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doi:10.1111/jog.12562
J. Obstet. Gynaecol. Res. Vol. 41, No. 4: 505–511, April 2015
Disturbed release of cholecystokinin in pregnant women with hyperemesis gravidarum Ebru Biberoglu1, Ayse Kirbas1, Cantekin Iskender1, Aylin Dirican1, Halil Daglar1, Canan Demirtas2, Beyza Doganay3, Dilek Uygur1 and Kutay Biberoglu4 1
Department of Obstetrics and Gynecology, High Risk Pregnancy Unit, Dr. Zekai Tahir Burak Women’s Health Care, Education and Research Hospital, 2Department of Biochemistry, 4Department of Obstetrics and Gynecology, Gazi University Medical School and 3Department of Biostatistics, Ankara University Medical School, Ankara, Turkey
Abstract Aims: We aimed to investigate cholecystokinin (CCK) release in pregnant women with and without hyperemesis gravidarum (HG). Material and Methods: In this case–control study including 40 pregnant women with HG and 40 women with healthy uncomplicated pregnancies, serum CCK levels in addition to hematological, biochemical and hormonal parameters were investigated. Results: Serum CCK values were found to be significantly lower in pregnant women with HG (P < 0.001). Additionally, while serum blood urea nitrogen and free thyroxine levels were significantly higher, sodium, potassium, and thyroid stimulating hormone levels were significantly lower in women with HG than in control women. No correlation was detected between CCK and other parameters like ketonuria and thyroid function tests. Conclusions: CCK release has been found to be halved in pregnant women with HG, which supports the hypothesis that gastrointestinal motility is increased in pregnant women with HG. A causal effect remains to be confirmed. Key words: gastrointestinal motility, gut hormone, pathogenesis of hyperemesis gravidarum, thyroid function tests.
Introduction Hyperemesis gravidarum (HG) is a condition of intractable vomiting in pregnancy, typically in the first trimester, resulting in dehydration and ketonuria that in some cases may be severe enough to justify hospital admission and require parenteral fluid therapy. Although investigators have tried to relate psychological factors, infections, immunological, metabolic, and anatomical factors1,2 to the pathogenesis of HG, the etiopathology is still elusive.3
Cholecystokinin (CCK) is a neuropeptide that binds to its CCK2 receptors in several brain regions, such as the brainstem or hypothalamus4 and is also a gut hormone, which binds to CCK1 receptors in peripheral tissues, including the gallbladder, pancreas and the smooth muscle cells of the gastrointestinal tract. It is released primarily in response to fat and protein intake and inhibits food intake.5–8 Alimentary CCK delays gastric emptying, modulates gastric sensory function, increases the rate of meal-induced esophageal sphincter relaxations and affects small bowel and colonic
Received: April 24 2014. Accepted: August 6 2014. Reprint request to: Professor Kutay Biberoglu, Obstetrics and Gynaecology, Gazi University Medical School, Ankara 06500, Turkey. Email: [email protected]
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
505
E. Biberoglu et al.
transit, by regulating gallbladder contractions and pancreatic enzyme secretion. From the clinical point of view, as most women admitted to hospital with HG usually stop vomiting when not fed by mouth but resume vomiting when they start eating again, it seems obvious that gastrointestinal stimuli play a role, perhaps through CCK release, in the pathogenesis of HG. Therefore, we aimed to investigate CCK release as the primary outcome parameter and other well-known markers, such as thyroid function tests and biochemical indices, as secondary outcome parameters in a group of pregnant women with and without HG, to see if it has a role in the etiopathogenesis of this condition. This study, to our knowledge, is the first to evaluate plasma CCK concentrations in pregnant women with HG.
