# Impact of Diabetic Ketoacidosis on Thyroid Function in Patients with Diabetes Mellitus

Authors: Yuling Xing; Jinhu Chen; Guangyao Song; Liying Zhao; Huijuan Ma
Journal: International Journal of Endocrinology
 (2021)

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## Abstract

Background. Changes in thyroid function in diabetes patients who developed diabetic ketoacidosis (DKA) still need to be fully elucidated. The aim of this study was to systematically review available data on the relationship between thyroid function and DKA in diabetes patients who developed DKA. Methods. Electronic databases (PubMed, EMBASE, Cochrane Library, and China Academic Journal Full-text Database (CNKI)) were searched systematically to search relevant literature before December 2020. The mean ± standard deviation and 95% confidence interval (95% CI) were used for evaluation, and sensitivity analysis was performed. Publication bias was estimated by funnel plot, Egger’s test, and Begger’s test. Results. 29 studies were included in the meta-analysis, and the indicators (T4, T3, FT3, FT4, TSH, T3RU, and rT3) of patients with DKA were compared and analyzed. The results of this study showed that the levels of T4, T3, FT3, FT4, and TSH were decreased and the level of rT3 was increased in patients with DKA. Compared with after treatment, the levels of T4, T3, FT3, and FT4 in patients with DKA were decreased before treatment, while the levels of rT3 were increased, and there was no significant difference in changes of TSH. With the aggravation of DKA, the levels of T4, T3, FT3, and FT4 will further decrease, while the changes of TSH have no statistical difference. Conclusion. Thyroid function changed in diabetic patients with DKA. It changed with the severity of DKA. This condition may be transient, preceding further recovery of DKA.


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## Body

## 1. Introduction

Diabetic ketoacidosis (DKA) is an acute life-threatening complication of diabetes. It is not only a sign of acute absolute insulin deficiency in type 1 diabetes mellitus (T1DM) but also increasingly seen in patients with type 2 diabetes mellitus. In patients with diabetes, ketoacidosis is caused by an acute decrease in insulin secretion and action in a severe insulin resistant state [1]. From 2002 to 2010 in the United States, about 30% of adolescents newly diagnosed with T1DM developed DKA [2]. The prevalence of DKA estimated at the onset of type 2 diabetes is quite different. African-American youth in Cincinnati and Arkansas was 41.4% [3] and 16% [4]. Statistics showed that thyroid dysfunction in people with diabetes is 2-3 times higher than people without diabetes [5]. The effect of nonthyroid diseases on thyroid function has been studied in anorexia nervosa, liver disease, kidney disease, and many other diseases [6]. Since the 1970s, it has been reported that acute disease can cause a variety of changes in the levels of thyroid hormones in patients who were not previously diagnosed with intrinsic thyroid disease. These changes are nonspecific and are related to the severity of the disease [7]. Diabetes can have a definite effect on thyroid function in various ways, leading to changes in the levels of thyroid hormones, including immunological mechanisms, cytokine pathways, and regulatory pathways of the hypothalamic-pituitary-thyroid axis [8]. When DKA occurred in patients with diabetes, the changes in thyroid function has received a great deal of attention from researchers. At present, there are limited studies on the changes in levels of thyroid hormone in patients with DKA. DKA and its implication in the thyroid function has not been adequately reviewed. The study aimed to analyze the changes in the levels of thyroid hormones in patients with DKA and the relationship between the changes and the severity of DKA.


## 2. Materials and Methods

### 2.1. Literature Search Strategy

Diabetic ketoacidosis, related indicators reflecting thyroid function (free triiodothyronine (FT3), free thyroxine (FT4), triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), T3 resin uptake (T3RU), and reverse triiodothyronine (rT3)) as subject terms and keywords for joint search. All relevant literature published before December 2020 was searched in PubMed, EMBASE, Cochrane Library, and CNKI.


### 2.2. Inclusion Criteria

(1) The article related to patients with DKA; (2) involving the changes of thyroid function indicators in patients with DKA before and after treatment or between the diabetic patients with and without DKA and providing the exact sample size and data on various indicators of thyroid function; and (3) the diagnosis of diabetic ketoacidosis is clear [9].


### 2.3. Exclusion Criteria

(1) The data of literature are incomplete and the information is not enough to calculate the statistics of this study; (2) case reports; (3) repeated articles; and (4) studies limited to animals.


