De Ritis score as an inflammatory marker in Hashimoto's thyroiditis

The aim of the study was assessing the De Ritis score, an inflammatory marker, in Hashimoto's thyroiditis (HT) patients which is characterized with autoimmunity and chronic inflammation.


| INTRODUCTION
The most common cause of hypothyroidism is Hashimoto's thyroiditis (HT) which is characterized with chronic inflammation in the gland due to autoimmunity. 1 At the time of diagnosis, hypothyroidism is present in approximately 20% of patients. 2In this disease, the thyroid gland is infiltrated by lymphocytes, and although it has different stages, it can be damaged enough to disrupt hormone production. 3e pathogenesis of HT is a multi-stage process involving the destruction of thyroid follicles as a result of autoimmune attack, including environmental and genetic factors.The triggering factor of the development of autoimmunity in HT is the initiation of inflammatory events in the thyroid gland and the deterioration of immune tolerance, with the initiating effect of viral or bacterial infection or toxins such as iodine.HT can often be observed together with other autoimmune diseases. 3,4partate amino transaminase (AST) and alanine amino transaminase (ALT) are liver enzymes although ALT is more specific to the liver than AST. 5 In hepatocytes, ALT is mainly present in the cytoplasm and the mitochondria. 6,7Other cells in the body, such as mucosa of stomach, adipose tissue, brain tissue, renal epithelium, muscles, also contain AST.Although ALT and AST levels in adults are usually stable at a certain level, hepatitis, heart failure, kidney disease and the use of certain drugs can alter AST and ALT levels.It is thought that the De Ritis score obtained by the ratio of AST and ALT provides more useful clinical data compared to the assessment of AST and ALT separately.Fernando De Ritis introduced the serum activity ratio of AST and ALT in 1975 and it is considered as a reliable marker in hepatitis. 5][10] In addition, the rate of De Ritis score was found to be high in various conditions such as cerebrovascular disease, congestive heart failure, and Covid-19 infection. 11,12Thus, tissue damage or systemic inflammatory conditions may cause an elevation in De Ritis score.
In present work, it was aimed to evaluate the De Ritis score in subjects with HT and to compare to that in control individuals.

| Study cohort
The subjects diagnosed with HT that diagnosed and followed up in internal medicine clinics of Abant Izzet Baysal University hospital between October 2021 and October 2022, were selected to enroll in the present work.Subjects with liver conditions, active infection or inflammatory disease, pregnant women and subjects with malignant diseases were excluded.Control group was consisted of healthy individuals whom were volunteer to participate in.
Database of the institution and patients' files were retrospectively searched and age, gender, and laboratory indices including alanine (ALT) and aspartate (AST) transaminases, hemogram markers including leukocyte count (WBC), blood hemoglobin (Hb), Hematocrit (Hct), and circulating platelet count (Plt), thyroid stimulating hormone (TSH), C-reactive protein (CRP), and free T4 (FT4) levels were obtained and recorded for all participants.De Ritis score was calculated with division of AST by ALT.Antibody titers including anti-thyroglobulin (anti-Tg) and anti-tiroid peroxidase (anti-TPO) of the HT subjects were recorded.Characteristics and laboratory data of the HT and healthy controls were analyzed comparatively.

| Ethics
All participants were agreed to participate.Ethical approval was received from local clinical studies ethics committee (approval no: 2022/270).

| RESULTS
There were 213 subjects in the study; 111 in HT group and 102 healthy participants as controls.The median age of the HT and controls were 42 (19) years and 38 (12) years, respectively ( p = .08).
Ninety nine (89%) of thyroiditis group and 82 (80%) of the control subjects were women, meaning that sex was not statistically different among study and control subjects ( p = .07).
The differences between HT and control individuals in terms of WBC (p = .16),Hb (p = .08),Htc (p = .37),and Plt (p = .11)were not statistically significant.Median AST (p = .03),ALT (p < .001),CRP (p < .001),TSH (p < .001),and FT4 (p < .001)levels of the thyroiditis and control groups were statistically different.General features and laboratory test results of the study cohort were summarized in Table 1.In ROC analysis, the sensitivity and specificity of CRP in detecting thyroiditis were higher than those of the De Ritis score.A CRP level higher than 0,95 mg/L has 70% sensitivity and 74% specificity in detecting thyroiditis (AUC: 0.79, p < .001,95% CI: 0.72-0.85).On the other hand, a De Ritis score higher than 0,9% has 67% sensitivity and 50% specificity in selecting patients with thyroiditis (AUC: 0.69, p < .001,95% CI: 0.63-0.76).ROC curves of the De Ritis score and CRP were given in Figure 1. Figure 2 shows the patient flow chart.

