Clinical pathways of patients with cirrhosis from registration to the liver transplantation program, analysis of 996 patients from the RH7 registry in Slovakia

Overview

By analyzing 996 patients from the RH7 cirrhosis registry within the 4.5 years of inclusion interval, we mapped the path of patients to liver transplantation. We found that 283 patients (28.4%) opened a transplant protocol with a median of 4 days from registration, of which 117 (11.7%) were placed on a waiting list with a median of 91 days from the start of the protocol, and 75 (7.5%) were transplanted with a median of 44 days from enlisting. Factors that increased the likelihood of starting a transplant protocol were younger age, better body constitution and performance (BMI, muscle strength, lower frailty), autoimmune etiology, severity of liver disease, and lower levels of systemic inflammation (leukocytes, CRP). Factors that increased the probability of being enrolled on the waiting list were male gender, better physical performance, and severity of liver disease. Factors that increased the probability of removal from the waiting list other than autoimmune etiology, were severity of liver disease and systemic inflammation. Overall survival of one and three years after liver transplantation was 82.6 and 78.1% of patients respectively. The study will serve as an important lesson in the functioning of the set processes to further streamline and improve the quality of our transplant program.

Keywords:

liver cirrhosis – liver transplantation – management – waiting list – prognosis

Introduction

Cirrhosis is the final stage of chronic liver disease. Slovakia is the leading place in the world in the morbidity of liver diseases. According to a recent report on the global burden of liver diseases, Slovakia ranks first in the incidence of decompensated cirrhosis [1]. The entire healthcare system should be involved in the management of this burden, from the prevention of liver diseases in primary care, through specialized outpatient care, and regional healthcare facilities, up to specialized liver centers. Over the past two decades, several centers have emerged intending to provide the best possible care for liver disease patients. However, the liver transplantation program currently operates only at the Department of Hepatology-Gastroenterology-Transplantation (HEGITO) at FNsP FR Roosevelt in Banská Bystrica. Due to the growing demands for specialized hepatological care and its concentration in one center, a unique RH7 cirrhosis registry was created in 2014. The registry prospectively collects data on hospitalized patients with cirrhosis and has created a research platform for the study of cirrhosis. Data from the registry have already been used for testing or introducing new predictive markers and treatment interventions [2–5]. Due to the inherent connection of RH7 with the liver transplantation program, the registry also provides an opportunity for evaluating patient care pathways from their first diagnosis and registration toward successful treatment, palliative care, or initiation of the liver transplantation protocol. For this study, we therefore used RH7 data to map:

1. patient pathways and factors associated with the opening of the transplant protocol;
2. patient pathways and factors associated with events on the transplant protocol;
3. patient pathways and factors associated with events on the waiting list;
4. overall survival after transplantation.

 

Patients and methods

The study is a prospective analysis of the RH7 registry. All consecutive patients hospitalized at the HEGITO department are included in the registry. The main inclusion criteria were cirrhosis and the first hospitalization at HEGITO. Exclusion criteria are inability to gain informed consent, and hospitalization at HEGITO for any other diagnosis other than cirrhosis. For this work, we analyzed data from the registry over 4.5 years from 1/1/2018 to 30/6/2022 with a follow-up of at least 6 months after patient registration. The follow-up was censored as of 7/1/2023. After admission to HEGITO, the patient‘s attending physician performs an initial clinical examination along with initial laboratory tests focused on liver disease. Based on the clinical examination and laboratory results, the CTP score and MELD-Na score are recorded. Within 24–72 hours of admission, the patient‘s frailty status is evaluated by the study nurse based on the so-called liver frailty index (LFI) [6]. Liver transplantation is usually considered according to the MELD-Na score (more than 15) or according to the so-called exemptions from MELD for liver transplantation [7]. When the indication criteria for liver transplantation are fulfilled, we open the transplant examination protocol, and the patient becomes a potential candidate for liver transplantation. After the successful completion of the protocol examinations, the patient is re-evaluated by the multidisciplinary transplant team, and after its approval, becomes enlisted for liver transplantation. During the follow-up of patients in the registry, we recorded the date of initiation of the protocol, date of enlistment or removal from the protocol and its cause, and dates of events while on the waiting list: liver transplantation, death, or removal from the waiting list.

Ethical aspects

The RH7 register is approved by the local ethics committee, where each patient signs an informed consent upon entry. The RH7 registry is also registered at clinicaltrials.gov under the number NCT04767945.

Statistical methods

We present the results of numerical variables without a normal distribution as the median and 25–75^th percentile, where the results of categorical variables are indicated as number and percentage of the total in Tab. 1. In Tab. 2–4 we compared the differences in parameters between subgroups of the set using the non-parametric Mann-Whitney test for numerical variables, and chi-square test for categorical ones. In the tables, we also present independent predictive factors for different events (protocol initiation, enlisting, de-listing) over time using multivariate regression for competing events according to Fine and Gray. The model included all of the listed variables, and hazard ratios with 95% confidence intervals for independent predictors are displayed in the last 2 columns of Tab. 2–4. We determined the probability of survival after transplantation using the Kaplan-Meier function.

