|Year : 2022 | Volume
| Issue : 3 | Page : 87-90
The erythrocyte sedimentation rate as a potential hepatocellular cancer surveillance tool
Nyam Paul David, Pantong Mark Davwar, Mary John Duguru, Jireh Dan Makpu, Atta Okwute, McHenry Ifeanyi Stephen, Edith Nonyelum Okeke
Department of Internal Medicine, JOS University Teaching Hospital, Jos, Nigeria
|Date of Submission||28-Apr-2022|
|Date of Decision||18-May-2022|
|Date of Acceptance||19-May-2022|
|Date of Web Publication||05-Jul-2022|
Nyam Paul David
Department of Internal Medicine, JOS University Teaching Hospital, Jos
Source of Support: None, Conflict of Interest: None
Background: There is a global search for biomarkers that will aid with the diagnosis of hepatocellular carcinoma (HCC) at an early stage when it is amenable to available treatment options. The inflammatory marker – erythrocyte sedimentation rate (ESR) has been studied for several decades for its role in inflammatory processes and malignancies. We evaluate its role as a potential surveillance tool for HCC in Jos, northern Nigeria. Objective: The study aims to determine if ESR can differentiate between patients at risk of HCC who have no liver fibrosis (patients with chronic hepatitis B infection)/liver cirrhosis, and those with HCC. Methods: This is a retrospective study among adult patients aged 18 years and above using secondary data obtained from patients who were recruited for previous studies carried out at the Jos University Teaching Hospital (From August 2019 to October 2021). HCC was confirmed using a triphasic computed tomography scan. FibroScan was carried out to determine the stage of fibrosis of the liver. The ESR rate was determined using the Westergren method. ANOVA was used to determine the difference between groups of patients. Results: There were 316 participants in this study, males were 140 (44.4%) and females were 176 (55.6%). Those with HCC were 88 (27.8%) whereas, those without HCC were 228 (72.2%). The mean age of the studied population was 47 ± 11.6 years. For those with HCC, it was 48.6 ± 13.4 years and for those without HCC, it was 47.4 ± 13.3. The mean ESR for those with HCC versus those without HCC was 60.67 ± 37.9mm/h versus 22.53 ± 8.3 mm/h, P = 0.001. ESR could discriminate between those with HCC from those without HCC, with an area under the curve of .803, sensitivity of 80%, and specificity of 67%. Conclusion: There is a need for novel methods that aid the early detection of HCC since evidence has shown that surveillance and early tumor detection improve survival. ESR is a simple, easy, and cheap test that has the potential to serve as a marker of early occurrence of HCC and should be further evaluated for this property in a prospective study.
Keywords: Cancer, esr, liver, marker, screening, surveillance
|How to cite this article:|
David NP, Davwar PM, Duguru MJ, Makpu JD, Okwute A, Stephen MI, Okeke EN. The erythrocyte sedimentation rate as a potential hepatocellular cancer surveillance tool. Gastroenterol Hepatol Endosc Pract 2022;2:87-90
|How to cite this URL:|
David NP, Davwar PM, Duguru MJ, Makpu JD, Okwute A, Stephen MI, Okeke EN. The erythrocyte sedimentation rate as a potential hepatocellular cancer surveillance tool. Gastroenterol Hepatol Endosc Pract [serial online] 2022 [cited 2022 Aug 14];2:87-90. Available from: http://www.ghepjournal.com/text.asp?2022/2/3/87/349945
Hepatocellular carcinoma (HCC) is known to be the fifth most common cancer in the world and constitutes almost 85% of all primary liver cancers. After East Asia, Sub-Saharan Africa is the most affected region of the world, owing to the high prevalence of risk factors for this cancer in these regions.
The average survival from the time of diagnosis to the time of death among HCC patients in Sub-Saharan Africa is about 2–3 months.,, This is because the majority of the patients present with advanced stages of the disease where no available treatment options exist.
There is a global search for biomarkers that will aid with the early diagnosis of these cancers at stages when they are amenable to treatment options. Complex metabolomics studies have demonstrated that there are urinary metabolites that can distinguish between HCC patients and nonHCC patients using principal component analysis., This and several other studies are still in preliminary translational stages and not yet available for clinical application.