### 2.4. Literature Screening

Two researchers independently screened the literature, extracted data, and cross-checked. If there is a disagreement on the results, they would discuss it together or resolve it by a third senior researcher. In the study, data were extracted from the literature finally included in the meta-analysis using a premade data extraction table. The extracted content included the first author, year of publication, study area, sample size, mean ± standard deviation of thyroid function indicators, inclusion criteria, exclusion criteria, DKA diagnostic cutoff point, the determination method of thyroid hormone, therapeutic approach, and duration of treatment of DKA (Table1).Table 1
Basic characteristics of included studies.
AuthorDiagnosis of DKADetermination of thyroxineInclusion criteriaExclusion criteriaTherapeutic methodTreatmenttimeSubgroupYan ZhaoNAhttps://fanyi.baidu.com/, https://fanyi.baidu.com/, https://fanyi.baidu.com/-zh/en/javascript:void(0), chemiluminescenceThere was no thyroid disease in the past, and no drugs affecting thyroid function were taken recentlyNAUntreatedMild: pH < 7.3 or HCO3− < 15 mmol·LModerate: pH < 7.2 or HCO3− < 10 mmol·LSevere: pH < 7.1 or HCO3− < 5 mmol·LShixiong ZhangMicroparticle automatic chemiluminescence immunoassay analyzer (Beckman, USA)There was no abnormal ECG and liver function.Patients with hypoproteinemia, thyroid disease, heart failure, fever, kidney disease, and acute viral hepatitis, as well as glucocorticoid, androgen, and estrogen were excludedOn the basis of routine diabetes treatment, the observation group was given routine treatment such as rehydration, removing inducement, maintaining acid-base and water-electrolyte balance, insulin, and other conventional treatment measures to correct ketoacidosis.3 wYunzhi WangBeckman microparticle automatic chemiluminescence immunoassay analyzer and corresponding kits provided by the companyThe liver function and ECG were normalThyroid disease, acute viral hepatitis, hypoproteinemia, heart failure, kidney disease, infection, fever, pregnant women, and the use of estrogen, androgen, and glucocorticoid.According to the treatment principle of ketoacidosis, the treatment includes removing the inducement, replenishing fluid, applying insulin, and maintaining the acid-base balance of water and electrolyte3 wYiping WangBeckman access 2 chemiluminescence immunoassay analyzer was usedThere was no history of other acute and chronic diseasesSevere heart, liver, kidney, and connective tissue diseasesPrevious history of thyroid disease, taking thyroid function drugsPregnant and lactating womenTreatment method unknownunknownMild pH < 7.3 or HCO3− < 15 mmol/LModerate pH < 7.2 or HCO3− < 10 mmol/LSevere pH < 7.1 or HCO3− < 5 mmol/LLan WangPrimary thyroid diseases, no history of antithyroid drugs and thyroid surgery were excludedTreatment method unknownunknownYu QiaoThe symptoms of diabetes were aggravated, nausea, vomiting, dizziness, and other discomfort clinical manifestationsDry skin, sunken orbit, rapid pulse, and other signsBlood glucose >16 mmol/L, urine ketone body and urine sugar positive, blood gas analysis, anion gap increased, HCO3−decreased, and binding rate decreased (note: due to individual differences, some patients who have no obvious clinical symptoms or signs but meet the laboratory examination are also diagnosed with diabetic ketoacidosis)Pregnant or lactating womenPatients with thyroid disease history and taking drugs affecting thyroid functionPatients with severe liver, heart, kidney, and connective tissue diseases; 40 patients with thyroid function analysisPatients with other crisis critical patients at admissionPatients without the thyroid function test and blood gas analysis on admission.UntreatedLianshan PiaoThe immunoassay kit was provided by the Institute of Isotope, Chinese Academy of Atomic EnergyNo pituitary, adrenal, and thyroid diseases were found, and no serious complications of chronic diabetes were foundAfter the treatment of high-dose rehydration and low-dose insulin continuous intravenous therapyUrinary ketone body turned negative and carbonate ion returned to normalLi LuoSiemens Centaur XP chemiluminescence immunoassay systemOther diseases that may affect thyroid function were excluded, and drugs affecting thyroid function were excludedUntreatedShengbin LiuCombined with serious heart, brain, liver, kidney, and other organ damage, thyroid disease, central nervous system systemic diseases, pregnant women having dopamine, glucocorticoid, androgen, and estrogen within 3 months may affect their own hormone levels, thus interfering with the drug use history of this study and having suffered from endocrine system diseases such as primary aldosteronism, and growth retardationUntreatedMild (pH ≥ 7.3)Moderate (7.3>pH ≥ 7.2)Severe (pH < 7.2)Bin LiuThere was no history of thyroid disease, endocrine, glucocorticoid, sedative, furosemide, dopamine, and other drugs in the past, except lactation and pregnancy women.UntreatedShaohui HuangMicroparticle automatic chemiluminescence analyzer (Beckman company, USA)All the patients met the diagnostic criteria of diabetes established by the WHOAbnormal ECG, abnormal liver function, the history of glucocorticoid, androgen, thyroid disease, infection, heart failure, and mental diseaseActive treatment of primary disease, adequate fluid supplement, insulin, correction of water-electrolyte balance disorder, acid-base balance, and symptomatic treatment measures were adopted.3 wRui FengBlood glucose was higher than 13.9 mmol/L, pH was less than 7.35, urine ketone was positive, anion gap was more than 16 mmol/L, and blood bicarbonate (HCO3−) was less than 18 mmol/LEnzyme linked immunosorbent assayKetoacidosis caused by acute cardiovascular and cerebrovascular diseases, gastrointestinal bleeding, major surgery, and pregnancy were excludedAll patients were treated with antibiotics to prevent infection, supplement electrolytes, and maintain body fluid balance. Patients with other basic diseases or complications were treated according to their condition. On this basis, the patients were treated with low-dose insulin intravenous drip, and the dose was 4–6 u/h24 hWen FanAbbott i2000 chemiluminescence immunoassay system and its kitAge ≥65 years.According to the diagnostic criteria issued by the American Diabetes Association in 2010.Informed consent in this study.There are hypothyroidism diseases, such as graves’ disease and Hashimoto’s thyroiditis.Those who have recently taken drugs that affect thyroid function, such as estrogen, androgen, and glucocorticoid.Combined with acute viral hepatitis, hypoproteinemia, heart failure, kidney disease, infection, and so on.Treatment method unknownUnknownFuwan DingRadioimmunoassayPatients with the history of thyroid disease, severe heart, liver, kidney disease, and connective tissue were excluded.Resuscitation measures such as fluid rehydration, use of insulin to lower blood sugar, correction of water-electrolyte and acid-base imbalance, treatment of complications and comorbidities, and removal of ketosis inducements have stabilized the condition within 1–3 days. All patients did not use thyroxine preparations2 wQing ChenChemiluminescenceThe history of thyroid diseases, patients taking drugs that affect thyroid function, severe heart, liver, kidney, and connective tissue diseases, breast-feeding, and pregnant womenuntreatedDaoxiong ChenDiabetes (according to the WHO’s diagnostic criteria for diabetes)Positive blood ketonesBlood gas analysis showed metabolic acidosisNone of the observed patients had clinical manifestations of hyperthyroidism or hypothyroidism and no history of thyroid diseaseTreatment method unknown2 wRashidi. HWithout any history of thyroid problems, systemic diseases, and using drugs which interfere with thyroid function were enrolled into the study.Treatment method unknown2wNaeije. R. GUntreated5 daysSchienger. J. LClinically euthyroidUntreatedAlexander 1983Double antibody RIA commercial method (Abbott Laboratories, North Chicago, IL).We limited the scope of our study to the effects of diabetes mellitus per se by excluding patients with other systemic illnessesInsulin5 daysMiboluk. AATwo different methods: radio immune assay (RIA) and immune-radiometric assay (IRMA)Blood sugar> 300 mg/dl, HCO3− ≤ 15 mol/l PH ≤ 7.3, urine ketone positiveSevere nutritional deficiency, neurologic side effects, and brain edema/coma in ketoacidotic statusInsulin5 daysLin. C. HSerum glucose level 300 mg/dl (16.7 mmol/L), a serum pH < 7.25 or serum bicarbonate  < 15 mmol/L, and the presence of ketones in the urine.T3 was measured by radioimmunoassay (ICN, New York, USA; reference range, 100 to 190 ng/dl), T4 by radioimmunoassay (Daiichi, Tokyo, Japan; reference range, 4.4–12.5μg/dl), TSH by radioimmunometric assay (Daiichi, Tokyo, Japan; reference range, 0.5–5.15 IU/ml), and free T4 by radioimmunoassay, using the 125I-labeled T4 analogue method (DPC, Los Angeles, USA; reference range, 0.8–2.0 ng/dl).Clinically euthyroid3 daysJiao WBlood glucose level >13.9 mmol/L, blood pH < 7.35, ketonuria positivity, anion gap (AG) > 16 mmol/L, and HCO3− level < 18 mmol/LEnzyme linked immunosorbent assay (ELISA)Patients with DKA induced by acute cardiovascular and cerebrovascular diseases, gastrointestinal haemorrhage, major surgery, or pregnancy were excludedSupportive treatment such as fluid infusion, acid-base imbalance correction, and electrolyte disturbance corintravenous insulin administered by an insulin pump at a rate of 4–6 U/h.24 hHu Y YBlood glucose (BG) > 11 mmol/L, venous pH < 7.3, or bicarbonate  < 15 mmol/LAutomated chemiluminescent immunoassay system (Advia Centaur, Siemens, Munich, Germany).Excluded patients with other endocrinological disorders, systemic illness, pituitary and thyroid disease, and a history of diabetes mellitus. Patients who had previously received any medication apart from insulin were also excludedAfter resolution of DKA, patients received multiple daily insulin injections, aspart (Novo Nordisk, Bagsvaerd, Denmark) immediately before each meal and glargine (Sanofi-Aventis, Paris, France) once daily at bedtime. The total daily insulin dose ranged from 0.6 to 1.5 IU/kg.7 daysD. Glinoer, RSerum FT 4 was measured using the kinetic FT4-I125 radioimmunoassay test system (kindly provided by Dr. G. Odstrchel, Corning Glass Works, Corning, NY, USA)Low-dose insulin. Fluids and electrolytes5 daysF. ChiarellipH < 7.2, HCO3− < 15 mmol/1, ketonuria: 4+).Without familiar or personal history for endocrinological diseases. No drugs (except insulin for the diabetics) were administered to the children. All the subjects examined were clinically euthyroid, and their weight did not exceed ideal body by more than 20%.UntreatedAlexander, 1982Double antibody RIAUntreatedXin YHyperglycaemia above 14 mmol/L and pH < 7.3 or bicarbonate < 15 mmol/L in the presence of ketonuriaUntreated


### 2.5. Statistical Analysis

According to the requirements of meta-analysis, the data were sorted out, the database was established, the data were carefully checked, and the standardized mean difference (SMD) and 95% CI were used to quantitatively analyze the measurement data. I2 was used to quantitatively test the heterogeneity among the studies. If I2 ≤ 50%, it was considered that the heterogeneity was not statistically significant, and the fixed effect model was used to analyze; on the contrary, if I2 > 50%, the heterogeneity was considered to be statistically significant, and the random effect model was used to analyze. Sensitivity analysis was performed to ensure the stability of the meta-analysis results. Funnel plot and Egger’s test were used to evaluate publication bias, andp<0.05 was considered as statistically significant, indicating that publication bias was not excluded. The trim-and-fill method was used to estimate the effect of publication bias on the interpretation of the results.


## 2.1. Literature Search Strategy

Diabetic ketoacidosis, related indicators reflecting thyroid function (free triiodothyronine (FT3), free thyroxine (FT4), triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), T3 resin uptake (T3RU), and reverse triiodothyronine (rT3)) as subject terms and keywords for joint search. All relevant literature published before December 2020 was searched in PubMed, EMBASE, Cochrane Library, and CNKI.


## 2.2. Inclusion Criteria

(1) The article related to patients with DKA; (2) involving the changes of thyroid function indicators in patients with DKA before and after treatment or between the diabetic patients with and without DKA and providing the exact sample size and data on various indicators of thyroid function; and (3) the diagnosis of diabetic ketoacidosis is clear [9].


## 2.3. Exclusion Criteria

(1) The data of literature are incomplete and the information is not enough to calculate the statistics of this study; (2) case reports; (3) repeated articles; and (4) studies limited to animals.


