Protective Effects of Coffee Consumption Following Liver Transplantation for Hepatocellular Carcinoma in Cirrhosis

Georg Wiltberger; Yan Wu; Undine Lange; Hans-Michael Hau; Elliot Tapper; Felix Krenzien; Georgi Atanasov; Christian Benzing; Linda Feldbrügge; Eva Csizmadia; Johannes Broschewitz; Michael Bartels; Daniel Seehofer; Sven Jonas; Thomas Berg; Phillip Hessel; Rudi Ascherl; Ulf P. Neumann; Johann Pratschke; Simon C. Robson; Moritz Schmelzle

Disclosures

Aliment Pharmacol Ther. 2019;49(6):779-788. 

In This Article

Abstract and Introduction

Abstract

Background: Increasing evidence suggests that coffee consumption might protect against hepatocellular carcinoma (HCC) and liver cirrhosis-associated death risk. Caffeine is a natural antagonist to extracellular adenosine and exhibits experimental tumoricidal activity.

Aim: To evaluate if coffee consumption has beneficial effects on HCC recurrence after orthotopic liver transplantation (OLT).

Methods: Coffee consumption of patients before and after OLT for HCC was assessed and correlated with HCC recurrence. HepG2 cells were analysed for proliferation and metastasis potential after treatment with adenosine, in the presence or absence of adenosine receptor antagonists. Expression of adenosine receptors was determined, and known adenosine-mediated cancer pathways inclusive of MAPK and NF-kappa B were tested.

Results: Ninety patients underwent OLT for HCC. Sixteen (17.8%) patients experienced HCC recurrence after median time of 11.5 months (range 1-40.5). For overall survival postoperative coffee intake emerged as major factor of hazard reduction in a multivariate analysis (HR = 0.2936, 95% CI = 0.12-0.71, P = 0.006). Those with such postoperative coffee intake (≥3 cups per day) had a longer overall survival than those who consumed less or no coffee: M = 11.0 years, SD = 0.52 years vs. M = 7.48 years, SD = 0.76 years = 4.7, P = 0.029).

Conclusions: Coffee consumption is associated with a decreased risk of HCC recurrence and provides for increased survival following OLT. We suggest that these results might be, at least in part, associated with the antagonist activity of caffeine on adenosine-A2AR mediated growth-promoting effects on HCC cells.

Introduction

Hepatocellular carcinoma (HCC) is the most common primary malignant tumour of the liver and its incidence has increased continuously in Western countries over the last decades.[1] Chronic liver disease represents the major risk factor for the development of HCC, with multiple known etiological factors, eg viral hepatitis, alcohol abuse or non-alcoholic steatohepatitis.[2,3] Orthotopic liver transplantation (OLT) represents a therapeutic option with the most favourable outcome, as it offers both radical removal of the tumour and eliminates the underlying chronic liver disease in selected patients or those with early stage HCC. However, HCC recurrence following OLT remains a serious issue with up to 20% experiencing this lethal complication.[4]

Recent studies identified several risk factors for HCC recurrence, such as biological and radiological progression on the waiting list, number of tumour nodules and poor differentiation.[5,6] However, underlying mechanisms are still poorly understood and potential strategies after OLT to prevent HCC recurrence are still lacking. There is an emerging clinical evidence that coffee consumption might be associated with a more favourable outcome in chronic liver disease and chronic hepatitis.[7,8] Subgroup analysis emphasised that the benefit is also dose dependent and strong coffee drinkers have a decreased risk of HCC development in comparison to low or noncoffee drinkers.[9]

The health benefits of coffee and its relationship to human diseases inclusive of cancer has been suggested, yet the underlying mechanisms remain largely elusive.[10–12] Extracellular adenosine (ADO) is a well-known molecular signal that could drive cancer cell growth through various purinergic receptors, namely A1, A2A, A2B and A3. Caffeine, a natural A2A receptor antagonist displaying tumouricidal activity in experimental settings, has been postulated to be, at least in part, responsible for such action.[13]

The aim of this study was to determine whether coffee consumption decreases HCC recurrence and promotes survival following orthotopic OLT and to examine putative mechanisms of action.

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