Constipation in Hepatocellular Carcinoma Patients: Navigating Clinical Challenges, Hospital Stays and Opioid-Related Risks for Enhanced Patient Care and Outcomes

Background: Constipation can be a significant clinical challenge, impacting patient care and extending hospital stays. We examined the effects of constipation on Hepatocellular carcinoma patients, especially due to increased risk from opioid use in cancer patients, which may affect overall hospital outcomes.

Methods: We retrospectively analyzed critically ill patients with hepatocellular carcinoma in the 2019 and 2020 National Inpatient Sample databases. Multivariate regression analysis was applied to adjust for confounding variables and study important outcomes: mortality, length of stay, the total cost of hospitalization, sepsis, acute kidney injury, acute respiratory failure, malnutrition, obesity, weight loss, diarrhea, nausea and vomiting, fatigue, and involvement of palliative care.

Results: Of the 38365 patients admitted with Hepatocellular carcinoma, 4685 (12.2%) had a secondary diagnosis of constipation, and 33680 had no constipation. After adjusting for confounding variables, mortality (OR 0.69 95% CI 0.49-0.96, P=0.028) and total hospitalization charges [-13906 USD, 95% CI -22750- (-5063), p = 0.002] were significantly reduced in HCC patients with concurrent constipation, while there was no difference in the length of stay between the two cohorts (0.93, 95% CI 0.37-1.48, p = 0.001. Constipation was associated with decreased odds of obesity (OR 0.78, 95% CI 0.61-0.99, P=0.042) and acute respiratory failure (OR 0.65 95% CI 0.44-0.95, p = 0.029); however, it was coupled with an increased risk of weight loss (OR 1.60 95% CI 1.07-2.40, p= 0.021), nausea/vomiting (OR 2.24 95% CI 1.55-3.24, p < 0.001), fatigue (OR 4.32 95% CI 2.25-8.31, p < 0.001), palliative care involvement (OR 1.88 95% CI 1.55-2.29, p < 0.001), malnutrition (OR 1.72 95% CI 1.46-2.04, p < 0.001) and opioid use disorder (OR 2.50 95% CI 1.62-3.84, p < 0.001).

Conclusion: Constipation has been associated with reduced mortality and overall hospitalization costs; however, it is also associated with multiple adverse health events that can contribute to increased morbidity. Additional prospective studies are required to confirm the results of our analysis. Early identification of constipation in high-risk cancer patients could be crucial for predicting morbidity and mortality, as well as aiding in risk stratification to improve outcomes.

Liver cancer is the sixth most diagnosed cancer and the third most common cause of cancer mortality in the world. In 2020, there were 906,000 new cases and 830,000 deaths. Among these cases, Hepatocellular Carcinoma (HCC) accounts for approximately 80% of the total liver cancer burden. HCC predominantly affects men, and its incidence varies by geographical region and ethnicity, which is largely attributed to the prevalence of major risk factors. Most cases of HCC are associated with all-causes of cirrhosis such as chronic infection with Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV), alcohol abuse or Alcohol Steatohepatitis (ASH), Non-Alcoholic Fatty Liver Disease (NAFLD), obesity, diabetes, and exposure to aflatoxins [1].

Constipation is one of the most common functional disorders of the gastrointestinal tract, with an average prevalence of around 16% worldwide; the majority of these cases are attributed to adults around the ages of 60 to 110 years old. Untreated constipation can have far reaching consequences on an individual’s health and well-being while simultaneously posing significant challenges to the healthcare system, which include higher rates of hospitalization, prolonged length-of-stay, and heightened total cost of treatment [2].

Constipation is a well-recognized problem in people in general, however it is of particular interest in patients with cancer. Notably, it is a common but troublesome problem in patients with advanced cancer and a significant cause of morbidity in this patient group. It is frequently reported as a common source of distress amongst patients with cancer due to its impact on activities of daily life, psychosocial well-being, and challenges associated with appropriate nutritional intake, all of which contribute to an impaired quality of life [3]. Constipation in cancer is associated with a variety of risk factors such as tumor type, the use of opioids and other medications such as antihistamines, selective-serotonin reuptake inhibitors (SSRIs), and strictures and adhesions because of surgical intervention or radiotherapy [4]. Constipation in HCC can be attributed to a number of different factors. These factors include liver dysfunction with advanced stages of HCC, portal hypertension that affects the normal functioning of the intestines, side effects of cancer treatment, dietary changes (such as reduced fiber intake or inadequate fluid intake) as a result of cancer treatments, as well as physical inactivity often associated with hospitalization [5].

In hepatocellular carcinoma, constipation-related distress is a common feature, particularly among those in the advanced stage due to various chemotherapeutic interventions [6]. Additionally, with over half of cancer patients suffering from pain and close to two-thirds being in the advanced stage of disease, management of pain through opioids is a common therapeutic practice. Although various chemotherapeutic interventions are associated with constipation as an adverse effect, opioid-induced constipation has been a particular area of interest due to its well-characterized role in modulating opioid receptors in the gastrointestinal tract [7].