Methods Eighty pregnant women in the first trimester, 40 with HG and the other 40 with healthy uncomplicated pregnancy, matched for maternal and gestational ages, were recruited consecutively between January and November 2013 at Dr. Zekai Tahir Burak Women’s Health Care, Education and Research Hospital, Ankara. Inclusion criteria for the HG group were having persistent vomiting, severe enough to require hospital admission due to fluid and electrolyte imbalance, ketonuria and weight loss of ≥5% of their prepregnancy weight. Exclusion criteria were: multiple gestation or trophoblastic disease; and history of any systemic, endocrine, gastrointestinal or urinary disease. The study was approved by the Institutional Review Board of Dr. Zekai Tahir Burak Women’s Hospital. The clinical data and blood samples were collected prospectively, but laboratory work-up and data evaluation were achieved retrospectively, without any intervention. The universal principles of the Helsinki Declaration were applied in this non-biomedical, prospective, case–control study. Blood samples were obtained from the antecubital vein early in the morning following 8 h of fasting, centrifuged at 3500 r.p.m. for 10 min and cholecystokinin serum levels were determined by ELISA kit; USCN Life Science Inc. (Lot No: L130531819). According to the sandwich Enzyme Immunoassay principle, the reaction plate was covered with the monoclonal antibody, which binds to the substance to be measured in the samples. To this material, enzyme (HRP) labeled second monoclonal antibody is bound. Added with a solution of the chromogenic enzyme interaction caused
506
by the intensity of the color measured is proportional to the concentration of the desired substance. The results were given in pg/mL. All of the other tests, including hematological, biochemical and hormonal assessments, were carried out at the central laboratories of Dr. Zekai Tahir Burak Women’s Hospital, Ankara. The statistical analyses were conducted with spss. Data are summarized as mean ± standard deviation and median (range). The Student’s t-test or the Mann– Whitney U-test were used for group comparisons. Correlations were assessed using Pearson or Spearman correlation coefficient along with related P-values. Statistical test and correlation coefficient were chosen according to whether the data distribution was normal or not. We utilized the Shapiro–Wilk test to show that our sample came from a normally distributed population.
Results The demographic and obstetric data of the HG and control groups were similar (Table 1). Mean gestational ages were 9.72 ± 3.49 and 9.52 ± 2.43 weeks (P = 0.122) in women with and without HG, respectively, based on ultrasonographic measurements. The daily frequency of vomiting was six times or more in 80% of women with HG (Table 2). Serum hemoglobin, white blood cells, platelet, total protein, albumin, serum creatinine, fasting blood sugar, liver transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), and free tri-iodothyronine (fT3) levels were within normal ranges and comparable in both groups. While blood urea nitrogen (BUN) and free thyroxine (fT4) levels were significantly higher, sodium, potassium, and thyroid-stimulating hormone (TSH) levels were significantly lower in women with HG than in controls (Table 3). Mean serum CCK levels were significantly lower in pregnant women with HG in comparison to those without HG (Table 4). There was no correlation between laboratory parameters, like ketonuria, TSH, fT3 and T4, and CCK concentration (Table 5).
Discussion Nausea and vomiting of pregnancy may be produced by visual, vestibular, olfactory, gustatory, psychogenic and emetogenic stimuli, which are modified in intensity by genetic variation, also by behavioral and psychological factors and triggered presumably by human
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Cholecystokinin in hyperemesis gravidarum
Table 1 Demographic and obstetric characteristics of hyperemesis gravidarum and control study populations Parameters
Normal pregnancy n = 40
Hyperemesis gravidarum n = 40
P
Age (years)
27.30 ± 5.49 27 (18–40) 162.95 ± 4.14 163 (155–171) 65.23 ± 13.09 61.5 (48–96) 1.65 ± 0.86 1 (1–5) 0.5 ± 0.68 0 (0–3) 0.48 ± 0.68 0 (0–3) 0.18 ± 0.38 0 (0–1)
27.40 ± 6.47 26.00 (17–40) 162.18 ± 4.62 161.50 (155–173) 61.63 ± 13.11 58 (40–94) 2.73 ± 2.22 2 (1–10) 0.83 ± 0.93 1 (0–4) 0.73 ± 0.75 1 (0–2) 0.35 ± 1.29 0 (0–8)
0.941*
Height (cm) Weight (kg) Gravidity (n) Parity (n) Live birth (n) Abortus (n)
0.432* 0.168** 0.008** 0.108** 0.107** 0.959**
Data are presented as mean ± standard deviation and median (min–max). *P-values are based on Student’s t-test. **P-values are based on Mann–Whitney U-test.
