High incidence of hepatocellular carcinoma and cirrhotic complications in patients with psychiatric illness: a territory-wide cohort study

Chronic liver diseases and the resultant portal hypertension and hepatocellular carcinoma (HCC) are among the leading causes of death worldwide [1]. Psychiatric illness is also highly prevalent and accounts for 13% of disability-adjusted life-years globally [2]. Patients with psychiatric illness are at risk of different liver diseases. Alcohol and substance abuse predisposes patients to alcohol-related liver disease and hepatitis C virus infection [3]. Excessive alcohol consumption also aggravates existing liver diseases such as chronic viral hepatitis.

Moreover, non-alcoholic fatty liver disease (NAFLD) affects a quarter of the global adult population and has become one of the leading causes of cirrhosis and HCC in the Western world [4‐6]. Patients with psychiatric illness often have obesity and metabolic syndrome [7]. A number of potential mechanisms have been proposed, including activation of the hypothalamus-pituitary-adrenal axis through acute stress response, abnormalities in the autonomic nervous system, systemic inflammation and oxidative stress, and changes in appetite-controlling hormones. Patients with psychiatric illness tend to lead a more sedentary lifestyle. Second generation antipsychotics, antidepressants and mood stabilizers may be obesogenic and/or hepatotoxic [8]. Some genes (e.g. CLOCK genetic variants) affect both metabolism and mental illness [9, 10]. Besides, diabetes, cardiovascular disorders and sleep and/or circadian disruptions are common in psychiatric illness.

Accordingly, a study by the United States Veterans Integrated Services Network showed that 22.4% of patients with schizophrenia had one or more liver diseases [11]. NAFLD patients with depression also have more severe liver histology [12]. However, liver biopsy is performed in a highly selected population, which cannot represent the average patients with psychiatric illness. The magnitude of liver-related morbidity and mortality among psychiatric patients is largely unknown.

In addition, comorbid illnesses are often underdiagnosed in psychiatric patients [13]. Currently, effective treatments for many chronic liver diseases exist and may reduce the risk of cirrhotic complications and HCC [14, 15]. A better understanding of the epidemiology of chronic liver diseases among patients with psychiatric illness would allow policymakers to determine the value of screening and formulate an action plan. In this project, we studied a large territory-wide Hong Kong cohort and determined the incidence of HCC and cirrhotic complications in patients with psychiatric illness.

In this large territory-wide study in Hong Kong, we demonstrate that HCC and cirrhotic complications are common in patients with psychiatric illness. Importantly, nearly 40% of patients were never diagnosed to have chronic liver diseases before the development of hepatic complications. While drug- and alcohol-induced mental disorders were associated with a 3-fold increase in HCC risk relative to the general population, the risk was also increased among patients with the common psychiatric conditions of mood disorders and psychotic disorders. Because of the low awareness of liver diseases in this population, the majority of patients with HCC could only receive supportive care.

Some psychiatric illnesses share obvious risk factors with liver diseases. In particular, 13.1% of patients with drug-induced mental disorders had documented history of CHC (Supplementary Table 6). In Hong Kong, 40–50% of injection drug users are chronically infected with hepatitis C virus [3, 26]. Although the diagnosis rate is 50% in the overall community [27], the diagnosis rate among injection drug users is much lower, and only a quarter of patients diagnosed to have CHC would eventually receive antiviral therapy. It is also noteworthy that the proportion of patients with other psychiatric illnesses who had CHC (0.9–3.3%) was still much higher than the population prevalence of positive anti-hepatitis C virus antibody (0.5%) [28]. This suggests high risk behaviours in some of the other psychiatric patients as well. Similarly, more patients with alcohol-related mental disorders had documented history of alcohol-related liver disease. The proportion of alcohol-related liver disease was relatively low about patients with other psychiatric illnesses (0.4–1.0%). The proportion of excessive alcohol use was also low in the general population [29].

As expected, the risk of HCC and cirrhotic complications was highest in patients with alcohol-induced mental disorders (5.7%) (Table 2). Nonetheless, 1.0–1.9% of the other psychiatric patients also developed hepatic complications. Although this may not be a high percentage, it is important to note that this incidence of liver-related events is much higher than what is projected from the population prevalence or incidence of advanced liver disease [29‐31]. In fact, all the common psychiatric illnesses were associated with a higher risk of HCC than the general population (Table 3). Liver disease was the third leading cause of death in patients with alcohol-induced mental disorders and fifth to sixth leading cause of death in patients with other psychiatric illnesses (Fig. 3). In contrast, liver disease is not among the top ten causes of death in the general population [32]. As an analogy, a study in Minnesota suggested that liver disease was the thirteenth leading cause of death in the general population but the third leading cause of death among NAFLD patients [33]. Specific liver assessments and managements are important in high-risk populations, and our study shows an increased risk of hepatic morbidity and mortality in the psychiatric population.