## 2.4. Literature Screening

Two researchers independently screened the literature, extracted data, and cross-checked. If there is a disagreement on the results, they would discuss it together or resolve it by a third senior researcher. In the study, data were extracted from the literature finally included in the meta-analysis using a premade data extraction table. The extracted content included the first author, year of publication, study area, sample size, mean ± standard deviation of thyroid function indicators, inclusion criteria, exclusion criteria, DKA diagnostic cutoff point, the determination method of thyroid hormone, therapeutic approach, and duration of treatment of DKA (Table1).Table 1
Basic characteristics of included studies.
AuthorDiagnosis of DKADetermination of thyroxineInclusion criteriaExclusion criteriaTherapeutic methodTreatmenttimeSubgroupYan ZhaoNAhttps://fanyi.baidu.com/, https://fanyi.baidu.com/, https://fanyi.baidu.com/-zh/en/javascript:void(0), chemiluminescenceThere was no thyroid disease in the past, and no drugs affecting thyroid function were taken recentlyNAUntreatedMild: pH < 7.3 or HCO3− < 15 mmol·LModerate: pH < 7.2 or HCO3− < 10 mmol·LSevere: pH < 7.1 or HCO3− < 5 mmol·LShixiong ZhangMicroparticle automatic chemiluminescence immunoassay analyzer (Beckman, USA)There was no abnormal ECG and liver function.Patients with hypoproteinemia, thyroid disease, heart failure, fever, kidney disease, and acute viral hepatitis, as well as glucocorticoid, androgen, and estrogen were excludedOn the basis of routine diabetes treatment, the observation group was given routine treatment such as rehydration, removing inducement, maintaining acid-base and water-electrolyte balance, insulin, and other conventional treatment measures to correct ketoacidosis.3 wYunzhi WangBeckman microparticle automatic chemiluminescence immunoassay analyzer and corresponding kits provided by the companyThe liver function and ECG were normalThyroid disease, acute viral hepatitis, hypoproteinemia, heart failure, kidney disease, infection, fever, pregnant women, and the use of estrogen, androgen, and glucocorticoid.According to the treatment principle of ketoacidosis, the treatment includes removing the inducement, replenishing fluid, applying insulin, and maintaining the acid-base balance of water and electrolyte3 wYiping WangBeckman access 2 chemiluminescence immunoassay analyzer was usedThere was no history of other acute and chronic diseasesSevere heart, liver, kidney, and connective tissue diseasesPrevious history of thyroid disease, taking thyroid function drugsPregnant and lactating womenTreatment method unknownunknownMild pH < 7.3 or HCO3− < 15 mmol/LModerate pH < 7.2 or HCO3− < 10 mmol/LSevere pH < 7.1 or HCO3− < 5 mmol/LLan WangPrimary thyroid diseases, no history of antithyroid drugs and thyroid surgery were excludedTreatment method unknownunknownYu QiaoThe symptoms of diabetes were aggravated, nausea, vomiting, dizziness, and other discomfort clinical manifestationsDry skin, sunken orbit, rapid pulse, and other signsBlood glucose >16 mmol/L, urine ketone body and urine sugar positive, blood gas analysis, anion gap increased, HCO3−decreased, and binding rate decreased (note: due to individual differences, some patients who have no obvious clinical symptoms or signs but meet the laboratory examination are also diagnosed with diabetic ketoacidosis)Pregnant or lactating womenPatients with thyroid disease history and taking drugs affecting thyroid functionPatients with severe liver, heart, kidney, and connective tissue diseases; 40 patients with thyroid function analysisPatients with other crisis critical patients at admissionPatients without the thyroid function test and blood gas analysis on admission.UntreatedLianshan PiaoThe immunoassay kit was provided by the Institute of Isotope, Chinese Academy of Atomic EnergyNo pituitary, adrenal, and thyroid diseases were found, and no serious complications of chronic diabetes were foundAfter the treatment of high-dose rehydration and low-dose insulin continuous intravenous therapyUrinary ketone body turned negative and carbonate ion returned to normalLi LuoSiemens Centaur XP chemiluminescence immunoassay systemOther diseases that may affect thyroid function were excluded, and drugs affecting thyroid function were excludedUntreatedShengbin LiuCombined with serious heart, brain, liver, kidney, and other organ damage, thyroid disease, central nervous system systemic diseases, pregnant women having dopamine, glucocorticoid, androgen, and estrogen within 3 months may affect their own hormone levels, thus interfering with the drug use history of this study and having suffered from endocrine system diseases such as primary aldosteronism, and growth retardationUntreatedMild (pH ≥ 7.3)Moderate (7.3>pH ≥ 7.2)Severe (pH < 7.2)Bin LiuThere was no history of thyroid disease, endocrine, glucocorticoid, sedative, furosemide, dopamine, and other drugs in the past, except lactation and pregnancy women.UntreatedShaohui HuangMicroparticle automatic chemiluminescence analyzer (Beckman company, USA)All the patients met the diagnostic criteria of diabetes established by the WHOAbnormal ECG, abnormal liver function, the history of glucocorticoid, androgen, thyroid disease, infection, heart failure, and mental diseaseActive treatment of primary disease, adequate fluid supplement, insulin, correction of water-electrolyte balance disorder, acid-base balance, and symptomatic treatment measures were adopted.3 wRui FengBlood glucose was higher than 13.9 mmol/L, pH was less than 7.35, urine ketone was positive, anion gap was more than 16 mmol/L, and blood bicarbonate (HCO3−) was less than 18 mmol/LEnzyme linked immunosorbent assayKetoacidosis caused by acute cardiovascular and cerebrovascular diseases, gastrointestinal bleeding, major surgery, and pregnancy were excludedAll patients were treated with antibiotics to prevent infection, supplement electrolytes, and maintain body fluid balance. Patients with other basic diseases or complications were treated according to their condition. On this basis, the patients were treated with low-dose insulin intravenous drip, and the dose was 4–6 u/h24 hWen FanAbbott i2000 chemiluminescence immunoassay system and its kitAge ≥65 years.According to the diagnostic criteria issued by the American Diabetes Association in 2010.Informed consent in this study.There are hypothyroidism diseases, such as graves’ disease and Hashimoto’s thyroiditis.Those who have recently taken drugs that affect thyroid function, such as estrogen, androgen, and glucocorticoid.Combined with acute viral hepatitis, hypoproteinemia, heart failure, kidney disease, infection, and so on.Treatment method unknownUnknownFuwan DingRadioimmunoassayPatients with the history of thyroid disease, severe heart, liver, kidney disease, and connective tissue were excluded.Resuscitation measures such as fluid rehydration, use of insulin to lower blood sugar, correction of water-electrolyte and acid-base imbalance, treatment of complications and comorbidities, and removal of ketosis inducements have stabilized the condition within 1–3 days. All patients did not use thyroxine preparations2 wQing ChenChemiluminescenceThe history of thyroid diseases, patients taking drugs that affect thyroid function, severe heart, liver, kidney, and connective tissue diseases, breast-feeding, and pregnant womenuntreatedDaoxiong ChenDiabetes (according to the WHO’s diagnostic criteria for diabetes)Positive blood ketonesBlood gas analysis showed metabolic acidosisNone of the observed patients had clinical manifestations of hyperthyroidism or hypothyroidism and no history of thyroid diseaseTreatment method unknown2 wRashidi. HWithout any history of thyroid problems, systemic diseases, and using drugs which interfere with thyroid function were enrolled into the study.Treatment method unknown2wNaeije. R. GUntreated5 daysSchienger. J. LClinically euthyroidUntreatedAlexander 1983Double antibody RIA commercial method (Abbott Laboratories, North Chicago, IL).We limited the scope of our study to the effects of diabetes mellitus per se by excluding patients with other systemic illnessesInsulin5 daysMiboluk. AATwo different methods: radio immune assay (RIA) and immune-radiometric assay (IRMA)Blood sugar> 300 mg/dl, HCO3− ≤ 15 mol/l PH ≤ 7.3, urine ketone positiveSevere nutritional deficiency, neurologic side effects, and brain edema/coma in ketoacidotic statusInsulin5 daysLin. C. HSerum glucose level 300 mg/dl (16.7 mmol/L), a serum pH < 7.25 or serum bicarbonate  < 15 mmol/L, and the presence of ketones in the urine.T3 was measured by radioimmunoassay (ICN, New York, USA; reference range, 100 to 190 ng/dl), T4 by radioimmunoassay (Daiichi, Tokyo, Japan; reference range, 4.4–12.5μg/dl), TSH by radioimmunometric assay (Daiichi, Tokyo, Japan; reference range, 0.5–5.15 IU/ml), and free T4 by radioimmunoassay, using the 125I-labeled T4 analogue method (DPC, Los Angeles, USA; reference range, 0.8–2.0 ng/dl).Clinically euthyroid3 daysJiao WBlood glucose level >13.9 mmol/L, blood pH < 7.35, ketonuria positivity, anion gap (AG) > 16 mmol/L, and HCO3− level < 18 mmol/LEnzyme linked immunosorbent assay (ELISA)Patients with DKA induced by acute cardiovascular and cerebrovascular diseases, gastrointestinal haemorrhage, major surgery, or pregnancy were excludedSupportive treatment such as fluid infusion, acid-base imbalance correction, and electrolyte disturbance corintravenous insulin administered by an insulin pump at a rate of 4–6 U/h.24 hHu Y YBlood glucose (BG) > 11 mmol/L, venous pH < 7.3, or bicarbonate  < 15 mmol/LAutomated chemiluminescent immunoassay system (Advia Centaur, Siemens, Munich, Germany).Excluded patients with other endocrinological disorders, systemic illness, pituitary and thyroid disease, and a history of diabetes mellitus. Patients who had previously received any medication apart from insulin were also excludedAfter resolution of DKA, patients received multiple daily insulin injections, aspart (Novo Nordisk, Bagsvaerd, Denmark) immediately before each meal and glargine (Sanofi-Aventis, Paris, France) once daily at bedtime. The total daily insulin dose ranged from 0.6 to 1.5 IU/kg.7 daysD. Glinoer, RSerum FT 4 was measured using the kinetic FT4-I125 radioimmunoassay test system (kindly provided by Dr. G. Odstrchel, Corning Glass Works, Corning, NY, USA)Low-dose insulin. Fluids and electrolytes5 daysF. ChiarellipH < 7.2, HCO3− < 15 mmol/1, ketonuria: 4+).Without familiar or personal history for endocrinological diseases. No drugs (except insulin for the diabetics) were administered to the children. All the subjects examined were clinically euthyroid, and their weight did not exceed ideal body by more than 20%.UntreatedAlexander, 1982Double antibody RIAUntreatedXin YHyperglycaemia above 14 mmol/L and pH < 7.3 or bicarbonate < 15 mmol/L in the presence of ketonuriaUntreated