Results

In the monitored period of 4.5 years, 996 patients were included in the RH7 registry. The median age of all patients was 57 years, the ratio of men and women was 64/36%, and the median body mass index (BMI) was 26 kg/m². The most common etiology of liver cirrhosis was alcoholic liver disease in 68.8% of cases, followed by steatotic liver disease in 13.3%, autoimmune hepatitis in 8.6%, viral hepatitis in 6.5%, and other etiologies accounted for 2.8% of cases. At enrollment, the median Child-Turcotte-Pugh score was 9 points and MELD-Na was 17 points. The basic characteristics of the set of registered patients are presented in Tab. 1.

Out of the total number of 996 patients, the protocol before liver transplantation was opened in 283 patients (28.4%). The median time from patient registration to the opening of the transplant protocol was 4 days (25–75^th percentile 0–28.5). In the remaining 713 cases (71.6%), the protocol was not initiated. A flowchart of the patients’ pathways is shown in Scheme 1. Graph 1 shows the cumulative incidence of events after registration: initiation of the transplant protocol or death. A comparison of the characteristics of patients according to the protocol initiation and its risk factors is shown in Tab. 2. We identified 8 independently associated factors with the opening of the protocol: younger age, higher BMI, hand grip strength, lower frailty index (LFI), autoimmune etiology, higher Child-Pugh-Turcotte score, and lower CRP and leukocytes.

After the opening of the protocol, 117 patients were enlisted (41.3% of those on the protocol, 11.7% of all of the registered). The median duration of completion of protocol examinations was 91 (36–154) days. Then, 73 patients (25.8%) were removed from the transplant protocol, of which 67 were due to improvement and 6 were due to deterioration; the protocol was still ongoing in 29 patients (10.2%) at the time of censoring. In Graph 2, we present the cumulative incidence plot of events after the opening of the transplant protocol. The most likely event after opening the protocol was the inclusion on the waiting list (black curve); the less likely events were withdrawal from the protocol (red curve) and death (green curve). After opening the protocol, we recorded deaths in 64 patients (22.6%). A comparison of the characteristics of the patients on the protocol and the results of the analysis of factors associated with enlisting are presented in Tab. 3. We identified 4 independently associated factors: male gender, lower frailty index (LFI), autoimmune etiology, and higher Child-Pugh-Turcotte score (CPT).

After enlisting (N = 117), 75 patients (64.1%) underwent liver transplantation. The median time on the waiting list was 44 days (14.5–128). At the time of evaluation, there were 25 patients (21.4) actively waiting for transplantation, 10 patients (8.5%) died while on the waiting list, three patients (2.6%) were excluded due to deterioration, and four patients (3.4%) were excluded due to improvement. In Graph 3, we present the cumulative incidence plot of events after enlistment. In this group of patients, liver transplantation was significantly the most likely event (black curve). Death on the waiting list (red curve) or removal from the waiting list (green curve) had a much lower probability. A comparison of the characteristics of patients on the waiting list and the results of the analysis of risk factors for withdrawal from the waiting list are shown in Tab. 4. We identified 3 factors independently associated with death or withdrawal from the waiting list: non-autoimmune etiology, Child-Pugh-Turcotte score, and CRP.

Graph 4 shows the probability of survival of patients after liver transplantation in our program, which led to 1-, 2-, and 3-year survival rates of 82.6, 78.1, and 78.1%.

Discussion

The main findings

By analyzing 996 patients from the RH7 registry within the 4.5 years of the inclusion interval, we mapped the path of patients to liver transplantation. We found that 283 patients (28.4%) opened a transplant protocol with a median of 4 days from registration, of which 117 (11.7%) were placed on a waiting list with a median of 91 days from the start of the protocol, and 75 (7.5%) were transplanted with a median of 44 days from enlisting. Factors that increased the likelihood of starting a transplant protocol were younger age, better body constitution and performance (BMI, muscle strength, lower frailty), autoimmune etiology, severity of liver disease, and lower levels of systemic inflammation (leukocytes, CRP). Factors that increased the probability of being enrolled on the waiting list were male gender, better physical performance, and severity of liver disease. Factors that increased the probability of removal from the waiting list other than autoimmune etiology, were severity of liver disease and systemic inflammation. Overall survival one and three years after liver transplantation was 82.6 and 78.1% of patients respectively.