Our study specifically analyzed the consequences of constipation in patients with hepatocellular carcinoma, exploring its implications for adverse patient and hospital outcomes. The aim is not only to gain a better understanding of the current challenges associated with concomitant constipation and hepatocellular carcinoma, but to provide valuable information for future interventions that will aid in better risk management to improve outcomes.

Data source

Our research relied on data sourced from the NIS database, an integral component of the Healthcare Cost and Utilization Project (HCUP), generously funded by the Agency for Healthcare Research and Quality (AHRQ). This extensive inpatient healthcare database, encompassing all payers, provides a rich source of public information for researchers. It comprises an impressive sample size, capturing approximately 20% of stratified discharges from community hospitals across the United States.

Employing a systematic sampling design, this comprehensive resource is constructed from state-initiated patient databases, resulting in unique discharge records that contain crucial medical information. These records include primary and secondary diagnoses, as well as procedures conducted during hospitalization. Beyond medical details, each record encompasses demographic information, comorbidities, severity of illness, and mortality risk based on All Patient Refined Diagnosis-Related Groups (APR-DRG). Additionally, data on the length of hospital stay (LOS), teaching status, hospital location, geographic region, and an estimated median household income quartile based on the patient’s zip code, are included. The records feature primary payer information, discharge disposition, and in-hospital mortality. This robust dataset is a valuable asset for researchers seeking a comprehensive understanding of inpatient healthcare dynamics in the United States.

Study design and population

This retrospective cohort study examined hospitalized critically ill adults (18 years and older) with hepatocellular carcinoma throughout the 2019-2020 calendar year. The dataset was divided into two cohorts: one consisting of individuals diagnosed with constipation and the other comprising those without a secondary diagnosis of constipation. Patients were meticulously grouped based on the presence or absence of constipation through a comprehensive assessment. The relevant ICD-10 codes were used for the identification of diagnosis and procedure variables.

Outcomes

The primary aim of the study was to examine and compare mortality rates between two groups. Alongside this critical outcome measure, various secondary parameters were also considered to gain a more comprehensive understanding of patient outcomes. These secondary parameters included factors such as the length of hospitalization and total hospital charges, providing insights into resource utilization patterns within each population. The other outcomes studied included odds ratios of obesity, acute respiratory failure, weight loss, nausea/vomiting, fatigue, palliative care involvement, malnutrition, and opioid use disorder. The study explored the Charlson comorbidity index, a tool capable of accounting for numerous confounding factors. A comparison was made between patients with concomitant constipation and those without this condition.

Statistical analysis

The study’s statistical analysis prioritized reliability and validity. St ata 17 software was used with weighted samples for national estimates following HCUP regulations for the NIS database. Descriptive statistics and inferential tests, including Student’s t-test for continuous variables and Chi-square test for categorical variables, were employed. Mean values and standard deviations conveyed continuous variables, while percentages represented categorical ones. To identify group differences, multivariate analysis considered variables with significant outcomes (p < 0.2) and crucial determinants, adjusting odds ratios for factors like age, gender, ethnicity, insurance, hospital details, and Charlson comorbidity index. The regression analysis established a critical p-value of 0.05 for statistical significance.

The older population, over 65, exhibited a lower prevalence of constipation than younger individuals (55.36% vs 59.32%, p = 0.006). HCC patients with constipation showed a higher representation of Black (18.18% vs 19.48%, p = 0.017) and Hispanic ethnic groups (17% vs 15.3%, p = 0.017) as opposed to other races. Medicare had fewer HCC patients with constipation (52.1% vs 57.4%, p = 0.001), while Medicaid had a higher proportion of such patients. (19.43% vs 14.77%, p = 0.001). The distribution did not vary significantly among individuals with private insurance (24.5 % vs 24.54%, p = 0.001) or no insurance (3.97% vs 3.3%, p = 0.001). Moreover, fluid and electrolyte disorders were found to be more widespread in HCC patients with constipation (48.99% vs. 36.46%, p <0.001), along with an increased percentage of opioid use in this group (3.95% vs. 1.54%, p < 0.001). Additionally, these patients also displayed a greater prevalence of malnutrition (30.52% vs. 18.48%, p < 0.001), fatigue (4.7% vs 0.99%, p < 0.001), nausea and vomiting (5.02% vs 2.51%, p < 0.001), as well as being on palliative care (29.46% vs 17.03%, p < 0.001). Furthermore, there was an observed trend where a more significant proportion of patients experiencing constipation were discharged to homes with home health services (39.97% vs. 29.02%, p < 0.001) compared to those without the condition; meanwhile, equal proportions were discharged to skilled nursing facilities (2.52% vs 2.52%, p < 0.001) (Table 1).