## 2.5. Statistical Analysis

According to the requirements of meta-analysis, the data were sorted out, the database was established, the data were carefully checked, and the standardized mean difference (SMD) and 95% CI were used to quantitatively analyze the measurement data. I2 was used to quantitatively test the heterogeneity among the studies. If I2 ≤ 50%, it was considered that the heterogeneity was not statistically significant, and the fixed effect model was used to analyze; on the contrary, if I2 > 50%, the heterogeneity was considered to be statistically significant, and the random effect model was used to analyze. Sensitivity analysis was performed to ensure the stability of the meta-analysis results. Funnel plot and Egger’s test were used to evaluate publication bias, andp<0.05 was considered as statistically significant, indicating that publication bias was not excluded. The trim-and-fill method was used to estimate the effect of publication bias on the interpretation of the results.


## 3. Result

### 3.1. Literature Search Results

314 related studies were initially retrieved based on keywords and subject terms, and finally, 29 studies met the predetermined inclusion and exclusion criteria (Figure1). 17 studies evaluated the changes of thyroid function before and after treatment in patients with DKA, 17 studies evaluated the difference of thyroid function between patients with diabetes with and without DKA, and 3 studies related to the changes of thyroid function with different severities of DKA. The relevant literature was published from 1978 to 2018 (Tables 1–3).Figure 1
The process of study selection.Table 2
Comparison of thyroid function before and after treatment in patients with diabetes and DKA.
AuthorYearCountryDKAAfter treatmentMeanSDnMeanSDnT4Daoxiong et al. [10]1999China79.3819.136578.3216.565Glinoer et al. [11]1980Belgium6.20.6179.70.717Wang [12]1999China110.2645.896211848.5762Piao and Li [13]1999China71.412.6870.912.38Lin et al. [14]2003China4.393.03767.722.2976Mirboluk et al. [15]2017Iran3.181.4165.172.416Naeije et al. [16]1978Germany5.73.05198.92.1819Rashidi et al. [17]2017Iran7.62.53208.412.5120Huang and Su [18]2016China96.415.1263110.348.3263Fan [19]2014China95.837.5481102.548.0481Wang and Du [20]2013China96.323.16910937.969Zhang [21]2014China95.823.274110.338.674Ding and Ji [22]2011China96.2920.130102.320.5530Wang et al. [23]2018China65.6820.324090.3320.9540T3Daoxiong et al. [10]1999China10.24651.160.2165Wang [12]1999China1.260.46622.290.5962Piao and Li [13]1999China51.433.51882.372.588Lin et al. [14]2003China59.3636.1176140.6348.2476Mirboluk et al. [15]2017Iran63.228.21678.526.216Naeije et al. [16]1978Germany37619105919Rashidi et al. [17]2017Iran8625.720161.253820Huang and Su [18]2016China1.340.25631.650.3163Fan [19]2014China1.380.12811.450.2181Wang and Du [20]2013China1.380.23691.520.3969Zhang [21]2014China1.390.24741.530.4174Ding and Ji [22]2011China0.750.2301.680.3330Wang et al. [23]2018China0.840.3401.550.3340FT4Daoxiong et al. [10]1999China14.212.86513.82.565Glinoer et al. [11]1980Belgium1.40.1171.70.117Hu et al. [24]2015China11.383.584015.572.9240Jiao et al. [25]2016China11.613.5312014.233.01120Lin et al. [14]2003China0.590.36761.290.3276Rashidi et al. [17]2017Iran1.070.43201.580.6220Feng [26]2014China11.623.526014.243.0360Huang and Su [18]2016China13.210.246315.280.6563Fan [19]2014China13.440.958114.021.2181Wang and Du [20]2013China132.36914.2169Zhang [21]2014China13.22.47414.61.174Ding and Ji [22]2011China13.322.523013.923.9930Wang et al. [23]2018China11.912.854014.262.4740FT3Daoxiong et al. [10]1999China2.480.9653.380.9865Hu et al. [24]2015China2.630.58404.771.1540Jiao et al. [25]2016China2.851.221203.981.02120Rashidi et al. [17]2017Iran1470.4203.80.8620Feng [26]2014China2.871.23603.961.0360Fan [19]2014China3.540.23813.60.3481Wang and Du [20]2013China3.540.53693.690.5169Zhang [21]2014China3.550.54743.650.4874Ding and Ji [22]2011China2.210.41304.080.5530Wang et al. [23]2018China2.710.83404.480.6740TSHDaoxiong et al. [10]1999China1.950.85651.740.8765Glinoer et al. [11]1980Belgium296117748217Hu et al. [24]2015China1.771.19402.170.9140Jiao et al. [25]2016China1.80.761202.330.87120Wang [12]1999China2.942.07623.212.3562Lin et al. [14]2003China1.371.46762.031.2976Mirboluk et al. [15]2017Iran1.851.5161.791.316Naeije et al. [16]1978Germany1.91.3192.61.319Feng [26]2014China1.820.75602.320.8660Huang and Su [18]2016China4.481.24634.091.0363Fan [19]2014China4.080.28813.890.4381Wang and Du [20]2013China4.471.59694.121.4769Zhang [21]2014China4.491.61744.241.5174Ding and Ji [22]2011China1.330.76301.560.7730Wang et al. [23]2018China1.751.28402.631.1840T3RUGlinoer et al. [11]1980Belgium31.14.51729.45.817Lin et al. [14]2003China33.334.527632.074.3176Mirboluk et al. [15]2017Iran32.41.81632.11.516Naeije et al. [16]1978Germany31.54.41930.86.519Rashidi et al. [17]2017Iran1.70.46204.050.7720rT3Ding and Ji [22]2011China1.30.3300.810.1630Naeije et al. [16]1978Germany4026.15192426.1519Daoxiong et al. [10]1999China0.780.09650.490.0965Table 3
Comparison of thyroid function between patients with diabetes with and without DKA.
AuthorYearCountryDKAControlMeanSDnMeanSDnT4Alexander et al. [27]1983United States5.50.6128.70.66Chiarelli et al.[28]1989Germany58.2215.021674.0423.0745Daoxiong et al. [10]1999China79.3819.136594.618.1260Li et al. [29]2012China82.428922.674338109.09417.929736Lin et al. [14]2003China4.393.03767.61.8662Schienger et al. [30]1982Germany7.60.387.80.58Huang and Su [18]2016China96.415.1263107.528.1262Fan [19]2014China95.837.5481106.459.0994Zhao et al. [31]2012China5.652.8919.282.85110Wang and Du [20]2013China96.323.169114.841.274Qiao [32]2012China5.951.57407.81.6740S. Liu [33]2016China92.918.7823114.0918.8331Chen et al. [34]2016China102.4622.7365107.2823.2865Zhang [21]2014China95.823.27416542.384Ding and Ji [22]2011China96.2920.130100.320.3330T3Alexander et al. [27]1983United States49.97.3128886Alexander et al. [6]1982United States4994103711Chiarelli et al.[28]1989Germany1.040.36161.390.4245Daoxiong et al. [10]1999China10.24651.250.3660Li et al. [29]2012China1.54820.4371381.94970.276236Lin et al. [14]200359.3636.117691.431.8562Schienger et al. [30]1982Germany12414811568Huang and Su [18]2016China1.340.25631.520.3162Fan [19]2014China1.380.12811.550.2194Zhao et al. [31]2012China0.540.51911.020.38110Wang and Du [20]2013China1.380.23691.590.4774Qiao [32]2012China0.750.22401.050.2140S. Liu [33]2016China1.60.41231.850.3331Chen et al. [34]2016China1.530.24651.720.2765Zhang [21]2014China1.390.24741.610.4584Ding and Ji [22]20110.750.2301.720.3130FT4Liu [35]2012China0.840.21201.150.3860Chiarelli et al.[28]1989Germany10.242.941611.553.6245Daoxiong et al. [10]1999China14.212.86512.132.8860Qiu et al. [36]2018China12.44.897515.973.0839Lin et al. [14]2003China0.590.36761.180.462Huang and Su [18]2016China13.210.246314.290.3162Fan [19]2014China13.440.958114.350.3694Xin et al. [37]2010China12.997.38515.343.97118Wang and Du [20]2013China132.369141.274Qiao [32]2012China1.130.26401.210.1740S. Liu [33]2016China10.762.12312.121.4631Chen et al. [34]2016China11.862.576512.512.7865Zhang [21]2014China13.22.47414.91.384Ding and Ji [22]2011China13.322.523014.314.0130Schienger et al. [30]1982Germany2.30.2982.20.298FT3Liu [35]2012China3.960.92205.831.9660Chiarelli et al.[28]1989Germany2.051.01162.350.7145Daoxiong et al. [10]1999China2.480.9653.460.8960Qiu et al. [36]2018China2.470.74753.070.9139Fan [19]2014China3.540.23813.690.4494Xin et al. [37]2010China2.611.93853.311.27118Wang and Du [20]2013China3.540.53693.650.4974Qiao [32]2012China2.210.61402.850.340S. Liu [33]2016China4.320.66234.950.6331Chen et al. [34]2016China3.951.14654.461.1765Zhang [21]2014China3.550.54743.640.5184Ding and Ji [22]2011China2.210.41304.250.4130TSHAlexander et al. [27]1983The United States3.40.9124.40.76Liu [35]2012China0.830.73201.251.1960Chiarelli et al.[28]1989Germany1.660.69162.561.2745Daoxiong et al. [10]1999China1.950.85652.020.9660Li et al. [29]2012China1.50921.3515382.02130.960436Lin et al. [14]2003China1.371.46761.61.0162Huang and Su [18]2016China4.481.24634.461.3162Fan [19]2014China4.080.28813.950.2394Xin et al. [37]2010China1.71.48851.660.77118Zhao et al. [31]2012China2.492.73912.452.01110Wang and Du [20]2013China4.471.59694.231.5374Qiao [32]2012China1.380.86401.820.8840S. Liu [33]2016China1.271.04232.171.3331Chen et al. [34]2016China3.150.58653.170.7165Zhang [21]2014China4.491.61744.231.584Ding and Ji [22]2011China1.330.76301.430.8230rT3Ding and Ji [22]2011China1.30.3300.830.1730Chiarelli et al.[28]1989Germany0.230.1160.220.0745Alexander et al. [27]1983The United States57.825.31235.78.36Schienger.J.B1982Germany25.23.4823.55.48Alexander et al. [6]1982The United States832433235Daoxiong et al. [10]1999China0.780.09650.520.170


