Predictive value of platelet counts to detect grade of esophageal varices in liver cirrhosis

ABSTRACT

Introduction:

Bleeding from esophageal varices (EVs) causes a significant risk in cirrhotic patients, often leading to life-threatening complications. While screening endoscopy is the recommended method to identify those at risk, its invasive nature and limitations prompt the search for alternative predictors. Thrombocytopenia has emerged as a potential marker for assessing the presence and severity of EVs. This study aims to establish a relationship between platelet count and predicted grading of EVs in individuals with liver cirrhosis.

Aim:

To study platelet count as a predictor of EVs in liver cirrhosis. Materials and Methods: This cross-sectional research was undertaken at KGMU, Lucknow. It encompassed newly identified cases of cirrhosis with varices of any degree detected through endoscopy. The endoscopic observations were standardized utilizing the Paquet grading system. Patients were categorized into four subgroups based on platelet count, and correlations between platelet count groups and EVs grading were examined using Spearman rank correlations. The association between platelet count and EVs grade was assessed using the Chi-square test.

Results:

The study comprised 50 patients, with 84% (n = 42) being male, and the mean age was 45.66 ± 10.26 years. Platelet counts were categorized as follows: <50,000/uL in 36% of patients, 50,000–99,000/uL in 28%, 100,000–150,000/uL in 14%, and >150,000/uL in 22% of patients. EVs were classified as grade I in 26% of patients, grade II in 20%, grade III in 34%, and grade IV in 20% of patients. When the platelet count is <50,000/uL, the patients present grade IV varices. With a platelet count of 50,000–99,000/μL, they present grade III varices; 100,000–150,000/μL corresponds to grade II; and > 150,000/μL to grade I EVs. The mean platelet count was 223245.53/mm³ in patients with grade I varices, decreasing to 109505.42/mm³, 57345.46/mm³, and 20502.00/mm³ in patients with grade II, III, and IV varices, respectively (p = <0.0001). A notable negative correlation was observed between platelet count and EVs grades (P < 0.001).

Conclusion:

Platelet count serves as a predictive factor for EVs grade in cirrhotic patients, with a significant negative correlation between platelet count and varices grades.

Introduction

Cirrhosis is a condition characterized by irreversible damage to the liver tissue, resulting in fibrosis and the formation of nodules throughout the organ. While the causes may vary, the outcome remains consistent. The progression of cirrhosis involves extensive fibrosis and the development of regenerative nodules, leading to a range of clinical symptoms that reflect the severity of liver damage rather than the specific cause. These symptoms include jaundice, edema, coagulopathy, and metabolic abnormalities, as well as complications such as portal hypertension (PH), gastroesophageal varices, splenomegaly, ascites, and hepatic encephalopathy.

Three types of cirrhosis are recognized based on anatomy: micronodular, macronodular, and mixed. Micronodular cirrhosis is characterized by thick, regular septae and small, uniform nodules that involve every lobule of the liver. Macronodular cirrhosis, however, may suggest impaired regrowth capacity, often associated with conditions such as alcoholism, malnutrition, old age, or anemia. In cases of micronodular cirrhosis, regeneration can result in a macronodular or mixed appearance over time. The causes of cirrhosis are diverse and include factors such as alcohol consumption, viral hepatitis (types B and C), metabolic disorders like hemochromatosis and Wilson’s disease, prolonged cholestasis, hepatic venous outflow obstruction, autoimmune hepatitis, exposure to toxins and drugs, Indian childhood cirrhosis, and cryptogenic cirrhosis.

Portal hypertension (PH), a common complication of liver cirrhosis, can lead to esophageal varices (EVs), which pose a risk of rupture and bleeding.[1] This bleeding is life-threatening and constitutes 20–35% of mortality due to upper gastrointestinal (GI) bleeding.[2] Around one-third of cirrhosis patients have EVs at diagnosis, increasing to 90% within a decade.[3] Progression from small to large varices occurs at a rate of 8–10% annually, with a 5% annual hemorrhage rate for small varices and 15% for large varices.[4] EVs typically manifest once the hepatic venous pressure gradient (HVPG) reaches a level of 10 to 12 mm Hg. Around one-third of gastrointestinal bleeds are linked to pre-existing cirrhosis.

