such as hepatotoxic injury caused by chronic HBV and/or HCV infections and immoderate alcohol consumption or metabolic syndromes that induce non-alcoholic fatty liver disease (NAFLD), characterized by liver steatosis exceeding 5% that can progress to non-alcoholic steatohepatitis (NASH) which is characterized by liver injury caused by excessive liver fat, inflammation and faster fibrosis progression, which can lead to cirrhosis and liver cancer (27).

Managing liver cirrhosis depends on the cause and extent of liver damage (28). The goal of treatment is to delay the progression of disease in the damaged liver by treating the etiological factors that contribute to the chronic injury and to decrease the production of proinflammatory or profibrogenic cytokines. The latter is the most direct and perhaps the most effective method of treating liver fibrosis (4). The treatment options include inhibition of HSC activation, HCV- and HBV-specific treatments, weight loss, maintaining healthy levels of blood sugar and lipids, no alcohol intake and anti-inflammatory and immunosuppressive therapies (29). In addition, a number of studies have been conducted using antifibrotic drugs such as silymarin (30), vitamin E (31) and obeticholic acid (32). Combination therapy may be convenient in terms of treating the etiologic, metabolic, anti-inflammatory and antifibrotic aspects of the disease (33).

Pentoxifylline (PTX) is a methylxanthine derivative and a non-specific phosphodiesterase inhibitor. PTX was approved by the U.S. Federal Drug Administration in 1984 for treating leg pain due to claudication (34). Several preclinical and clinical studies have provided evidence that PTX has potent anti-inflammatory and antifibrotic properties (35,36). PTX inhibits the NF-κB transcription factor, decreasing the proinflammatory cytokine levels in the liver (37). PTX can decrease pulmonary fibrosis in patients who are administered chemotherapy and radiotherapy (38), and is potentially effective in treating NAFLD (39,40). Additionally, PTX exhibits an antitumor effect in hepatocellular carcinoma (41). The present study aimed to evaluate the improvement in the survival of patients with compensated cirrhosis administered long-term PTX.

Despite advances in medical care and additional expenditure in the treatment of liver cirrhosis, the mortality rate has increased (46). Patients with liver cirrhosis have a life expectancy of 2-12 years. In the present study, 37 of the 118 patients with compensated liver cirrhosis were treated with PTX. The most notable observation of the present study was the increased life expectancy in patients treated with PTX, which was 20 years; this represented an increase of Δ%=80 in life-years, compared with the overall survival time of the historical background and with those 81 (68.6%) patients who died within the first 12 years following a cirrhosis diagnosis, which was consistent with that previously reported (1,5,43,44).

The comorbidities of patients with cirrhosis include other diseases that are not caused by cirrhosis but comprise risk factors that increase mortality. In this regard, 43.2% of patients treated with PTX in the present study did not develop other diseases. In further studies, it will be interesting to ascertain the role of PTX in the incidence of such comorbidities. In addition, serum AST, TP and TBili levels exhibited slight progressive increases that were statistically significant but not clinically relevant. By contrast, PTX reduced ALT serum levels by ~12% after 20 years. These results can indicate good hepatic function or a reduction in inflammation without the disappearance of the disease. It is noteworthy that the natural progression of cirrhosis did not cease in the present study; 4 patients continued in Child-Pugh class A (well-compensated disease), 24.3% of patients progressed to class B (significant functional compromise) and 64.8% of patients progressed to class C (decompensated disease) within a period of 20.6 years. However, PTX significantly delayed the progression of the disease with a more prolonged overall survival time compared with that estimated in the patients studied. Recently, we published encouraging results utilizing PTX to treat patients with fulminant C hepatitis, Hepatocellular carcinoma and Hepatitis C; we demonstrated that PTX has improved medical conditions and increased patient survival rates (47-49). These studies support our hypothesis of the potential benefits of PTX in treating compensated cirrhosis.

PTX is a methylxanthines derivative and is a less expensive drug with >30 years of clinical use in reducing blood viscosity and platelet aggregation. PTX possesses anti-inflammatory, antioxidant, antitumor and antifibrotic properties (50), and suppresses NF-κB activation, specifically suppressing proinflammatory gene transcription, preventing tumor necrosis factor (TNF)α, interleukin (IL)-6 and transforming growth factor (TGF)-β synthesis (35). Additionally, PTX inhibits cyclooxygenase activity and fibrosis. Elevated serum concentrations of proinflammatory cytokines, such as TNFα, IL-1β, IL-6, interferon-γ and TGF-β, contribute to liver cell necrosis and the fibrotic development of liver cirrhosis (51). Several reports have demonstrated that PTX inhibits TNFα (37,52-54). In addition, it has been shown that PTX can reduce the development of hepatorenal syndrome and improve the survival of patients with this disease (55). Oakley et al (56) reported that inhibition of the kinase/NF-κB pathway is sufficient to increase the rate at which activated HSCs undergo apoptosis both in vitro and in vivo, and it was concluded that drugs that inhibit this pathway have potential therapeutic benefits. Other reports in the literature support the observations of the present study in that it is well-known that PTX exhibits a protective effect against chemotherapy- and radiotherapy-induced fibrosis (57), and PTX is also well-known to possess antifibrotic effects (50,58). In addition, PTX inhibits the TGF-β/SMAD pathway, reducing fibroblast activity and inhibiting fibrosis (36). Furthermore, PTX is well-tolerated and effective as a treatment for NASH and is an effective option in the treatment of complications of advanced liver disease (59,60). Collectively, these data provide an alternative explanation for the effect of PTX on the increased life expectancy of patients with compensated liver cirrhosis. In addition, our previous research has indicated that PTX may be beneficial in managing fulminant hepatitis and hepatocarcinoma (41,48).

With the data available, it is impossible to identify the underlying effects of PTX in patients with cirrhosis; the only hypotheses that could be arrived at concern the proposed antioxidant, anti-inflammatory and antifibrotic effects. Notably, PTX did not cause severe adverse events or side effects; only eight patients (3%) who received a PTX + propranolol-based regimen showed nausea and vomiting, but the patients did not discontinue their medications. The present study demonstrated that PTX was well-tolerated in patients with cirrhosis for 20.6 years, and the data suggested that PTX may be a candidate for repurposing in compensated cirrhosis. The strength of the present study lies in that, to the best of our knowledge, there has been no other similar study. Nonetheless, one limitation of the present study is that it was conducted at a single hospital and included a small number of clinical records. Prospective studies are therefore needed to further validate PTX administration management in patients with cirrhosis.