To the best of our knowledge, this is the first study that evaluates the clinical relevance of RLR in patients with PBC. The results showed that RLR, an easily-acquired parameter through blood routine tests, can effectively differentiate advanced cirrhosis from early cirrhosis. RLR may also serve as a valuable marker for estimating the therapeutic response and to predict prognosis.
PBC is a chronic disease that is increasingly being recognized in recent years and its prevalence is growing worldwide. The disease onset is typically insidious and is associated with non-specific symptoms. Pruritus and fatigue were reported in 80% and 20% to 70% patients, respectively. Symptoms of decompensated cirrhosis may be seen in advanced stage. The presence of AMA is an important diagnostic marker of PBC that has a sensitivity and specificity of 90% to 95%.
Liver biopsy is still the gold standard for diagnosis and staging of PBC and is useful for monitoring of therapeutic response. Moreover, it can also predict prognosis of PBC. Liver biopsy is essential when PBC-specific antibodies are absent, or when coexisting autoimmune hepatitis (AIH) or non-alcoholic steatohepatitis is suspected. However, it is not essential and, indeed, not accepted by many patients owing to its invasive nature and the associated risk of complications.[25,26] The risk associated with liver biopsy in patients with advanced stage of cirrhosis is much higher than that in patients with early stage. Patients with early-stage disease generally show good clinical and biochemical response to ursodeoxycholic acid (UDCA) therapy. Patients with advanced-stage cirrhosis tend to easily develop hepatic decompensation and show poor response to UDCA. In addition, UDCA treatment in advanced stage does not decrease the risk of mortality or hepatocellular carcinoma in patients with PBC. The prognosis of patients with early stage of cirrhosis is better than that of patients with advanced stage. Thus, figuring out the stage of PBC with noninvasive method is a key imperative.
Parameters like RDW, RPR, AST/ALT ratio (AAR), and neutrophil to lymphocyte ratio (NLR) were shown to predict the degree of cirrhosis. In a study by Lou et al, RDW value was shown to directly correlate with the severity of cirrhosis. In addition, RDW was shown to predict 3-month mortality in patients with hepatitis B. In a study by Chen et al, RPR was shown to accurately predict the degree of cirrhosis. Use of this index may reduce the need for liver biopsy. Similar results pertaining to the ability of RPR to predict the degree of cirrhosis were reported by Taefi et al. Another study from Sweden concluded that the AST/ALT ratio may help identify cirrhosis in patients with PBC. Alkhouri et al showed a positive correlation between NLR and the severity of cirrhosis.
RDW reflects the variation in the distribution of RBC volume in circulation. High values imply greater variation that may relate to anemia. Also, RDW is a marker of chronic inflammation. RDW has been shown to be related with various diseases, such as cardiovascular diseases, renal diseases, and some malignant diseases.[13,15,40] In this study, RDW increased with increase in the severity of disease. Thrombocytopenia is a well-known complication of cirrhosis; therefore, platelet count decreases with the severity of cirrhosis. PBC is an autoimmune disease. Lymphocytes play a crucial role in immune surveillance. A decrease in lymphocyte count may relate with apoptosis and dysfunction of immune cells. Development of advanced cirrhosis is associated with a progressive decrease in lymphocyte count.
In this study, we observed significant difference between patients with early and advanced cirrhosis with respect to RPR, RLR, APRI, and FIB-4. In addition to APRI and FIB-4, which are commonly used noninvasive markers of disease severity, we observed a particularly good ability of RPR and RLR to distinguish between early and advanced cirrhosis. The diagnostic specificity of both RPR (86.4%) and RLR (78.3%) was higher than that of APRI and FIB-4. However, the sensitivity was lower than that of APRI and FIB-4. Therefore, RLR may serve as a valuable supplement to APRI and FIB-4 owing to its high specificity. RLR showed the highest AUROC among all the noninvasive markers (0.744). The results pertaining to APRI in this study contradict those reported from a study conducted in Turkey, in which APRI value decreased with increase in the severity of PBC. Of note, there were no significant differences pertaining to baseline data between patients with early-stage and late-stage disease in the Turkish study; this may have contributed to the contradictory results. Nonetheless, our findings pertaining to APRI and FIB-4 are consistent with those of other studies.[42,43]
There were some limitations of this study. First, the sample size of this study was limited. Most patients in our hospital tend to refuse biopsy owing to the invasive nature and pain associated with this procedure. In addition, patients with decompensated cirrhosis are not suitable for invasive procedure due to the high risk of hemorrhage. In our further study, more patients will be enrolled to minimize the bias caused by sample size. Second, this was a single-center retrospective study, which lacked data from other areas. The results need to be validated internally and externally. We will enroll patients from other areas prospectively to validate these results.
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