Varices of significant size, accompanied by indicators of redness, advanced liver illness, and portal pressure exceeding 12 mm Hg, are indicative of a heightened risk of bleeding. The mortality rate within six weeks following an episode of bleeding from EVs is approximately 20%.[5] The severity of liver cirrhosis, the size of EVs, and the presence or absence of the red sign (RS) are related indicators of EVs bleeding.[6] For routine assessment of the above indicators, the Baveno VI consensus recommends that patients with cirrhosis undergo regular upper gastrointestinal endoscopy screening so that appropriate preventive treatment can be administered to prevent variceal bleeding events. To date, HPVG and upper gastrointestinal endoscopy are considered the gold standards for the assessment of PH and EVs, respectively.[6] However, the prevalence of varicose veins requiring treatment (VNT), as defined by the Baveno VI guidelines, is very low in compensated advanced chronic liver disease (cACLD) patients who are detected at an early stage. HPVG and esophagogastroduodenoscopy (EGD) are invasive procedures and expensive, and the patient compliance associated with them is poor.[7] Therefore, in clinical practice, it is necessary to develop a safe, non-invasive, and patient-acceptable prediction model that can not only prevent frequent HPVG or gastrointestinal endoscopy examinations but also better predict high-risk EVs (HEVs) in patients with viral cirrhosis.

Platelet function, especially aggregation, is compromised in individuals with cirrhosis, particularly those classified as Child’s grade C, due to an inherent defect and circulating serum factors. This results in reduced arachidonic acid availability for prostaglandin production, as well as decreased platelet adenosine triphosphate and 5-hydroxytryptamine. Thrombocytopenia, typically ranging from 60–90 × 10^9/L, is highly prevalent in chronic liver disease and is largely attributed to hypersplenism.[8] Various studies have investigated the role of platelet count in predicting the presence of EVs. According to Pilette et al.[9] (1999), a platelet count <160,000 showed a sensitivity of 80% and specificity of 58% for detecting large varices, while a count of ≥260,000 had a negative predictive value of ≥91%. Schepis et al. (2001)[10] found that a platelet count <100 × 10^9/L was associated with predicting EVs. Madhotra et al.[11] (2002) reported a specificity of 73% for predicting varices with a platelet count of <68,000/cubic mm[12] identified a platelet count of 90 × 10^3/μL or less as predictive of varices, while Ng et al. (1999)[13] determined an optimal critical value of 150 × 10^9/L for platelet count in patients without thrombocytopenia and ascites.

Typically, in clinical practice, all patients diagnosed with cirrhosis are usually screened via upper endoscopy to detect varices. Treating patients with large varices involves using non-selective beta-blockers to decrease the risk of initial variceal bleeding. However, fewer than half of cirrhotic patients exhibit varices during screening, and most of these are small and pose a low bleeding risk. To alleviate the potential strain on endoscopy units, some studies have sought to identify non-invasive predictors of EVs or large varices. These studies have demonstrated that biochemical, clinical, and ultrasonographic factors alone or combined exhibit strong predictive capabilities for assessing EVs without invasive procedures. Generally, these studies found that parameters associated with PH, such as splenomegaly and reduced platelet count, were common predictors of EVs.

In a study by Thomopoulos et al. (2003)[14], 17 variables relevant to EVs were examined, concluding that thrombocytopenia, splenomegaly, and ascites are independent predictors of large EVs in cirrhotic patients. They propose that in cirrhotic patients lacking these predictive factors, endoscopy might be safely avoided since large varices are unlikely. However, in patients with chronic liver disease, decreased platelet count may be influenced by factors beyond PH, such as reduced platelet lifespan, decreased thrombopoietin production, or the effects of alcohol or hepatitis viruses. Conversely, splenomegaly in cirrhotic patients is likely due to vascular disturbances associated with PH. In line with this, Giannini et al. (2003)[8] introduced the platelet count/spleen diameter ratio as a parameter to link thrombocytopenia to spleen size, considering the decrease in platelet count, which is likely related to hypersplenism. Hence, preventing portal hypertensive bleeding remains a primary focus in the long-term care of cirrhotic patients. While screening endoscopy is recommended for early detection and grading of varices, it is invasive, operator-dependent, burdensome, affects patient compliance, and escalates healthcare costs. Hence, non-invasive methods are sought to predict varices and their grades.[15,16,17,18] Thrombocytopenia (<150,000/uL) is prevalent in 64–76% of PH and cirrhosis cases due to various factors including reduced thrombopoietin production and platelet sequestration.[19,20] Studies indicate an inverse correlation between platelet count and varices grades.[21] Limited endoscopic resources in developing countries like India necessitate non-invasive markers for varices grading. Thus, this study aimed to establish the correlation between platelet count and varices grades in the Indian population, potentially aiding the prioritization of endoscopic screening for high-risk patients.