The acute-phase inflammatory marker, erythrocyte sedimentation rate (ESR) has been studied over several decades for its role in inflammatory processes and malignancies. The test is widely carried out using the Westergren method to measure the degree of fall in a vertical column of red cells in a glass tube. We have observed, in our clinical practice, the uniform elevation in ESR among patients with viral hepatitis and coexisting HCC. This has prompted us to ask the question if this is a possible marker for the presence of a developing tumor in our patients with risk factors for HCC. We have also noted that patients with only liver cirrhosis or chronic hepatitis B do not have this degree of elevation in ESR. It is based on this that we are evaluating ESR in our cohort of patients to see if there exist any pointers that will support our observation.
The current guidelines recommend 6 monthly surveillance for patients who are at risk for HCC, that is those with either hepatitis B virus (HBV) infection or those with liver cirrhosis. Surveillance is implemented using an ultrasound scan and alpha-fetoprotein. This has been demonstrated to be cost-effective and reduce mortality from several studies., It is expected that if there is a new mass in the liver or an elevation in the level of alpha-fetoprotein compared to the previous, HCC is suspected, and further evaluation will be put in place such as a triphasic computed tomography (CT) scan to interrogate this new mass seen. We postulate that ESR, which is a cheap and widely available investigation modality, will be able to discriminate between cirrhosis, chronically infected HBV patients without cirrhosis, and HCC, therefore, it can serve as a possible tool for HCC surveillance that marks the transition from cirrhosis to HCC.
| Aim|| |
The study aims to determine if ESR can differentiate between patients at risk of HCC with no fibrosis/liver cirrhosis, and those with HCC.
| Methods|| |
This study was carried out at the Jos University Teaching Hospital as a retrospective study among adult patients aged 18 years and above using secondary data obtained from patients who were recruited for a previous study carried out at the Jos University Teaching Hospital, between August 2019 and October 2021. All patients recruited into this study with HCC had a triphasic CT scan done to confirm the diagnosis of HCC. This was based on the characteristic findings of HCC at triphasic CT scan. While those without HCC had a FibroScan done to determine the degree of fibrosis in the liver. FibroScan was carried out using a medium probe of the Echosens FibroScan Mini.
There were two broad groups in this study: HCC and nonHCC groups. The nonHCC group was further subdivided into two: those with liver cirrhosis and those without cirrhosis. No cirrhosis group, defined by transient elastography (TE) score ≤12.5kpa, and cirrhosis defined by TE score >12.5kpa (cirrhosis).
FibroScan was carried out using the Echosens FibroScan medium probe. The scores were recorded in kilopascals (Kpa). Furthermore, all patients were stratified (arbitrarily) into three groups based on their TE score: Group 1, 1–12kpa, Group 2, 13–30 kpa, and Group 3, >30kpa. Data on demographic, clinical features, and radiologic features were extracted from the data store and presented on an Excel spreadsheet. We retrieve the results of ESR that were done using the Westergren method. ESR was determined as the degree of fall along the column of blood after 1 h of the blood sample left standing. These readings were then recorded in an Excel sheet in mm/hr. We also retrieved results of alpha-fetoprotein, hepatitis B surface antigen, anti-HCV, and liver function test.
Data were captured in Excel and analyzed using SPSS version 20. Basic descriptive statistics were performed and displayed as frequencies. ANOVA was used to compare the three groups. Spearman's correlation was used to determine the relationship between ESR and AFP/FibroScan score. ROC curves were generated to determine the performance of ESR as a diagnostic tool in predicting the presence of HCC.
| Results|| |
There were 316 participants in this study, males were 140 (44.4%) and females were 176 (55.6%). Those with HCC were 88 (27.8%) whereas those without HCC were 228 (72.2%). The mean age of the studied population was 47 ± 11.6 years. For those with HCC, it was 48.6 ± 13.4 years and for those without HCC, it was 47.4 ± 13.3. Those who were HBV positive were 190 (44.7%) while those who were HCV were 119 (28%). The mean ESR for those with HCC versus those without HCC was 60.67 ± 37.9 mm/h versus 22.53 ± 8.3 mm/h, P = 0.001. When stratified to a cutoff of 100 mmh/h, 72% of patients with an ESR above 100 had HCC.