Table 2 Daily frequency of vomiting in pregnant women with hyperemesis gravidarum study population Frequency/day
n
%
3 4 5 6 7 8 12 Total
3 3 2 12 10 9 1 40
7.5 7.5 5.0 30.0 25.0 22.5 2.5 100.0
chorionic gonadotrophin and estrogens.2 Neuromuscular abnormalities of the stomach associated with nausea and vomiting have been described in women with HG. These patients do not have any mucosal or structural abnormalities in their stomach but rather have disorders of neuromuscular function, including gastric dysrhythmias, and in severe cases, gastroparesis.9 It has been shown that estrogen and progesterone administered to healthy women induce gastric dysrhythmias, particularly bradygastrias.10–12 Hyperthyroidism and hypothyroidism may also disrupt intestinal pacemaker activity.13–15 A correlation between levels of human chorionic gonadotrophin, estradiol, thyroxine hormones, and severity of nausea and vomiting of pregnancy have already been reported.16
Regardless of the type of stimuli, the emetic response is processed by a series of events, including marked reduction in gastric tone and motility followed by a retrograde strong contraction moving small intestinal contents into the stomach, followed by contractions of the diaphragm and abdominal muscles in combination with relaxation of the gastroesophageal sphincter to facilitate passage of gastrointestinal contents.17 These neuromuscular events are mediated by vagal and sympathetic nervous system inputs to the stomach, a variety of hormonal influences elicited by particular meals, and the activity of the wall of the stomach musculature.18,19 In accordance with these physiologic changes, a sudden increase in nausea and vomiting with meal ingestion, immediately triggering the release of CCK by enteroendocrine cells,20 correlates well with the changes in gastric activity.21 Duodenal CCK then increases the firing rate of vagus nerve afferents and information is conveyed to the nucleus of the solitary tract in the brainstem and also directly to the hypothalamus. This stimulus slows gastric emptying by increasing both the frequency and amplitude of contractions in the distal stomach.22–24 This is in harmony with the finding that the CCK1 antagonists have accelerated gastric emptying by increasing both the frequency and amplitude of contractions in the distal stomach, thereby reducing both exogenous and endogenous CCK-induced delay in gastric emptying of liquids and solids in healthy human subjects.25
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
507
E. Biberoglu et al.
Table 3 Biochemical, hematologic and hormonal parameters in hyperemesis gravidarum and control study populations Parameter
Normal pregnancy n = 40
Hyperemesis gravidarum n = 40
Hb (g/dL)
13.11 ± 1.36 13.00 (10.20–17.30) 8 631.50 ± 1 880.51 9 000 (5 000–13 000) 252 575.00 ± 51 762.22 247 000 (178 000–405 000) 7.15 ± 0.31 7.15 (6.50–8.10) 4.24 ± 0.29 4.30 (3.60–4.70) 89.18 ± 9.74 88.50 (72.00–112.00) 15.08 ± 3.38 14.00 (9.00–25.00) 13.46 ± 7.64 11.00 (4.00–34.00) 17.55 ± 4.25 17.00 (4.00–24.00) 0.55 ± 0.10 0.60 (0.30–0.70) 139.63 ± 2.37 139.50 (134.00–144.00) 3.99 ± 0.25 4.00 (3.40–4.50) 1.56 ± 1.07 1.45 (0.02–4.90) 1.12 ± 0.14 1.10 (0.80–1.50) 3.24 ± 0.44 3.20 (2.20–4.09)
12.74 ± 1.03 12.75 (9.90–15.00) 8 741.00 ± 2 358.48 8 000 (5 810–14 580) 259 325.00 ± 84 869.85 248 500 (143 000–539 000) 7.21 ± 0.51 7.20 (6.20–8.20) 5.10 ± 5.99 4.20 (3.60–42.00) 91.60 ± 12.68 90.50 (67.00–120.00) 17.30 ± 7.32 15.00 (9.00–41.00) 18.23 ± 15.65 14.00 (7.00–71.00) 26.06 ± 32.68 21.00 (11.00–224.00) 0.52 ± 0.09 0.50 (0.30–0.70) 136.80 ± 2.34 136.00 (134.00–144.00) 3.84 ± 0.34 3.90 (2.90–4.50) 1.01 ± 1.02 0.96 (0.02–5.80) 1.25 ± 0.30 1.25 (0.02–1.80) 3.37 ± 0.51 3.30 (2.26–4.90)