Materials and Methods

Study Design and Participants: This descriptive cross-sectional study was conducted at the Department of Physiology in collaboration with the Department of Gastromedicine in KGMU Lucknow. Newly diagnosed cases of cirrhosis with varices of any grade on endoscopy, aged 18 to 70 years, regardless of the cause of cirrhosis, with or without ascites and splenomegaly, were eligible. Diagnosis of cirrhosis relied on clinical, laboratory, and ultrasonographic findings. Patients with hematological disorders, portal vein thrombosis, undergoing beta-blocker prophylactic therapy, or having undergone endoscopic band ligation or sclerotherapy were excluded. The sample size of 50 was determined using a sample size calculator for cross-sectional studies with a 95% confidence level.

Data collection

Endoscopy was conducted by the same endoscopist using an Olympus GIF type Q260 endoscope (The Olympus GIF Type Q260 Endoscopy used in this study was manufactured by Olympus Medical Systems Corp.), following an 8-h fasting period. Endoscopic findings were standardized using the Paquet grading system.[13] Blood samples were collected before endoscopy, and platelet count was determined using an automatic hematology analyzer (Sysmex XN-1000), confirmed by manual counting. Demographic details, endoscopic findings, and platelet count were obtained from medical records. Patients were categorized into four subgroups based on platelet count as follows: <50,000/uL as group 1, 50,000–99,000/uL as group 2, 100,000–150,000/uL as group 3, and > 150,000/uL as group 4.

Data analysis

Data analysis was performed using IBM SPSS Statistics version 19.0. Mean and standard deviation were calculated for quantitative data, while frequency and percentage were determined for gender, platelet count, and grade of EVs. Spearman rank correlations were used to assess the correlation between platelet count group and EVs grading. The association between platelet count and EVs grade was evaluated using the Chi-square test, with a significance level set at P ≤ 0.05.

Results

In total, 50 patients participated in the study, with 84% (n = 42) being male and 16% (n = 8) female. The mean age of the patients was 45.66 ± 10.26 years. Platelet count distribution was as follows: <50,000/uL in 36% (n = 18) of patients, 50,000–99,000/uL in 28% (n = 14), 100,000–150,000 in 14% (n = 7), and >150,000/uL in 22% (n = 11) patients. EVs grading revealed: grade I in 26% (n = 13) patients, grade II in 20% (n = 10), grade III in 34% (n = 17), and grade IV in 20% (n = 10) of patients [Table 1]. A notable association was observed between platelet count groups and EVs grades, indicating that lower platelet count groups were associated with higher-grade varices, while higher platelet count groups were linked with lower-grade varices [Table 2]. Spearman’s correlation is negative between grades of EVs and platelet count [Table 3].

Table 1.

Association of platelet count group with grading of esophageal varices

Platelet count		Variceal grade I	Variceal grade II	Variceal grade III	Variceal Grade IV	Total	P
<50,000/uL	Group 1	1	2	7	8	18
50,000–99,000/uL	Group 2	1	3	8	2	14	<0.01
100,000–150000/uL	Group 3	1	4	2	0	7
>150,000/uL	Group 4	10	1	0	0	11

Table 2.

Correlation of platelet count with grades of esophageal varices

			Platelet Count	Grades of varices
	Platelet Count	Correlation coefficient	1.0	-0.71<0.01
Spearman’s Rho	Paquet variceal grade	P-value	/
		Correlation coefficient	- 0.71	1.0
		P-value		/

Table 3.

Association of mean platelet count with Paquet variceal grade

Variceal grade	Mean platelet count (mm3)	SDN (mm3)	N	P
I	223245.53	85423.765	12
II	109505.42	67134.927	11	<0.01
III	57345.46	32176.244	17
IV	20502.0	15652.637	10

Discussion

Upper gastrointestinal bleeding (UGIB), a potentially lethal consequence of PH, occurs in approximately 30% to 40% of individuals with cirrhosis owing to the seriousness of the long-standing liver disease. Variceal bleeding is linked to notable rates of illness, death, and medical expenses. Several investigations have affirmed the effectiveness of beta-blockers in preventing initial variceal hemorrhage among high-risk patients, underscoring the importance of gastroscopy for EVs screening. Present recommendations advise endoscopic screening for all cirrhosis patients upon diagnosis to pinpoint those at heightened risk.

Bleeding and the potential benefits of primary prophylaxis are significant considerations. Yet, this strategy places a considerable strain on endoscopy facilities, and repeated testing may hinder patient compliance over time. Consequently, there’s a pressing need for non-invasive predictors to alleviate the medical, social, and economic burdens associated with the disease. Interestingly, numerous previous studies have identified various non-endoscopic variables with good predictive value for the presence or absence of gastroesophageal varices. Platelet count, with or without spleen size measurement, has emerged as one such variable for predicting the occurrence of EVs in many investigations.

