Platelet count, spleen length, and platelet-to-spleen length ratio for the diagnosis of oesophageal varices in people with liver disease

Background

Hepatic cirrhosis is a severe disease with scars and nodules on the liver tissue. As a result, the normal function of the liver is impaired. Whatever the cause of cirrhosis, changes in the structure of and blood flow within the liver increase pressure in the portal vein (called portal vein hypertension), which is the vein that drains blood from the bowels to the liver. Portal hypertension induces dilatation (extension) of veins within the wall of the oesophagus (food pipe or gullet), which often rupture (break) with severe bleeding. Thus, when liver cirrhosis is diagnosed, an oesophago-gastro-duodenoscopy (OGD) is recommended to detect the presence of oesophageal varices (areas of abnormal dilatation of veins). During OGD, a small camera at the end of a tube is inserted down the oesophagus from the mouth and pictures are relayed back to a screen. Large varices or red signs on even small varices show high risks of rupture and bleeding. If high-risk varices are found, treatment with beta-blockers is effective in reducing the risk of bleeding. Three simple non-invasive tests could be used to identify people with liver diease at high risk of having oesophageal varices: platelet count - a simple laboratory test on a blood sample by which the number of platelets (a blood element ensuring coagulation) is measured; length (maximal diameter) of the spleen measured during ultrasound examination of the abdomen; and ratio of platelet count to spleen length.

Study characteristics

We searched scientific databases for clinical studies comparing platelet count, spleen length, or platelet count-to-spleen length ratio versus oesophago-gastro-duodenoscopy in detecting the presence of varices in children or adults with chronic liver disease or portal vein thrombosis (narrowing of the portal vein). The evidence is current to June 2016.

Key results

We found 25 studies with 5096 participants assessing the use of platelet count to diagnose the presence of varices and grade the risk of bleeding, and comparing platelet count versus oesophago-gastro-duodenoscopy in adults with cirrhosis: 13 studies with 1489 participants assessed the diagnostic ability of spleen length, and 38 studies with 5235 participants assessed the diagnostic ability of platelet count-to-spleen length ratio. Platelet count-to-spleen length ratio was the most accurate and could be used to identify people with liver disease who were at high risk of having oesophageal varices. Particularly, in people with hepatic cirrhosis among whom 580 out of 1000 people are expected to have oesophageal varices, only 41 (7% of 580) people will be missed as having varices and will have no appropriate preventive treatment or follow-up. Thus, if platelet count-to-spleen length ratio is lower than 909 (n/mm3)/mm (the most used threshold), the presence of oesophageal varices can be excluded. Thus, it is possible to reduce the number of endoscopic examinations needed to find a person with oesophageal varices. On the contrary, this ratio is not accurate enough to replace endoscopy for identification of high risk of bleeding oesophageal varices.

Quality of the evidence

All but one study had problems of risk of bias involving mainly the definition of positive or negative index tests (platelet count, spleen length, and their ratio), which should be defined before and not after data analyses, and blinding of test results to the endoscopists who performed oesophago-gastro-duodenoscopy. Hence, these problems could impair the accuracy estimates of the three tests.

Authors' conclusions: 

Platelet count-to-spleen length ratio could be used to stratify the risk of oesophageal varices. This test can be used as a triage test before endoscopy, thus ruling out adults without varices. In the case of a ratio > 909 (n/mm3)/mm, the presence of oesophageal varices of any size can be excluded and only 7% of adults with varices of any size would be missed, allowing investigators to spare the number of oesophago-gastro-duodenoscopy examinations. This test is not accurate enough for identification of oesophageal varices at high risk of bleeding that require primary prophylaxis. Future studies should assess the diagnostic accuracy of this test in specific subgroups of patients, as well as its ability to predict variceal bleeding. New non-invasive tests should be examined.

Read the full abstract...
Background: 

Current guidelines recommend screening of people with oesophageal varices via oesophago-gastro-duodenoscopy at the time of diagnosis of hepatic cirrhosis. This requires that people repeatedly undergo unpleasant invasive procedures with their attendant risks, although half of these people have no identifiable oesophageal varices 10 years after the initial diagnosis of cirrhosis. Platelet count, spleen length, and platelet count-to-spleen length ratio are non-invasive tests proposed as triage tests for the diagnosis of oesophageal varices.

Objectives: 

Primary objectives

To determine the diagnostic accuracy of platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices of any size in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology. To investigate the accuracy of these non-invasive tests as triage or replacement of oesophago-gastro-duodenoscopy.