Univariate analysis did not reveal any significant difference in the mortality rates between the two groups (OR 0.77, 95% CI 0.58-1.04, p = 0.091). However, following adjusting for confounding variables through multivariate regression analysis, it was discerned that HCC patients with constipation exhibited lower odds of mortality than those without constipation (OR 0.69, 95% CI 0.49-0.96, p=0.028). Similarly, the total cost of hospitalization was observed to be decreased in patients with constipation as opposed to those without this condition [-13906 USD, 95% CI -22750- (-5063), p = 0.002]. Nevertheless, no statistically significant difference in the length of hospital stay was detected between these two patient groups. (0.93, 95% CI 0.37-1.48, p = 0.001) (Table 2).

Subgroup analysis of length of stay and total hospitalization charges related to baseline demographic characteristics is presented in table 3.

After conducting logistic regression analysis, several secondary outcomes were calculated for the two groups of patients. It was found that HCC patients with constipation had lower odds of obesity (OR 0.78, 95% CI 0.61-0.99, p = 0.042) and acute respiratory failure (OR 0.65, 95% CI 0.44-0.95, p = 0.029). However, those with constipation were at an increased risk of weight loss (OR 1.60, 95% CI 1.07-2.40, p = 0.021), malnutrition (OR 1.72, 95 CI 1.46-2.04, p < 0.001), fatigue (OR 4.32, 95% CI 2.25-8.31, p < 0.001), nausea and vomiting (OR 2.24, 95% CI 1.55-3.24, p < 0.001), opioid use disorder (OR 2.50, 95%CI 1.62-3.84, p < 0.001), and palliative care involvement (OR 1.88, 95% CI 1.55-2.29, p < 0.001). No notable difference was observed between the two groups regarding pneumonia (OR 0.09, 95% CI 0.60-1.58, p = 0.948), acute kidney injury (OR 1.02, 95% CI 0.85-1.23, p = 0.788), ICU admission (OR 0.92, 95% CI 0.64-1.32, p = 0.665), acute coronary syndrome (OR 0.88, 95 % CI 0.20-3.82, p = 0.869), or sepsis (OR 0.51, 95% CI 0.25-1.04, p = 0.065) (Table 4).

In this retrospective analysis, encompassing a substantial cohort of 38,365 HCC patients, a notable 12.2% presented with constipation as a secondary diagnosis. The multifaceted approach to the study, employing multivariate regression analysis to account for confounding variables, provided a nuanced understanding of the diverse outcomes associated with constipation in this population.

Surprisingly, the study revealed a seemingly paradoxical association between constipation and reduced mortality, along with decreased total hospitalization charges. The nuanced exploration of secondary outcomes elucidates the complex interplay between constipation and various health events, including a decreased likelihood of obesity and acute respiratory failure but an increased risk of weight loss, nausea/vomiting, fatigue, palliative care involvement, malnutrition, and opioid use disorder.

Honda, et al. [8] conducted a study of 12,217 participants who were undergoing hemodialysis and experienced concurrent constipation. The participants were enrolled in the Japan-Dialysis Outcomes and Practice Patterns study. The primary endpoint of the study focused on mortality, while cause-specific death was considered as the secondary endpoint. The findings concluded that patients undergoing hemodialysis with concurrent constipation exhibited higher mortality rates compared to those without constipation [8].

In a retrospective analysis of a cohort of 3,359,653 US Veterans, Sumida, et al. [9] investigated the relationship between constipation and mortality. Their findings revealed that patients with constipation had a significantly higher all-cause mortality rate (hazard ratio [HR], 1.12; 95% CI, 1.11-1.13), indicating a potential connection between gastrointestinal health and overall longevity within this population.

However, in a study by Yoshida, et al. [10], it was found that mortality did not show an association with increased odds of mortality. The authors carried out a retrospective cohort study involving 1933 ICU patients from 2011-2018. The univariate analysis revealed that constipation was linked to decreased mortality in this patient population; however, the multivariate regression analysis indicated no association between constipation and increased mortality [10].

It is widely acknowledged that obesity is linked to a higher incidence of acute respiratory failures, which in turn can lead to increased mortality. Interestingly, lower rates of obesity and acute respiratory failures may have a protective effect on mortality. These findings warrant further exploration through prospective studies. Additionally, our analysis has revealed the need for more in-depth research into the impact of obesity on mortality in HCC patients. Several studies have reported associations between obesity and both acute respiratory failure as well as increased mortality. Our conclusions align with Flegal KM, et al. [11] systematic review and meta-analysis which highlighted the association between obesity and higher all-cause mortalit.