WBC (103/μL) PLT (103/ μL) TP (g/dL) Alb (g/dL) FBG (mg/dL) AST (IU/L) ALT (IU/L) BUN (mg/dL) CR (mg/dL) Na (mEq/L) K (mEq/L) TSH (μIU/mL) fT4 (ng/dL) fT3 (pg/mL)
P 0.172* 0.787** 0.904** 0.542* 0.423** 0.341* 0.315** 0.071** 0.016** 0.088**
doi:10.1111/jog.12562
J. Obstet. Gynaecol. Res. Vol. 41, No. 4: 505–511, April 2015
Disturbed release of cholecystokinin in pregnant women with hyperemesis gravidarum Ebru Biberoglu1, Ayse Kirbas1, Cantekin Iskender1, Aylin Dirican1, Halil Daglar1, Canan Demirtas2, Beyza Doganay3, Dilek Uygur1 and Kutay Biberoglu4 1
Department of Obstetrics and Gynecology, High Risk Pregnancy Unit, Dr. Zekai Tahir Burak Women’s Health Care, Education and Research Hospital, 2Department of Biochemistry, 4Department of Obstetrics and Gynecology, Gazi University Medical School and 3Department of Biostatistics, Ankara University Medical School, Ankara, Turkey
Abstract Aims: We aimed to investigate cholecystokinin (CCK) release in pregnant women with and without hyperemesis gravidarum (HG). Material and Methods: In this case–control study including 40 pregnant women with HG and 40 women with healthy uncomplicated pregnancies, serum CCK levels in addition to hematological, biochemical and hormonal parameters were investigated. Results: Serum CCK values were found to be significantly lower in pregnant women with HG (P < 0.001). Additionally, while serum blood urea nitrogen and free thyroxine levels were significantly higher, sodium, potassium, and thyroid stimulating hormone levels were significantly lower in women with HG than in control women. No correlation was detected between CCK and other parameters like ketonuria and thyroid function tests. Conclusions: CCK release has been found to be halved in pregnant women with HG, which supports the hypothesis that gastrointestinal motility is increased in pregnant women with HG. A causal effect remains to be confirmed. Key words: gastrointestinal motility, gut hormone, pathogenesis of hyperemesis gravidarum, thyroid function tests.
Introduction Hyperemesis gravidarum (HG) is a condition of intractable vomiting in pregnancy, typically in the first trimester, resulting in dehydration and ketonuria that in some cases may be severe enough to justify hospital admission and require parenteral fluid therapy. Although investigators have tried to relate psychological factors, infections, immunological, metabolic, and anatomical factors1,2 to the pathogenesis of HG, the etiopathology is still elusive.3
Cholecystokinin (CCK) is a neuropeptide that binds to its CCK2 receptors in several brain regions, such as the brainstem or hypothalamus4 and is also a gut hormone, which binds to CCK1 receptors in peripheral tissues, including the gallbladder, pancreas and the smooth muscle cells of the gastrointestinal tract. It is released primarily in response to fat and protein intake and inhibits food intake.5–8 Alimentary CCK delays gastric emptying, modulates gastric sensory function, increases the rate of meal-induced esophageal sphincter relaxations and affects small bowel and colonic
Received: April 24 2014. Accepted: August 6 2014. Reprint request to: Professor Kutay Biberoglu, Obstetrics and Gynaecology, Gazi University Medical School, Ankara 06500, Turkey. Email: [email protected]
