Milk thistle may improve steatohepatitis, capsaicin from chilli peppers may slow fibrosis

People who used silymarin, derived from the milk thistle plant, experienced a resolution of non-alcoholic steatohepatitis (NASH) and a reduction in liver fibrosis in a randomised, placebo-controlled trial, researchers reported at the European Association for the Study of the Liver (EASL) 50th International Liver Congress held in April in Vienna, Austria. Another study found that dietary capsaicin, derived from chili peppers, was associated with improvement in mice with artificially induced fibrosis, the precursor to cirrhosis.

While effective new direct-acting antiviral drugs can now cure most people with hepatitis C and older therapies can suppress hepatitis B indefinitely, managing liver injury resulting from long-term infection, as well as liver damage due to other causes, remains a challenge.

A number of herbal therapies have been used to treat liver disease, with some – such as milk thistle – being common across different regional medical traditions. Results from a global survey of people with hepatitis C presented at the International Liver Congress showed that almost all respondents had tried herbal remedies either to slow liver disease progression or to ameliorate symptoms.

Wah Kheong Chan of the University of Malaya in Kuala Lumpur and colleagues conducted a randomised, double-blind, placebo-controlled trial to evaluate silymarin for the treatment of NASH, or liver fat accumulation and inflammation not associated with alcohol use. NASH and its less severe form, non-alcoholic fatty liver disease (NAFLD), rival viral hepatitis and heavy alcohol consumption as a cause of cirrhosis and liver cancer.

Silymarin, derived from the milk thistle plant Silybum marianum, has been shown to have anti-oxidant, anti-inflammatory and anti-fibrotic properties in laboratory, animal and human studies.

This poster presentation included 64 participants with biopsy-confirmed NASH who had completed the study at the time of the interim analysis. More than half were women and the average age was 50 years. A majority had grade 2 (moderate) steatosis and inflammation, followed by stage 1 (mild), with a small number having stage 3 (severe). The average NAFLD activity score – which incorporates steatosis, inflammation, and swelling or 'ballooning' of hepatocytes – was 5, with two-thirds having scores of 5-8. A majority of participants had absent or mild liver fibrosis (stage F0-F1), but about one-third had advanced (F3) fibrosis.

Participants were randomly assigned to receive 700mg silymarin three times daily or placebo for 48 weeks, along with counselling about lifestyle factors such as diet and weight loss. Repeat liver biopsies were performed at the end of the study.

More people in the silymarin group experienced at least a 30% improvement in their NAFLD activity score after 48 weeks compared to the placebo group (33% vs 21%, respectively), but the difference did not reach statistical significance. However, significantly more people in the silymarin arm experienced NASH resolution, defined as NAFLD activity score <3 (13% vs 0%, respectively).

Similar proportions of participants in both groups showed some improvement in their NAFLD activity scores (60% vs 59%), and participants in both groups experienced significant improvement in these scores relative to baseline (mean -0.733 with silymarin and -0.706 with placebo).

About the same proportion of people in both the silymarin and placebo groups saw an improvement in steatosis (23% vs 24%). Fewer people in the silymarin group experienced improvement in inflammation compared to the placebo group (27% vs 41%), but the difference was not significant. Half of people in the silymarin group and 35% in the placebo group saw an improvement in hepatocyte ballooning, again not a significant difference.

Fibrosis scores decreased significantly in the silymarin group (mean -0.367), while there was no notable change in the placebo group (mean +0.147). A significantly higher proportion of people in the silymarin group showed improvement in their fibrosis score (37% vs 15%, respectively). Four people in the placebo group (12%) developed liver cirrhosis during follow-up, while none in the silymarin group did so.     

"A significantly higher percentage of patients experienced NASH resolution and improvement in fibrosis stage after 48 weeks of treatment with silymarin compared to placebo," the researchers concluded.

Chronic hepatitis B or C, heavy alcohol use and other factors can cause liver fibrosis, or accumulation of collagen and other scar tissue components. Over years or decades, this can progress to cirrhosis, in which scar tissue blocks blood circulation and replaces so much functional liver tissue that vital functions are impaired. Though the process is not fully understood, hepatic stellate cells (HSCs) are known to play a key role in fibrosis development and progression.

Shanna Bitencourt of Vrije Universiteit in Brussels and colleagues evaluated the inhibitory effects of capsaicin as a dietary supplement on HSC activity in mice with artificially induced liver fibrosis.

Laboratory studies have shown that capsaicin – the main compound that gives chilli peppers their heat – can affect the activation, proliferation, and migration of HSCs in vitro, the researchers noted as background.

In this study, mice were given capsaicin as a dietary supplement mixed in their chow (0.01%). Some mice were subject to bile duct ligation to simulate cholestasis or bile accumulation, which can lead to fibrosis. Others were exposed to carbon tetrachloride, a chemical sometimes used as a cleaning agent and fire extinguisher that is toxic to the liver. The researchers dissected the mouse livers and isolated and analysed their HSCs. In addition, freshly isolated HSCs were cultured and exposed to capsaicin for 7 days in vitro.

Capsaicin partially improved liver damage in the bile duct ligation mice. Dissected livers showed decreased collagen deposition and fewer areas of necrosis (dead tissue), while isolated HSCs showed down-regulation of markers associated with fibrosis.

Capsaicin inhibited further progression of liver injury in mice with ongoing exposure to carbon tetrachloride. Mice that were fed capsaicin prior to toxin exposure were protected against development of liver injury and up-regulation of fibrosis activation markers. However, capsaicin did not reduce toxin-induced fibrosis that was already established before mice received the supplement. Capsaicin treatment also inhibited autophagic flux, or self-degradation of cells.

"Dietary capsaicin decreases the severity of liver injury" in mouse bile duct ligation and "hinders fibrogenesis" in the bile duct ligation and carbon tetrachloride-induced liver fibrosis models, the researchers summarised.

"Collectively, these results support that daily dietary consumption of capsaicin has beneficial effects on liver injury, especially on HSC activation," they concluded.