Our findings demonstrate a significant inverse relationship between platelet count and EVs severity. Patients with lower platelet counts tended to have higher varices grades. For instance, in group 1 patients with platelet counts <50,000/uL, the majority had grade III or IV varices, whereas in group 4 patients with platelet counts >150,000/uL, most had grade I varices. This suggests that platelet count can serve as a reliable predictor of varices grades, reducing the need for frequent upper GI endoscopy. Similar findings were observed in the studies conducted by Abbasi et al. and Philips and Sahney[22] where platelet count was correlated inversely with the esophageal variceal grading.[18,19] This might be due to the splenomegaly-induced sequestration of the spleen leading to decreased platelet count. The other reason is due to decreased thrombopoietin production because of liver cirrhosis.

Regarding gender distribution, our study reflects a male predominance in cirrhosis cases, consistent with previous research in Taiwan where 71% of patients with cirrhosis were male[23] indicating a higher incidence of cirrhosis in males due to slower fibrosis progression.[24] Hence, the male predominance in liver cirrhosis could be attributed to a greater degree of involvement in risk factors among men compared to women. For instance, alcohol consumption, a leading cause of cirrhosis, tends to be higher in men than in women. Additionally, the higher prevalence of chronic hepatitis B (HBV) and C in men compared to women could further explain this male predominance. As noted by Khan et al.,[25] chronic hepatitis B and C are more frequently observed in men than in women.

The mean age of 45.66 ± 10.26 years of our study participants aligns with typical age ranges for cirrhosis incidence reported in previous studies by Devrajani et al.[26] These variations can be attributed to the differing causes of liver disease across various regions. For instance, compared to Western countries like France and Italy, individuals from Asian and African populations diagnosed with liver cirrhosis tend to be younger. This trend of younger onset could likely be linked to the early transmission of viruses within our population. As highlighted by Lavanchy’s study published in 2004, in Western nations, the disease is relatively rare and typically acquired in adulthood, whereas in Asia and much of Africa, chronic HBV infection is prevalent and often acquired during infancy or childhood.

Consequently, the onset of cirrhosis in our patients occurs at a younger age compared to Western patients. Conversely, in industrialized nations such as France and Italy, alcohol represents the most common cause of liver cirrhosis, with alcohol consumption habits typically developing in adulthood. This explains why the average age of patients with liver disease in these countries tends to be higher than in ours.

Furthermore, our study confirms previous findings that lower platelet counts are associated with higher varices grades, which is indicative of advanced cirrhosis. Notably, we found similar results to other studies, supporting the utility of platelet count as a predictor for large varices.[21,27]

The mean platelet count showed a significant decrease in patients with grade III (57345.46/mm³) and IV (20502.00/mm³) EVs compared to those with grade I (223245.53/mm³) and II (109505.42/mm³) varices in our study. These findings align with research from Egypt, where platelet count was notably lower in patients with grades II and III than in those with grade I.[28] Thus, platelet count can serve as an indicator to identify patients at risk of large varices, guiding the need for prophylactic endoscopic treatment to prevent upper GI bleeding, rather than conducting endoscopy for all cirrhosis patients. While our study solely relied on platelet count as a predictive marker, other studies have utilized additional non-invasive parameters like platelet count/spleen diameter ratio and AST Platelet Ratio Index (APRI) to predict varices grades. However, we advocate for the use of platelet count alone due to its accessibility, cost-effectiveness, and ease of use.

Limitations: It was a single-center study with patients of cirrhosis regardless of the cause, and we did not investigate additional predictive markers or impending bleeding signs. Future multicentric studies focusing on specific causes of cirrhosis and incorporating additional markers like spleen size ratio are recommended to further enhance predictive accuracy.

Conclusion

According to this study, the majority of cirrhotic patients are male, with a mean age of 45.66 ± 10.26 years old. The platelet count serves as a crucial predictive factor for the presence of EVs in cirrhotic patients. A platelet count below 223000 lakhs/mm³ indicates a high likelihood of EVs with both sensitivity and specificity. Moreover, a platelet count below 109505 lakhs/mm³ can predict the presence of large EVs with high accuracy.

Platelet count, as a non-invasive parameter, demonstrates high accuracy in predicting EVs. In financially constrained developing countries, cirrhotic patients with normal platelet counts may not require immediate endoscopic screening, as they are at low risk for the presence of EVs and subsequent bleeding. However, in cases where the platelet count falls below 223000/mm³, gastroscopy becomes a valuable diagnostic and therapeutic tool for identifying and managing EVs.

The observed significant negative correlation between platelet count and grades of EVs indicates that lower platelet counts are linked to higher grades of varices. This suggests that platelet count could serve as a reliable predictor for determining the severity or grade of EVs.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.