We stratified patients (arbitrarily) into three groups based on their FibroScan scores: Group 1, 1–12kpa, Group 2, 13–30kpa, and Group 3, >30kpa. ESR was significantly different among the three groups with P < 0.001, on post hoc testing, the difference was between those in Groups 1 and 3 and those in Groups 2 and 3, P < 0.001, respectively. ESR also correlated positively with degree of FibroScan score r = 0.36, P < 0.001. [Figure 1] shows the correlation graph for ESR with FibroScan: FibroScan® Echosens, Paris, E100m002, 13-version; CT Scan: GE brightspeed elite select 16 slice CT machine, and [Figure 2] shows the mean ESR score of the three groups based on fibrosis score. There is also a positive correlation between ESR and alpha-fetoprotein r = 0.321 P < 0.001.
|Figure 1: Correlation between degree of FibroScan (kpa) score and ESR( mm/hr). ESR: Erythrocyte sedimentation rate|
Click here to view
|Figure 2: Mean score of ESR for patients in all three groups. Key: No fibrosis: ≤12kpa; Moderate: >12 – 30kpa; High fibrosis >30kpa. ESR: Erythrocyte sedimentation rate|
Click here to view
ESR could discriminate between those with HCC and those without HCC, with an area under the curve (AUC).803 and sensitivity of 80% and specificity of 67% at an ESR of 19.5 mm/h. [Figure 3] below shows the ROC curve for ESR in HCC patients. AFP could also discriminate those with HCC using ROC curves with an AUC of .905 while the sensitivity and specificity of AFP to determine if a patient had HCC was 72% and 96% at a cutoff value of 101 ng/ml.
|Figure 3: ROC curve for ESR to determine the presence of hepatocellular carcinoma ESR: Erythrocyte sedimentation rate|
Click here to view
| Discussion|| |
In this retrospective study, we evaluated the role of erythrocytes sedimentation rate in distinguishing and identifying patients who have HCC from those who do not. Our data clearly showed that based on ESR alone, there is a difference between those with HCC, liver cirrhosis, and those without cirrhosis. One of the key problems in HCC is a late presentation when patients present with late stages of disease that are not amenable to definitive therapy. This late presentation is mainly because the initial stage of HCC is asymptomatic and patients go on carrying life-threatening tumors ignorantly. We have observed that when patients present with advanced HCC, they tend to have high ESR values and we wondered if there is a transition point between cirrhosis and HCC at which point ESR begins to rise.
In our study, we had a group of patients with risk factors for HCC who had either liver FibroScan scores below or in the region of cirrhosis. The ESR score between the three groups of patients was significantly different. When the ESR of those with liver cirrhosis and those without cirrhosis were compared, there was a significant difference and this difference was also seen between those with liver cirrhosis and those with HCC with a P < 0.001.
The main strategy for early diagnosis of liver cancer is hinged on HCC surveillance which utilizes an abdominal ultrasound scan and alpha-fetoprotein every 6 months. The idea is that a rise in the tumor marker AFP and the finding of a small hepatic mass should raise the suspicion for a liver cancer developing and definitive treatment options offered. Based on our observation, we propose that ESR, which is a simple and readily available test, has the potential to be able to discriminate which patients have developed HCC. It has the advantage of being readily available and a short time to completion of an hour and it is also remarkably reproducible. A role for ESR in combination with CRP has been demonstrated in a study from Turkey where it was shown that an elevated ESR and CRP are indicative of the extent of disease and survival in HCC patients.
We performed the ROC curve and the AUC for ESR in predicting HCC performed very well (0.803) with a sensitivity and specificity of 80% and 67%, respectively. In comparison to the gold standard AFP, which has a sensitivity and specificity of 45%–100% and 70%–75%, respectively. If ESR was to be a screening tool for HCC, it would perform quite well in comparison to this gold standard. This is an important observation, especially because up to 31% of patients with liver cancer do not have elevated AFP. Further studies will be required to demonstrate that ESR is not inferior to AFP and also show that ESR is elevated in patients with early HCC and not only advanced HCC. Although our data did not show the different stages of the disease of the HCC group, we know from previous studies that over 80% of our patients present late and also die within 3 months of presentation. Thus, we can extrapolate that these patients were also likely to have advanced forms of HCC.