| DISCUSSION
In the current study, we showed that median AST, CRP, ALT, TSH, and FT4 levels of the HT and control subjects were statistically different.In addition, the median De Ritis score of the HT group was significantly increased compared to that of the healthy controls.Transaminases are frequently used to determine liver functions in clinical practice.The release of these enzymes from hepatocytes is usually stable.Serum levels of transaminases are increased in conditions related with hepatocellular damage. 13 know that changes in liver enzymes are generally associated with various inflammatory conditions.Inflammation plays pivotal role in initiation and progression of these hepatic conditions and elevated liver function tests.On the other hand, high sensitive C-reactive protein levels in plasma was found to be associated with transaminases. 14Furthermore, C-reactive protein (CRP), the commonly assessed marker of inflammation, is reported to be elevated in hepatic steatosis in an another study. 15Liver enzymes show changes in systemic inflammatory conditions as well as in the inflammatory states of the liver itself.Consequently, De Ritis score, which first appeared in order to evaluate the liver functions itself, then started to be studied in different inflammatory conditions in medical literature.In routine biochemistry of the blood, it is obvious that ALT is usually higher than AST resulting in a De Ritis score lower than 1 in healthy population. 7In our study, median De Ritis score of the thyroiditis group (1,11 (0,56)%) was significantly higher than that of the control group (0,91 (0,41)%).The increased AST/ALT ratio in our current study and its correlation with CRP indicate that the rate of De Ritis score may increase in nonhepatic inflammatory diseases.7][18] Moreover, it has been reported as a useful indicator of prostate cancer risk and an independent predictor of prostatic malignancy. 19agnosis of HT is based on characteristic findings in physical examination along with positive antibody titers (Anti-TPO, Anti-Tg).
However, these antibodies can also be positive in Graves' disease.Our study has some limitations.The study was designed retrospectively, our results should be considered cautiously.Other limitations may include relatively small study cohort and single center nature which prevents globalizing the results.
In conclusion, due to considerable sensitivity and specificity in detecting the disease, we think that elevated De Ritis score can be used as an adjunctive tool in the diagnosis of HT.

A
commercial statistics software (SPSS 20.0 for Windows, IBM Co., Armonk, NY) was utilized in statistical analyses.To determine whether the variables have normal or skewed distribution, Kolmogorov-Smirnov test was conducted.Since none of the variables were fit into normal distribution all of the continuous variables were compared with Mann-Whitney U test and expressed as medians and interquartile ranges (IQR).Comparison of the categorical variables were held with X 2 test and these parameters were given as numbers and percentage.The correlation between De Ritis score and CRP was revealed by Parsons's correlation analysis test.Receiver operative characteristics (ROC) test was conducted to determine the sensitivity and specificity of De Ritis score and CRP in showing subjects with HT.The results were considered as significant when the p values were lower than 5%.

F I G U R E 1
ROC curve De Ritis score in predicting Hashimoto's thyroiditis.F I G U R E 2 Patient flow chart.Furthermore, De Ritis score and CRP values were significantly and positively correlated.

1
Data of study population.
Note: Bold indicates significant p values.DUMAN ET AL.
Sonographic characteristics are not always useful in differentiation of HT from other thyroid conditions.Decreased uptake in thyroid scintigraphy in HT is useful in establishing the diagnosis, however, it is not always available in all clinical settings.Therefore, other diagnostic markers for HT are needed.De Ritis score is an inexpensive, easy to assess and easily repeatable marker which can be used for this purpose.Results of the present study confirmed the diagnostic role of De Ritis score in Hashimoto's thyroidits.
20In our study, we wanted to evaluate the changes in liver function tests especially in patients with Hashimoto's disease, an autoimmune disease with chronic inflammation.Our study contributes to the literature as it is the first study to evaluate this issue in the literature.In addition, De Ritis ratio can provide useful data in diagnosis of HT along with imaging studies and elevated thyroid autoantibody titers.It is also a