### 3.2. Meta-Analysis Results

#### 3.2.1. Comparison of Thyroid Function between Patients with Diabetes with and without DKA

15 studies involved the comparison of T4 between patients with diabetes with and without DKA, involving 751 patients with DKA and 817 patients with diabetes but without DKA; 16 studies involved the comparison of T3, involving 755 patients with DKA and 828 patients with diabetes but without DKA; 15 studies involved the comparison of FT4, involving 790 patients with DKA and 876 patients with diabetes but without DKA; 12 studies involved the comparison of FT3, involving 643 patients with DKA and 744 patients with diabetes but without DKA; 16 studies involved the comparison of TSH, involving 848 patients with diabetes and DKA and 981 patients with diabetes but without DKA; and 6 studies involved the comparison of rT3, involving 135 patients with DKA and 194 patients with diabetes but without DKA. The results showed that compared with patients with diabetes, patients with DKA had lower levels of T4, T3, FT4, and FT3 and higher level of rT3. The difference was statistically significant (T4 : I2 = 83.9%,p<0.01, Z = 7.2, p<0.01, SMD = −1.030, 95% CI: −1.310 to −0.749; T3 : I2 = 82.1%, p<0.01, Z = 7.4, p<0.01, SMD = −1.022, 95% CI: −1.292 to −0.751; FT4 : I2 = 93.9%, p<0.01, Z = 3.45, p<0.01, SMD = −0.758, 95% CI: −1.189 to −0.327; FT3 : I2 = 89.6%, p<0.01, Z = 4.82, p<0.01, SMD = −0.884, 95% CI: −1.243 to −0.524; rT3 : I2 = 95.8%, p<0.01, Z = 3.15, p<0.01, SMD = 2.534, 95% CI: 0.956 to 4.112; TSH : I2 = 61.1%, p<0.01, Z = 1.33, p=0.185, SMD = −0.106, 95% CI: −0.261 to 0.05; Figure 2). There was no statistical difference in TSH between patients with diabetes with and without DKA. After sensitivity analysis, the result showed that TSH was significantly different (I2 = 42.6%, p<0.05, Z = 2.01, p<0.05, SMD = −0.138, 95% CI: −0.273 to −0.003 Figure 3). Therefore, patients with DKA have lower levels of T4, T3, FT4, FT3, and TSH and higher level of rT3. Egger’s test (T4, p=0.861; FT4, p=0.504; rT3, p=0.445) showed that there was no obvious publication bias. Further analysis by the cut-and-fill method showed that the publication bias (T3, p=0.043; FT3, p=0.003; TSH, 0.003) did not affect the estimator. It is more certain that the effect estimates obtained in the meta-analysis are effective. The funnel plot is shown in Figure 4.Figure 2
Forest plot of T4, T3, FT4, FT3, rT3, and TSH compared with patients with DKA and diabetes.
(a)(b)(c)Figure 3
Sensitivity analysis of TSH.Figure 4
Funnel plot of T4, T3, FT4, FT3, rT3, and TSH compared with patients with DKA and diabetes.


#### 3.2.2. Comparison of Thyroid Function before and after Treatment in Patients with Diabetes and DKA

14 studies involved the comparison of T4 before and after treatment in patients with DKA, including a total of 640 patients with DkA; 13 studies involved the comparison of T3 before and after treatment, including a total of 623 patients with DkA; 13 studies involved the comparison of FT4 before and after treatment, including a total of 755 patients with DkA; 10 studies involved the comparison of FT3 before and after treatment, including a total of 599 patients with DkA; 15 studies involved the comparison of TSH before and after treatment, including a total of 832 patients with DkA; 5 studies involved the comparison of T3RU before and after treatment, including a total of 148 patients with DkA; and 3 studies involved the comparison of rT3 before and after treatment, including a total of 114 patients with DkA. The results showed that patients with DKA had lower levels of T4, T3, FT4, and FT3 and higher level of rT3 compared with after treatment. The difference was statistically significant (T4 : I2 = 86.2%,p<0.01, Z = 4.50, p<0.01, SMD = −0.742, 95% CI: −1.066 to 0.419; T3 : I2 = 93%, p<0.01, Z = 6.04, p<0.01, SMD = −1.538, 95% CI: −2.037 to −1.039; FT4 : I2 = 93.8%, p<0.01, Z = 4.52, p<0.01, SMD = −1.035, 95% CI: −1.483 to −0.586; FT3 : I2 = 95.9%, p<0.01, Z = 3.68, p<0.01, SMD = −1.258, 95% CI: −1.926 to −0.589; rT3 : I2 = 94.7%, p<0.01, Z = 2.57, p=0.01, SMD = 1.967, 95% CI: 0.467 to 3.467 Figure 5). There was no significant difference in TSH and T3RU in patients with DKA before and after treatment. Egger’s test (T4, p=0.566; T3RU, p=0.243; FT4, p=0.175; FT3, p=0.988; TSH, 0.599; rT3, p=0.236) showed that there was no obvious publication bias, further analysis by the trim-and-fill method showed that the publication bias (T3, p=0.006) did not affect the estimator, and it was more certain that the effect estimation obtained in the meta-analysis was effective. The funnel plot is shown in Figure 6.Figure 5
Forest plot of T4, T3, FT4, FT3, and rT3 compared with patients with DKA before and after treatment.
(a)(b)(c)Figure 6
Funnel plot of T4, T3, FT4, FT3, and rT3 compared with patients with DKA before and after treatment.