It is plausible that ESR can serve as a biomarker for HCC screening because it is a marker of acute inflammation. Patients with HCC tend to have etiology such as hepatitis B and C and NAFLD which are all driven by inflammation. Previous studies have demonstrated that extreme elevation in the ESR is associated with poor prognosis or metastatic disease including HCC. In our study, the percentage of people with extreme elevation in ESR was 72% among those with HCC. We think that if ESR is serially monitored in patients at risk of developing HCC (such as liver cirrhosis which is considered to be a premalignant condition and has an annual rate of HCC occurrence of 1.5% and chronic HBV infection with and without cirrhosis which has an annual rate of 1.5%), a serial rise in the ESR will be a pointer to the presence of developing malignancy. The current standard of care for the patient at risk of having HCC is to have an ultrasound and AFP done at 6 months. This has been demonstrated to improve mortality and survival in patients with HCC in a previous study which showed that 3-year survival rates were improved with a combination of USS and AFP. The combination of ESR, AFP, and USS is likely going to be the improved detection rate of early HCC in this at-risk group, hence, this should be a subject of further research.
| Conclusion|| |
There is a need for newer methods for early detection of HCC since evidence has shown that surveillance and early tumor detection improve survival. ESR is simple, reproducible, and cheap and it has the potential to serve as a marker of early occurrence of HCC and should be further evaluated in a prospective study for this property.
1. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number U54CA221205, and by the Fogarty International Center of the National Institutes of Health under award number D43TW009575. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Rawla P, Sunkara T, Muralidharan P, Raj JP. Update in global trends and aetiology of hepatocellular carcinoma. Contemp Oncol (Pozn) 2018;22:141-50.
Okeke E, Ladep N, Davwar PM, Duguru M, Banwat E, Crossey M, et al.
Factors in the mortality of newly diagnosed HCC patients in Nigeria. J Hepatol 2014;60:S209.
Okeke E, Mark Davwar P, Mullen B, Duguru M, Agbaji O, Sagay A, et al.
The impact of HIV on hepatocellular cancer survival in Nigeria. Trop Med Int Health 2021;26:335-42.
Yang JD, Mohamed EA, Aziz AO, Shousha HI, Hashem MB, Nabeel MM, et al.
Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: A multicountry observational study from the Africa Liver Cancer Consortium. Lancet Gastroenterol Hepatol 2017;2:103-11.
Kim AK, Hamilton JP, Lin SY, Chang TT, Hann HW, Hu CT, et al.
Urine biomarker: Novel approach to hepatocellular carcinoma screening. medRxiv 2020.
Ladep NG, Dona AC, Lewis MR, Crossey MM, Lemoine M, Okeke E, et al.
Discovery and validation of urinary metabotypes for the diagnosis of hepatocellular carcinoma in West Africans. Hepatology 2014;60:1291-301.
Brigden ML. Clinical utility of the erythrocyte sedimentation rate. Am Fam Physician 1999;60:1443-50.
Westergren A. The technique of the red cell sedimentation reaction. Am Rev Tuberc 1926;14:94-101.
Gebo KA, Chander G, Jenckes MW, Ghanem KG, Herlong HF, Torbenson MS, et al.
Screening tests for hepatocellular carcinoma in patients with chronic hepatitis C: A systematic review. Hepatology 2002;36:S84-92.
Chaiteerakij R, Chattieng P, Choi J, Pinchareon N, Thanapirom K, Geratikornsupuk N. Surveillance for hepatocellular carcinoma reduces mortality: An inverse probability of treatment weighted analysis. Ann Hepatol 2017;16:421-9.
Hennedige T, Venkatesh SK. Imaging of hepatocellular carcinoma: Diagnosis, staging and treatment monitoring. Cancer Imaging 2012;12:530.
Foucher J, Chanteloup E, Vergniol J, Castéra L, Le Bail B, Adhoute X, et al.
Diagnosis of cirrhosis by transient elastography (FibroScan): A prospective study. Gut 2006;55:403-8.
Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul JL, et al
. EASL clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2018;69:182-236.
Akkiz H, Carr BI, Bag HG, Karaoğullarından Ü, Yalçın K, Ekin N, et al.
Serum levels of inflammatory markers CRP, ESR and albumin in relation to survival for patients with hepatocellular carcinoma. Int J Clin Pract 2021;75:e13593.
Agopian VG, Harlander-Locke MP, Markovic D, Zarrinpar A, Kaldas FM, Cheng EY, et al.
Evaluation of patients with hepatocellular carcinomas that do not produce α-fetoprotein. JAMA Surg 2017;152:55-64.
Okeke E, Davwar PM, Roberts L, Sartorius K, Spearman W, Malu A, et al.
Epidemiology of liver cancer in Africa: Current and future trends. Semin Liver Dis 2020;40:111-23.
[Figure 1], [Figure 2], [Figure 3]