If we agree that psychiatric patients represent a high-risk group for liver diseases, the next question is how to identify patients with liver disorders. The low rate of liver disease diagnosis prior to the development of liver-related complications in our study highlights the importance of improving case finding. For similar reasons, the age at HCC diagnosis was older and the overall survival after HCC diagnosis was shorter in this cohort than other reports from Hong Kong [34]. Previously, our group demonstrated the possibility to detect advanced liver disease by transient elastography in a large number of patients with type 2 diabetes [35]. Previous studies also showed that simple fibrosis scores such as the fibrosis-4 index and aspartate aminotransferase-to-platelet ratio index had high negative predictive values in excluding future liver-related events in the general population [36]. In a United Kingdom model, initial screening by the fibrosis-4 index followed by the enhanced liver fibrosis panel at the primary care setting increased the number of patients detected to have advanced fibrosis by 5 folds [37]. The alternative approach would be to detect specific liver diseases such as through screening for chronic viral hepatitis and alcohol use disorder, followed by evaluation for the severity of liver disease. At present, the implementation of methods to detect advanced liver disease in the psychiatric population has not been tested. The setting for assessment and its uptake as well as the referral pathway need to be addressed in future prospective studies. Since patients with psychiatric illnesses may be on medications that affect liver enzyme levels, the accuracy of simple fibrosis scores in such patients should be evaluated.

Before we have concrete idea about the best way to use the diagnostic tests, the current study provides important data on factors associated with liver-related events (Table 1). Male sex and older age are well known risk factors for HCC and cirrhosis [38]. Thrombocytopenia, hypoalbuminemia, hyperbilirubinemia and high alanine aminotransferase level are markers of cirrhosis and liver injury. Moreover, patients who developed liver-related events had higher fasting glucose and hemoglobin A_1c level at baseline. This may suggest that some patients had NAFLD [39]. Alternatively, insulin resistance is also common among patients with cirrhosis [40]. Intriguingly, patients who developed liver-related events also had lower total and LDL-cholesterol. While the exact mechanism is unclear, lipids are involved in the life cycle of hepatitis C virus [41], and eradication of hepatitis C virus is associated with a rapid increase in serum LDL-cholesterol [42].

In our study, patients who developed liver-related events were more likely to receive anxiolytics and antipsychotics but less likely to be on antidepressants (Table 1). However, the difference was confounded by indications; patients with different psychiatric illnesses were at risk of different liver diseases. Thus, the association between individual agents and liver-related outcomes was not the primary focus of this study. Previous studies showed that some antidepressants (e.g. nefazodone and trazodone) could cause serious liver injury [43]. On the other hand, a study based on the Taiwan insurance database suggests that users of tricyclic antidepressants and selective serotonin reuptake inhibitors were less likely to develop HCC [44]. While the findings are in keeping with our observation, careful assessment of confounders is required.

The association between psychiatric illness and liver-related complications is likely to be bi-directional. Some liver diseases, notably chronic hepatitis B, likely occurred before the onset of psychiatric illness. Alcohol contributes to psychiatric illness and liver disease simultaneously. NAFLD was probably aggravated by the sedentary lifestyle and obesogenic effect of drug treatments in psychiatric patients. Besides, alcohol use is common in patients with different psychiatric illnesses even though the level may not reach the definition of alcohol use disorder [45]. In NAFLD patients, modest alcohol consumption is associated with increased liver stiffness and a lower chance of histological improvement over time [29, 46].

Our study has the strength of a large sample size, long follow-up duration and the use of territory-wide data representative of the local population. Nonetheless, it also has a few limitations. First, despite the large sample size, a significant proportion of patients with psychiatric illness do not seek medical attention and would not be captured in this study [47]. The cohort is thus more representative of psychiatric patients attending hospital clinics. Second, we included patients with psychiatric diagnoses in 2003–2007, whereas the epidemiology and treatment of chronic liver diseases have changed over the years. However, we also captured treatments and interventions during follow-up until December 2017. Third, although we have laboratory data of the included patients, the database does not include non-invasive tests of liver fibrosis. A prospective study with systematic collection of fibrosis data for this special population would be informative. Fourth, a comparison of cumulative incidence of HCC among patients with psychiatric illnesses and the general population after adjusting the difference in prevalence of hepatitis viral infection and history of alcohol use was not possible due to unavailable data in the general population. In our study, the prevalence of CHC and excessive alcohol use are potentially higher among patients with psychiatric illnesses. Finally, there are notable differences in the epidemiology of liver diseases across countries. Further studies should be conducted to generate data from other regions.

HCC, cirrhotic complications and liver-related deaths are common in psychiatric patients, but liver diseases are often undiagnosed. More efforts are needed to identify liver diseases in the psychiatric population so that treatments and screening for HCC and varices can be provided to patients in need.