#### 3.2.3. Comparison of Severity of DKA and Thyroid Function in Patients with Diabetes and DKA

Three studies involved the comparison of the severity of DKA with thyroid function. The results showed that as the degree of DKA aggravated, the levels of T4, T3, FT4, and FT3 further decreased. The level of TSH increased with the aggravation of DKA, but it was not statistically significant (Figure7).Figure 7
Comparison of severity of DKA and thyroid function in patients with diabetes and DKA.
(a)(b)


## 3.1. Literature Search Results

314 related studies were initially retrieved based on keywords and subject terms, and finally, 29 studies met the predetermined inclusion and exclusion criteria (Figure1). 17 studies evaluated the changes of thyroid function before and after treatment in patients with DKA, 17 studies evaluated the difference of thyroid function between patients with diabetes with and without DKA, and 3 studies related to the changes of thyroid function with different severities of DKA. The relevant literature was published from 1978 to 2018 (Tables 1–3).Figure 1
The process of study selection.Table 2
Comparison of thyroid function before and after treatment in patients with diabetes and DKA.
AuthorYearCountryDKAAfter treatmentMeanSDnMeanSDnT4Daoxiong et al. [10]1999China79.3819.136578.3216.565Glinoer et al. [11]1980Belgium6.20.6179.70.717Wang [12]1999China110.2645.896211848.5762Piao and Li [13]1999China71.412.6870.912.38Lin et al. [14]2003China4.393.03767.722.2976Mirboluk et al. [15]2017Iran3.181.4165.172.416Naeije et al. [16]1978Germany5.73.05198.92.1819Rashidi et al. [17]2017Iran7.62.53208.412.5120Huang and Su [18]2016China96.415.1263110.348.3263Fan [19]2014China95.837.5481102.548.0481Wang and Du [20]2013China96.323.16910937.969Zhang [21]2014China95.823.274110.338.674Ding and Ji [22]2011China96.2920.130102.320.5530Wang et al. [23]2018China65.6820.324090.3320.9540T3Daoxiong et al. [10]1999China10.24651.160.2165Wang [12]1999China1.260.46622.290.5962Piao and Li [13]1999China51.433.51882.372.588Lin et al. [14]2003China59.3636.1176140.6348.2476Mirboluk et al. [15]2017Iran63.228.21678.526.216Naeije et al. [16]1978Germany37619105919Rashidi et al. [17]2017Iran8625.720161.253820Huang and Su [18]2016China1.340.25631.650.3163Fan [19]2014China1.380.12811.450.2181Wang and Du [20]2013China1.380.23691.520.3969Zhang [21]2014China1.390.24741.530.4174Ding and Ji [22]2011China0.750.2301.680.3330Wang et al. [23]2018China0.840.3401.550.3340FT4Daoxiong et al. [10]1999China14.212.86513.82.565Glinoer et al. [11]1980Belgium1.40.1171.70.117Hu et al. [24]2015China11.383.584015.572.9240Jiao et al. [25]2016China11.613.5312014.233.01120Lin et al. [14]2003China0.590.36761.290.3276Rashidi et al. [17]2017Iran1.070.43201.580.6220Feng [26]2014China11.623.526014.243.0360Huang and Su [18]2016China13.210.246315.280.6563Fan [19]2014China13.440.958114.021.2181Wang and Du [20]2013China132.36914.2169Zhang [21]2014China13.22.47414.61.174Ding and Ji [22]2011China13.322.523013.923.9930Wang et al. [23]2018China11.912.854014.262.4740FT3Daoxiong et al. [10]1999China2.480.9653.380.9865Hu et al. [24]2015China2.630.58404.771.1540Jiao et al. [25]2016China2.851.221203.981.02120Rashidi et al. [17]2017Iran1470.4203.80.8620Feng [26]2014China2.871.23603.961.0360Fan [19]2014China3.540.23813.60.3481Wang and Du [20]2013China3.540.53693.690.5169Zhang [21]2014China3.550.54743.650.4874Ding and Ji [22]2011China2.210.41304.080.5530Wang et al. [23]2018China2.710.83404.480.6740TSHDaoxiong et al. [10]1999China1.950.85651.740.8765Glinoer et al. [11]1980Belgium296117748217Hu et al. [24]2015China1.771.19402.170.9140Jiao et al. [25]2016China1.80.761202.330.87120Wang [12]1999China2.942.07623.212.3562Lin et al. [14]2003China1.371.46762.031.2976Mirboluk et al. [15]2017Iran1.851.5161.791.316Naeije et al. [16]1978Germany1.91.3192.61.319Feng [26]2014China1.820.75602.320.8660Huang and Su [18]2016China4.481.24634.091.0363Fan [19]2014China4.080.28813.890.4381Wang and Du [20]2013China4.471.59694.121.4769Zhang [21]2014China4.491.61744.241.5174Ding and Ji [22]2011China1.330.76301.560.7730Wang et al. [23]2018China1.751.28402.631.1840T3RUGlinoer et al. [11]1980Belgium31.14.51729.45.817Lin et al. [14]2003China33.334.527632.074.3176Mirboluk et al. [15]2017Iran32.41.81632.11.516Naeije et al. [16]1978Germany31.54.41930.86.519Rashidi et al. [17]2017Iran1.70.46204.050.7720rT3Ding and Ji [22]2011China1.30.3300.810.1630Naeije et al. [16]1978Germany4026.15192426.1519Daoxiong et al. [10]1999China0.780.09650.490.0965Table 3
Comparison of thyroid function between patients with diabetes with and without DKA.
AuthorYearCountryDKAControlMeanSDnMeanSDnT4Alexander et al. [27]1983United States5.50.6128.70.66Chiarelli et al.[28]1989Germany58.2215.021674.0423.0745Daoxiong et al. [10]1999China79.3819.136594.618.1260Li et al. [29]2012China82.428922.674338109.09417.929736Lin et al. [14]2003China4.393.03767.61.8662Schienger et al. [30]1982Germany7.60.387.80.58Huang and Su [18]2016China96.415.1263107.528.1262Fan [19]2014China95.837.5481106.459.0994Zhao et al. [31]2012China5.652.8919.282.85110Wang and Du [20]2013China96.323.169114.841.274Qiao [32]2012China5.951.57407.81.6740S. Liu [33]2016China92.918.7823114.0918.8331Chen et al. [34]2016China102.4622.7365107.2823.2865Zhang [21]2014China95.823.27416542.384Ding and Ji [22]2011China96.2920.130100.320.3330T3Alexander et al. [27]1983United States49.97.3128886Alexander et al. [6]1982United States4994103711Chiarelli et al.[28]1989Germany1.040.36161.390.4245Daoxiong et al. [10]1999China10.24651.250.3660Li et al. [29]2012China1.54820.4371381.94970.276236Lin et al. [14]200359.3636.117691.431.8562Schienger et al. [30]1982Germany12414811568Huang and Su [18]2016China1.340.25631.520.3162Fan [19]2014China1.380.12811.550.2194Zhao et al. [31]2012China0.540.51911.020.38110Wang and Du [20]2013China1.380.23691.590.4774Qiao [32]2012China0.750.22401.050.2140S. Liu [33]2016China1.60.41231.850.3331Chen et al. [34]2016China1.530.24651.720.2765Zhang [21]2014China1.390.24741.610.4584Ding and Ji [22]20110.750.2301.720.3130FT4Liu [35]2012China0.840.21201.150.3860Chiarelli et al.[28]1989Germany10.242.941611.553.6245Daoxiong et al. [10]1999China14.212.86512.132.8860Qiu et al. [36]2018China12.44.897515.973.0839Lin et al. [14]2003China0.590.36761.180.462Huang and Su [18]2016China13.210.246314.290.3162Fan [19]2014China13.440.958114.350.3694Xin et al. [37]2010China12.997.38515.343.97118Wang and Du [20]2013China132.369141.274Qiao [32]2012China1.130.26401.210.1740S. Liu [33]2016China10.762.12312.121.4631Chen et al. [34]2016China11.862.576512.512.7865Zhang [21]2014China13.22.47414.91.384Ding and Ji [22]2011China13.322.523014.314.0130Schienger et al. [30]1982Germany2.30.2982.20.298FT3Liu [35]2012China3.960.92205.831.9660Chiarelli et al.[28]1989Germany2.051.01162.350.7145Daoxiong et al. [10]1999China2.480.9653.460.8960Qiu et al. [36]2018China2.470.74753.070.9139Fan [19]2014China3.540.23813.690.4494Xin et al. [37]2010China2.611.93853.311.27118Wang and Du [20]2013China3.540.53693.650.4974Qiao [32]2012China2.210.61402.850.340S. Liu [33]2016China4.320.66234.950.6331Chen et al. [34]2016China3.951.14654.461.1765Zhang [21]2014China3.550.54743.640.5184Ding and Ji [22]2011China2.210.41304.250.4130TSHAlexander et al. [27]1983The United States3.40.9124.40.76Liu [35]2012China0.830.73201.251.1960Chiarelli et al.[28]1989Germany1.660.69162.561.2745Daoxiong et al. [10]1999China1.950.85652.020.9660Li et al. [29]2012China1.50921.3515382.02130.960436Lin et al. [14]2003China1.371.46761.61.0162Huang and Su [18]2016China4.481.24634.461.3162Fan [19]2014China4.080.28813.950.2394Xin et al. [37]2010China1.71.48851.660.77118Zhao et al. [31]2012China2.492.73912.452.01110Wang and Du [20]2013China4.471.59694.231.5374Qiao [32]2012China1.380.86401.820.8840S. Liu [33]2016China1.271.04232.171.3331Chen et al. [34]2016China3.150.58653.170.7165Zhang [21]2014China4.491.61744.231.584Ding and Ji [22]2011China1.330.76301.430.8230rT3Ding and Ji [22]2011China1.30.3300.830.1730Chiarelli et al.[28]1989Germany0.230.1160.220.0745Alexander et al. [27]1983The United States57.825.31235.78.36Schienger.J.B1982Germany25.23.4823.55.48Alexander et al. [6]1982The United States832433235Daoxiong et al. [10]1999China0.780.09650.520.170