Several studies have shown the significant impact of chronic constipation on healthcare resource utilization. In 2010, Cai Q, et al. [12] conducted a retrospective analysis using the HealthCore Integrated Research Database to identify patients with chronic constipation, concluding that it poses a substantial burden on healthcare costs. Similarly, Fine PG, et al. [13] retrospective analysis from 2006-2014, utilizing the same database and focusing on cancer patients aged >18, revealed that opioid-induced constipation was associated with heightened healthcare resource utilization and economic burden among this cohort. Notably, our own study yielded different findings; however, there are several complex factors specific to our patient cohort that require careful consideration.

This calls for further investigation into the admission of patients with HCC cancers who are undergoing complex chemotherapeutic regimens that result in side effects such as constipation. Our study also indicates that these hospitalized patients experience increased nausea and vomiting, which could potentially be attributed to the side effects of chemotherapy medications. The adverse events leading to hospitalization may have necessitated the suspension of anticancer medications, possibly contributing to decreased hospitalization costs. However, NIS does not provide data on the treatment of medical conditions, highlighting the need for prospective studies to address this information gap and gain a better understanding of the reasons behind reduced hospitalization costs.

Our study revealed a significant correlation between constipation and opioid medication use among HCC patients. Additionally, the cohort with constipation exhibited a higher likelihood of experiencing malnutrition, fatigue, palliative care involvement, and a decreased incidence of obesity. While obesity is often associated with constipation, further exploration is necessary to elucidate how constipation impacts the odds of obesity. These studies may be more complex, as there are myriad factors that contribute to constipation to begin with such as diets low in fiber, inadequate fluid intake, different physical activity levels, opioid-use, pregnancy, stress and mental health. Other factors include comorbidities such as irritable bowel syndrome, hypothyroidism, diabetes, neurological disorders, or colon or rectal issues [14]. A review of literature yielded varying findings on the association between constipation and both malnutrition as well as overweight/obesity.

A cross-sectional analysis conducted by Yurtdaş Depboylu, et al. [15] encompassing 883 adults aged over 65 from nursing homes and community centers in Turkey concluded that there is an association between malnutrition and an increased risk of developing constipation. Larkin and colleagues conducted a comprehensive study to thoroughly investigate the relationship between palliative care and constipation. Their methodology involved meticulous scrutiny of existing literature and the development of evidence-based recommendations. The thorough analysis led to the significant finding that patients in palliative care settings face a heightened risk of experiencing constipation [16].

Dzierżanowski T, et al. [17] conducted an in-depth epidemiology study that involved 51 hospice and 49 nursing home patients. The predominant diagnosis among both sets of patients was cancer. Their research revealed a strong association between palliative care and constipation, highlighting the vulnerability of cancer patients under palliative care in both nursing homes and hospices to developing constipation. The results underline the need for a holistic understanding of constipation’s impact, considering both positive and negative aspects. While the reduced mortality and hospitalization costs are promising, the elevated risks of adverse health events emphasize the need for vigilance in managing constipation in HCC patients. The study also hints at the potential role of opioid use in shaping these outcomes, calling attention to the elaborate balance required in pain management strategies.

This study not only presents significant strengths but also notable weaknesses that merit thorough consideration. Being an administrative database, the NIS is susceptible to sampling bias due to potential inaccuracies in data entry, incomplete information, and coding discrepancies. While it offers extensive patient data, the absence of specific clinical details, laboratory findings, and post-discharge patient outcomes, could potentially influence the conclusions drawn from this study. The failure to consider outpatient care and readmissions following surgery makes it challenging to comprehensively assess long-term complications and fatalities using NIS data alone. Furthermore, the inpatient data does not provide insights into major events during surgery or complications that may impact length of stay and hospital costs with a level of depth necessary for comprehensive analysis. However, the study based on NIS has several advantages. One of its key strengths is the ability to evaluate a nationally representative study population derived from the largest publicly available inpatient database. This allows for the generation of comprehensive regional and national statistics and estimates on patient outcomes, inpatient utilization, healthcare costs, and various other related factors.

In conclusion, our retrospective analysis of hepatocellular carcinoma patients reveals that while constipation is paradoxically associated with reduced mortality rates and total hospitalization charges, its concurrent presence poses a significant risk for adverse health events. This dual nature underscores the complexity of constipation in the context of hepatocellular cancer care, challenging conventional expectations. The observed benefits suggest potential avenues for enhanced patient comfort and cost-effectiveness through improved pain management, yet the heightened risks of weight loss, nausea/vomiting, fatigue, and opioid use disorder necessitate a nuanced approach. Early identification of constipation in high-risk cancer patients emerges as crucial for predicting morbidity and mortality, advocating for a multidisciplinary strategy to improve outcomes. The need for further prospective studies is evident to validate and examine these complex associations, ensuring a comprehensive understanding and strategy for interventions in the management of constipation in hepatocellular carcinoma patients.

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