Waiting times

For comparison, the waiting time in the Dutch liver transplant registry is 196 days [8]. In the United Kingdom, the waiting time for a liver transplant in patients with liver cirrhosis is 142 days, and in patients with hepatocellular carcinoma (HCC) within the Milan criteria, the time from the diagnosis of HCC to liver transplantation is 183 days [9], while the time spent on the waiting list is 62 days [10]. In Spain, the average waiting time for a liver transplant ranges from 103 to 124 days, with an average time of 71 days spent on the waiting list. In the field of liver transplantation, we did not come across similar data on the duration of time from the diagnosis of liver cirrhosis to liver transplantation. In hematology, such data are available, for example, for acute myeloid leukemia, and the time from diagnosis to bone marrow transplantation is about 120 days [11]. In total, of all patients with liver cirrhosis hospitalized in our department, the transplantation protocol was opened in 28%, while the vast majority of protocols were opened within 30 days (median 4 days). We assume that the correctness of patient selection for liver transplantation is confirmed by the fact that the most likely event after opening the transplant protocol was enrollment on the waiting list, and liver transplantation was consequently the most likely after inclusion on the waiting list.

Age and body constitution

The task of the transplant center is also to identify those patients who are already too sick for a transplant. This identification is very important to minimize wastage of resources. In our study, we found that younger age increased the probability of starting a transplant protocol. Older age and higher BMI are prognostic indicators of worse survival after transplantation [12]. Physical constitution in the sense of a normal BMI of 25 increases the probability of selecting a patient for transplantation. Deviation below that increases the probability of not being suitable for transplantation. Higher muscle strength is associated with a higher probability of transplantation, better survival, and a lower number of complications. Frailty has also been shown in the literature to be a significant predictor of the success of the protocol and placement on the waiting list, as well as the outcome [13]. Physical performance plays an important role in our decision-making and favors the patient to be put on the waiting list for a liver transplant. It has been shown by many studies, that patients with better performance have a higher probability of surviving transplantation as well as lower mortality and morbidity [14].

Systemic inflammation

Lower activity of inflammation (CRP and leukocytes) in our study increased the probability of opening the protocol. Inflammation is the most common trigger of acute liver decompensation and ACLF with organ dysfunction, which are barriers to opening a protocol. Another factor may be the presence of severe alcoholic hepatitis, in which inflammatory markers are often significantly elevated, and when liver transplantation is less often considered. On the contrary, if the inflammatory activity is low, or the patient does not have alcoholic hepatitis, the probability of opening the protocol increases [12]. Systemic inflammation is also a risk for enlisted patients. It is responsible for worsening the underlying disease and often makes patients too sick for a transplant. There is also evidence from the literature that inflammation increases the risk of removal from the waiting list as well as the probability of death on the list [15].

Autoimmune etiology

In our patient cohort, we observed that the autoimmune etiology of liver dis- ease decreased the probability of removal from the waiting list. This contrasts with the study by Goyes et al., who found that in their group of patients, autoimmune etiology of the disease was associated with a higher risk of dropping out of the protocol. Autoimmune liver diseases occur in 75% of cases as chronic diseases. Studies showed that MELD often underestimated the severity of liver cirrhosis of autoimmune etiology [16]. There are reports in the literature that the progressive character of the disease, the risk of complications after transplantation, and the recurrence of the disease in the graft also lower the threshold for considering the patient for transplantation [17]. On the other hand, autoimmune etiology, except for PSC, is usually well-controlled with treatment. In the case of refractory cases of autoimmune etiology, where PSC is most likely the case, our patients had twice the chance of starting the protocol, almost twice the chance of being enlisted, and the highest probability of being transplanted.

Sex differences

In our study, we also found that the male gender increases the probability of being placed on the waiting list. Less muscle mass causes serum creatinine to underestimate renal function in women, resulting in a MELD score 1–2 points lower than in men. MELD-Na further highlights this difference to the level of 4 points. This has an impact on women‘s access to liver transplantation [18]. Furthermore, women in general constituted only slightly more than a third of the registered patients, which is probably the main explanation of the observed sex differences.

MELD and CTP scores

We observed that a higher CPT score increased the likelihood of opening a protocol. Correct timing of the indication for transplantation is an important part of clinical practice. Studies have shown that the annual mortality of patients with cirrhosis in stage CPT A is 0%, CPT B is 20%, and CPT C is 55% [19]. The likelihood of being removed from the waiting list within a year of enrollment also increases with advanced liver disease. Within one year, 11% of patients in stage CTP A, 21% in stage CTP B, and 36% in stage CTP C are removed from the waiting list. Compared to stage CTP A, the probability of removal in CTP B is almost twice as high, and in CTP C it is more than triple [20].

Survival

Survival 1 and 3 years after transplantation was recorded in 82.6 and 78.1% of patients respectively. These results are comparable with data from other world transplant centers [21,22].

Limitations of study

Our study evaluates the journey of a patient with cirrhosis in the transplant program of the only center in Slovakia. More than half of the monitored period included the COVID-19 pandemic, which could have distorted some of the findings. However, the study contains a sufficient number of registered patients, from which it is possible to draw an important lesson from the effectiveness and benefit of our program.

 

Conclusion

In our study, we carefully mapped the paths of patients with cirrhosis from their registration to the transplant program, the effectiveness of protocol examinations, inclusion on the waiting list, and their fate on it. The study will serve as an important lesson in the functioning of the set processes to further streamline and improve the quality of our transplant program.