## 3.2. Meta-Analysis Results

### 3.2.1. Comparison of Thyroid Function between Patients with Diabetes with and without DKA

15 studies involved the comparison of T4 between patients with diabetes with and without DKA, involving 751 patients with DKA and 817 patients with diabetes but without DKA; 16 studies involved the comparison of T3, involving 755 patients with DKA and 828 patients with diabetes but without DKA; 15 studies involved the comparison of FT4, involving 790 patients with DKA and 876 patients with diabetes but without DKA; 12 studies involved the comparison of FT3, involving 643 patients with DKA and 744 patients with diabetes but without DKA; 16 studies involved the comparison of TSH, involving 848 patients with diabetes and DKA and 981 patients with diabetes but without DKA; and 6 studies involved the comparison of rT3, involving 135 patients with DKA and 194 patients with diabetes but without DKA. The results showed that compared with patients with diabetes, patients with DKA had lower levels of T4, T3, FT4, and FT3 and higher level of rT3. The difference was statistically significant (T4 : I2 = 83.9%,p<0.01, Z = 7.2, p<0.01, SMD = −1.030, 95% CI: −1.310 to −0.749; T3 : I2 = 82.1%, p<0.01, Z = 7.4, p<0.01, SMD = −1.022, 95% CI: −1.292 to −0.751; FT4 : I2 = 93.9%, p<0.01, Z = 3.45, p<0.01, SMD = −0.758, 95% CI: −1.189 to −0.327; FT3 : I2 = 89.6%, p<0.01, Z = 4.82, p<0.01, SMD = −0.884, 95% CI: −1.243 to −0.524; rT3 : I2 = 95.8%, p<0.01, Z = 3.15, p<0.01, SMD = 2.534, 95% CI: 0.956 to 4.112; TSH : I2 = 61.1%, p<0.01, Z = 1.33, p=0.185, SMD = −0.106, 95% CI: −0.261 to 0.05; Figure 2). There was no statistical difference in TSH between patients with diabetes with and without DKA. After sensitivity analysis, the result showed that TSH was significantly different (I2 = 42.6%, p<0.05, Z = 2.01, p<0.05, SMD = −0.138, 95% CI: −0.273 to −0.003 Figure 3). Therefore, patients with DKA have lower levels of T4, T3, FT4, FT3, and TSH and higher level of rT3. Egger’s test (T4, p=0.861; FT4, p=0.504; rT3, p=0.445) showed that there was no obvious publication bias. Further analysis by the cut-and-fill method showed that the publication bias (T3, p=0.043; FT3, p=0.003; TSH, 0.003) did not affect the estimator. It is more certain that the effect estimates obtained in the meta-analysis are effective. The funnel plot is shown in Figure 4.Figure 2
Forest plot of T4, T3, FT4, FT3, rT3, and TSH compared with patients with DKA and diabetes.
(a)(b)(c)Figure 3
Sensitivity analysis of TSH.Figure 4
Funnel plot of T4, T3, FT4, FT3, rT3, and TSH compared with patients with DKA and diabetes.


### 3.2.2. Comparison of Thyroid Function before and after Treatment in Patients with Diabetes and DKA

14 studies involved the comparison of T4 before and after treatment in patients with DKA, including a total of 640 patients with DkA; 13 studies involved the comparison of T3 before and after treatment, including a total of 623 patients with DkA; 13 studies involved the comparison of FT4 before and after treatment, including a total of 755 patients with DkA; 10 studies involved the comparison of FT3 before and after treatment, including a total of 599 patients with DkA; 15 studies involved the comparison of TSH before and after treatment, including a total of 832 patients with DkA; 5 studies involved the comparison of T3RU before and after treatment, including a total of 148 patients with DkA; and 3 studies involved the comparison of rT3 before and after treatment, including a total of 114 patients with DkA. The results showed that patients with DKA had lower levels of T4, T3, FT4, and FT3 and higher level of rT3 compared with after treatment. The difference was statistically significant (T4 : I2 = 86.2%,p<0.01, Z = 4.50, p<0.01, SMD = −0.742, 95% CI: −1.066 to 0.419; T3 : I2 = 93%, p<0.01, Z = 6.04, p<0.01, SMD = −1.538, 95% CI: −2.037 to −1.039; FT4 : I2 = 93.8%, p<0.01, Z = 4.52, p<0.01, SMD = −1.035, 95% CI: −1.483 to −0.586; FT3 : I2 = 95.9%, p<0.01, Z = 3.68, p<0.01, SMD = −1.258, 95% CI: −1.926 to −0.589; rT3 : I2 = 94.7%, p<0.01, Z = 2.57, p=0.01, SMD = 1.967, 95% CI: 0.467 to 3.467 Figure 5). There was no significant difference in TSH and T3RU in patients with DKA before and after treatment. Egger’s test (T4, p=0.566; T3RU, p=0.243; FT4, p=0.175; FT3, p=0.988; TSH, 0.599; rT3, p=0.236) showed that there was no obvious publication bias, further analysis by the trim-and-fill method showed that the publication bias (T3, p=0.006) did not affect the estimator, and it was more certain that the effect estimation obtained in the meta-analysis was effective. The funnel plot is shown in Figure 6.Figure 5
Forest plot of T4, T3, FT4, FT3, and rT3 compared with patients with DKA before and after treatment.
(a)(b)(c)Figure 6
Funnel plot of T4, T3, FT4, FT3, and rT3 compared with patients with DKA before and after treatment.


### 3.2.3. Comparison of Severity of DKA and Thyroid Function in Patients with Diabetes and DKA

Three studies involved the comparison of the severity of DKA with thyroid function. The results showed that as the degree of DKA aggravated, the levels of T4, T3, FT4, and FT3 further decreased. The level of TSH increased with the aggravation of DKA, but it was not statistically significant (Figure7).Figure 7
Comparison of severity of DKA and thyroid function in patients with diabetes and DKA.
(a)(b)


## 3.2.1. Comparison of Thyroid Function between Patients with Diabetes with and without DKA

15 studies involved the comparison of T4 between patients with diabetes with and without DKA, involving 751 patients with DKA and 817 patients with diabetes but without DKA; 16 studies involved the comparison of T3, involving 755 patients with DKA and 828 patients with diabetes but without DKA; 15 studies involved the comparison of FT4, involving 790 patients with DKA and 876 patients with diabetes but without DKA; 12 studies involved the comparison of FT3, involving 643 patients with DKA and 744 patients with diabetes but without DKA; 16 studies involved the comparison of TSH, involving 848 patients with diabetes and DKA and 981 patients with diabetes but without DKA; and 6 studies involved the comparison of rT3, involving 135 patients with DKA and 194 patients with diabetes but without DKA. The results showed that compared with patients with diabetes, patients with DKA had lower levels of T4, T3, FT4, and FT3 and higher level of rT3. The difference was statistically significant (T4 : I2 = 83.9%,p<0.01, Z = 7.2, p<0.01, SMD = −1.030, 95% CI: −1.310 to −0.749; T3 : I2 = 82.1%, p<0.01, Z = 7.4, p<0.01, SMD = −1.022, 95% CI: −1.292 to −0.751; FT4 : I2 = 93.9%, p<0.01, Z = 3.45, p<0.01, SMD = −0.758, 95% CI: −1.189 to −0.327; FT3 : I2 = 89.6%, p<0.01, Z = 4.82, p<0.01, SMD = −0.884, 95% CI: −1.243 to −0.524; rT3 : I2 = 95.8%, p<0.01, Z = 3.15, p<0.01, SMD = 2.534, 95% CI: 0.956 to 4.112; TSH : I2 = 61.1%, p<0.01, Z = 1.33, p=0.185, SMD = −0.106, 95% CI: −0.261 to 0.05; Figure 2). There was no statistical difference in TSH between patients with diabetes with and without DKA. After sensitivity analysis, the result showed that TSH was significantly different (I2 = 42.6%, p<0.05, Z = 2.01, p<0.05, SMD = −0.138, 95% CI: −0.273 to −0.003 Figure 3). Therefore, patients with DKA have lower levels of T4, T3, FT4, FT3, and TSH and higher level of rT3. Egger’s test (T4, p=0.861; FT4, p=0.504; rT3, p=0.445) showed that there was no obvious publication bias. Further analysis by the cut-and-fill method showed that the publication bias (T3, p=0.043; FT3, p=0.003; TSH, 0.003) did not affect the estimator. It is more certain that the effect estimates obtained in the meta-analysis are effective. The funnel plot is shown in Figure 4.Figure 2
Forest plot of T4, T3, FT4, FT3, rT3, and TSH compared with patients with DKA and diabetes.
(a)(b)(c)Figure 3
Sensitivity analysis of TSH.Figure 4
Funnel plot of T4, T3, FT4, FT3, rT3, and TSH compared with patients with DKA and diabetes.