Secondary objectives

To compare the diagnostic accuracy of these same tests for the diagnosis of high-risk oesophageal varices in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology.

We aimed to perform pair-wise comparisons between the three index tests, while considering predefined cut-off values.

We investigated sources of heterogeneity.

Search strategy: 

The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE (OvidSP), Embase (OvidSP), and Science Citation Index - Expanded (Web of Science) (14 June 2016). We applied no language or document-type restrictions.

Selection criteria: 

Studies evaluating the diagnostic accuracy of platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices via oesophago-gastro-duodenoscopy as the reference standard in children or adults of any age with chronic liver disease or portal vein thrombosis, who did not have variceal bleeding.

Data collection and analysis: 

Standard Cochrane methods as outlined in the Cochrane Handbook for Diagnostic Test of Accuracy Reviews.

Main results: 

We included 71 studies, 67 of which enrolled only adults and four only children. All included studies were cross-sectional and were undertaken at a tertiary care centre. Eight studies reported study results in abstracts or letters. We considered all but one of the included studies to be at high risk of bias. We had major concerns about defining the cut-off value for the three index tests; most included studies derived the best cut-off values a posteriori, thus overestimating accuracy; 16 studies were designed to validate the 909 (n/mm3)/mm cut-off value for platelet count-to-spleen length ratio. Enrolment of participants was not consecutive in six studies and was unclear in 31 studies. Thirty-four studies assessed enrolment consecutively. Eleven studies excluded some included participants from the analyses, and in only one study, the time interval between index tests and the reference standard was longer than three months.

Diagnosis of varices of any size. Platelet count showed sensitivity of 0.71 (95% confidence interval (CI) 0.63 to 0.77) and specificity of 0.80 (95% CI 0.69 to 0.88) (cut-off value of around 150,000/mm3 from 140,000 to 150,000/mm3; 10 studies, 2054 participants). When examining potential sources of heterogeneity, we found that of all predefined factors, only aetiology had a role: studies including participants with chronic hepatitis C reported different results when compared with studies including participants with mixed aetiologies (P = 0.036). Spleen length showed sensitivity of 0.85 (95% CI 0.75 to 0.91) and specificity of 0.54 (95% CI 0.46 to 0.62) (cut-off values of around 110 mm, from 110 to 112.5 mm; 13 studies, 1489 participants). Summary estimates for detection of varices of any size showed sensitivity of 0.93 (95% CI 0.83 to 0.97) and specificity of 0.84 (95% CI 0.75 to 0.91) in 17 studies, and 2637 participants had a cut-off value for platelet count-to-spleen length ratio of 909 (n/mm3)/mm. We found no effect of predefined sources of heterogeneity. An overall indirect comparison of the HSROCs of the three index tests showed that platelet count-to-spleen length ratio was the most accurate index test when compared with platelet count (P < 0.001) and spleen length (P < 0.001).

Diagnosis of varices at high risk of bleeding. Platelet count showed sensitivity of 0.80 (95% CI 0.73 to 0.85) and specificity of 0.68 (95% CI 0.57 to 0.77) (cut-off value of around 150,000/mm3 from 140,000 to 160,000/mm3; seven studies, 1671 participants). For spleen length, we obtained only a summary ROC curve as we found no common cut-off between studies (six studies, 883 participants). Platelet count-to-spleen length ratio showed sensitivity of 0.85 (95% CI 0.72 to 0.93) and specificity of 0.66 (95% CI 0.52 to 0.77) (cut-off value of around 909 (n/mm3)/mm; from 897 to 921 (n/mm3)/mm; seven studies, 642 participants). An overall indirect comparison of the HSROCs of the three index tests showed that platelet count-to-spleen length ratio was the most accurate index test when compared with platelet count (P = 0.003) and spleen length (P < 0.001).

DIagnosis of varices of any size in children. We found four studies including 277 children with different liver diseases and or portal vein thrombosis. Platelet count showed sensitivity of 0.71 (95% CI 0.60 to 0.80) and specificity of 0.83 (95% CI 0.70 to 0.91) (cut-off value of around 115,000/mm3; four studies, 277 participants). Platelet count-to-spleen length z-score ratio showed sensitivity of 0.74 (95% CI 0.65 to 0.81) and specificity of 0.64 (95% CI 0.36 to 0.84) (cut-off value of 25; two studies, 197 participants).

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