## 3.2.2. Comparison of Thyroid Function before and after Treatment in Patients with Diabetes and DKA

14 studies involved the comparison of T4 before and after treatment in patients with DKA, including a total of 640 patients with DkA; 13 studies involved the comparison of T3 before and after treatment, including a total of 623 patients with DkA; 13 studies involved the comparison of FT4 before and after treatment, including a total of 755 patients with DkA; 10 studies involved the comparison of FT3 before and after treatment, including a total of 599 patients with DkA; 15 studies involved the comparison of TSH before and after treatment, including a total of 832 patients with DkA; 5 studies involved the comparison of T3RU before and after treatment, including a total of 148 patients with DkA; and 3 studies involved the comparison of rT3 before and after treatment, including a total of 114 patients with DkA. The results showed that patients with DKA had lower levels of T4, T3, FT4, and FT3 and higher level of rT3 compared with after treatment. The difference was statistically significant (T4 : I2 = 86.2%,p<0.01, Z = 4.50, p<0.01, SMD = −0.742, 95% CI: −1.066 to 0.419; T3 : I2 = 93%, p<0.01, Z = 6.04, p<0.01, SMD = −1.538, 95% CI: −2.037 to −1.039; FT4 : I2 = 93.8%, p<0.01, Z = 4.52, p<0.01, SMD = −1.035, 95% CI: −1.483 to −0.586; FT3 : I2 = 95.9%, p<0.01, Z = 3.68, p<0.01, SMD = −1.258, 95% CI: −1.926 to −0.589; rT3 : I2 = 94.7%, p<0.01, Z = 2.57, p=0.01, SMD = 1.967, 95% CI: 0.467 to 3.467 Figure 5). There was no significant difference in TSH and T3RU in patients with DKA before and after treatment. Egger’s test (T4, p=0.566; T3RU, p=0.243; FT4, p=0.175; FT3, p=0.988; TSH, 0.599; rT3, p=0.236) showed that there was no obvious publication bias, further analysis by the trim-and-fill method showed that the publication bias (T3, p=0.006) did not affect the estimator, and it was more certain that the effect estimation obtained in the meta-analysis was effective. The funnel plot is shown in Figure 6.Figure 5
Forest plot of T4, T3, FT4, FT3, and rT3 compared with patients with DKA before and after treatment.
(a)(b)(c)Figure 6
Funnel plot of T4, T3, FT4, FT3, and rT3 compared with patients with DKA before and after treatment.


## 3.2.3. Comparison of Severity of DKA and Thyroid Function in Patients with Diabetes and DKA

Three studies involved the comparison of the severity of DKA with thyroid function. The results showed that as the degree of DKA aggravated, the levels of T4, T3, FT4, and FT3 further decreased. The level of TSH increased with the aggravation of DKA, but it was not statistically significant (Figure7).Figure 7
Comparison of severity of DKA and thyroid function in patients with diabetes and DKA.
(a)(b)


## 4. Discussion

This meta-analysis study showed that the levels of T4, T3, FT3, FT4, and TSH were lower and the level of rT3 was higher in patients with DKA compared with patients with diabetes but not DKA. The levels of T4, T3, FT3, and FT4 were lower and the level of rT3 was higher compared with after treatment in patients with diabetes and DKA. As the aggravation of DKA, the levels of T4, T3, FT3, and FT4 would further decrease, but there was no statistical difference in the change of TSH.DKA can affect the function of the hypothalamus-pituitary-thyroid axis directly or indirectly due to various factors such as relatively insufficient insulin secretion and metabolic disorders, thus affecting thyroid function [38]. Piconi et al. found that large blood glucose fluctuations trigger the production of nitrotyrosine and induce the expression of adhesion molecules and IL-6 [39]. The release of a large number of cytokines acted on the hypothalamus-pituitary-thyroid axis through a variety of ways, which can also affect the synthesis, secretion, metabolism, and feedback of thyroid hormones [40]. An increase in cytokines such as IL-6 synchronizing with a low T3 level is often observed which may cause hypothalamus involvement [41]. The body’s caloric intake is seriously insufficient in patients with DKA, leading to hypoxia in the cells, which reduced the biological activity of 5′-deiodinase, resulting in a significant reduction in the conversion of T4 to T3, and a significant reduction in the levels and activity of thyroid hormones [42]. Studies have shown that T1DM and thyroid diseases have a common genetic basis [43]. There is a significant positive correlation between serum TSH and antithyroid antibodies (TRAb, TPOAb, and TGAb) in patients with T2DM, suggesting that abnormal thyroid function in patients with T2DM is autoimmune-mediated pathogenesis [44].Studies also found that the severity of impaired hypothalamus-hypophysial-thyroid regulation seems to be related to the degree of metabolic disorders regardless of the presence of antithyroid antibodies [45]. Previous studies have shown that the levels of serum T3 and T4 are related to the severity of the disease [46, 47]. Similarly, Balsamo et al. showed that changes in hormone levels are usually related to the severity of metabolic disorders, among which thyroid function is one of the most serious disorders. The hypothalamus-pituitary-thyroid axis showed variable damage, which was defined as nonthyroid disease syndrome (NTIS) [45]. The relationship between the degree of NTIS and the severity of metabolic disorders has previously been reported in adults and children [48–51]. NTIS is now more commonly used to describe a typical change in the serum levels of thyroid-related hormones that may occur after an acute or chronic disease not caused by intrinsic abnormalities in thyroid function. Changes in the hypothalamic-pituitary-thyroid axis also occur in diseases, usually associated with low levels of T3, which gave rise to the term “low T3 syndrome” [52].It was now well known that most circulating T3 and almost all rT3 came from the peripheral deiodination of T4 [53, 54]. Pittman et al. found that DKA played a certain role in the peripheral transformation of T4 [55]. The moderate decrease in serum T4 observed in patients with DKA has been described previously, which was corrected after treatment, and it seemed to be due to acquired deficiency of T4 binding to serum protein [56]. The factors of dietary, especially carbohydrates, played an important role in the regulation of T3 [57, 58]. The presence of carbohydrate deprivation in DKA seemed to rapidly inhibit the deiodination of T4 by type 1 iodothyronine-deiodinase in the liver, thereby inhibiting the production of T3 and preventing the metabolism of rT3 [59]. Carbohydrate deprivation will lead to a decrease in basal metabolic rate. The decrease in thyroid hormones is represented the body’s remaining adaptive response to calories and protein by inducing hypothyroidism theoretically [60]. It was reported that the average level of rT3 was increased in patients with insulin-dependent diabetes, and the average metabolic clearance rate of rT3 is decreased [55, 61]. The result of Pittman CS et al. suggested that T4 monodeiodination of both phenyl rings was significantly impaired in uncontrolled diabetes, and they believed that long-term insulin insufficiency could lead to a more severe and extensive damage of T4 deiodination [55]. Type 2 deiodinase (Dio2) is an intracellular enzyme that catalyzes the conversion of T4 to T3 [62]. A meta-analysis showed that the polymorphism of Dio2 Thr92Ala is associated with poor blood glucose control in patients with T2DM [63].The limitation of this study is that meta-analysis is a secondary literature analysis based on previous research evidence, so there are limitations and bias in the analysis. The study lacked data for long-term follow-up. The methods used to measure thyroid hormones were much less sensitive than those used in the last decade.


## 5. Conclusion

Thyroid function changed in patients with DKA. It changed with the severity of DKA. This condition may be transient, preceding further recovery of DKA.



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*Source: 2421091-2021-03-22.xml*