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
505
E. Biberoglu et al.
transit, by regulating gallbladder contractions and pancreatic enzyme secretion. From the clinical point of view, as most women admitted to hospital with HG usually stop vomiting when not fed by mouth but resume vomiting when they start eating again, it seems obvious that gastrointestinal stimuli play a role, perhaps through CCK release, in the pathogenesis of HG. Therefore, we aimed to investigate CCK release as the primary outcome parameter and other well-known markers, such as thyroid function tests and biochemical indices, as secondary outcome parameters in a group of pregnant women with and without HG, to see if it has a role in the etiopathogenesis of this condition. This study, to our knowledge, is the first to evaluate plasma CCK concentrations in pregnant women with HG.
Methods Eighty pregnant women in the first trimester, 40 with HG and the other 40 with healthy uncomplicated pregnancy, matched for maternal and gestational ages, were recruited consecutively between January and November 2013 at Dr. Zekai Tahir Burak Women’s Health Care, Education and Research Hospital, Ankara. Inclusion criteria for the HG group were having persistent vomiting, severe enough to require hospital admission due to fluid and electrolyte imbalance, ketonuria and weight loss of ≥5% of their prepregnancy weight. Exclusion criteria were: multiple gestation or trophoblastic disease; and history of any systemic, endocrine, gastrointestinal or urinary disease. The study was approved by the Institutional Review Board of Dr. Zekai Tahir Burak Women’s Hospital. The clinical data and blood samples were collected prospectively, but laboratory work-up and data evaluation were achieved retrospectively, without any intervention. The universal principles of the Helsinki Declaration were applied in this non-biomedical, prospective, case–control study. Blood samples were obtained from the antecubital vein early in the morning following 8 h of fasting, centrifuged at 3500 r.p.m. for 10 min and cholecystokinin serum levels were determined by ELISA kit; USCN Life Science Inc. (Lot No: L130531819). According to the sandwich Enzyme Immunoassay principle, the reaction plate was covered with the monoclonal antibody, which binds to the substance to be measured in the samples. To this material, enzyme (HRP) labeled second monoclonal antibody is bound. Added with a solution of the chromogenic enzyme interaction caused
506
by the intensity of the color measured is proportional to the concentration of the desired substance. The results were given in pg/mL. All of the other tests, including hematological, biochemical and hormonal assessments, were carried out at the central laboratories of Dr. Zekai Tahir Burak Women’s Hospital, Ankara. The statistical analyses were conducted with spss. Data are summarized as mean ± standard deviation and median (range). The Student’s t-test or the Mann– Whitney U-test were used for group comparisons. Correlations were assessed using Pearson or Spearman correlation coefficient along with related P-values. Statistical test and correlation coefficient were chosen according to whether the data distribution was normal or not. We utilized the Shapiro–Wilk test to show that our sample came from a normally distributed population.
Results The demographic and obstetric data of the HG and control groups were similar (Table 1). Mean gestational ages were 9.72 ± 3.49 and 9.52 ± 2.43 weeks (P = 0.122) in women with and without HG, respectively, based on ultrasonographic measurements. The daily frequency of vomiting was six times or more in 80% of women with HG (Table 2). Serum hemoglobin, white blood cells, platelet, total protein, albumin, serum creatinine, fasting blood sugar, liver transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), and free tri-iodothyronine (fT3) levels were within normal ranges and comparable in both groups. While blood urea nitrogen (BUN) and free thyroxine (fT4) levels were significantly higher, sodium, potassium, and thyroid-stimulating hormone (TSH) levels were significantly lower in women with HG than in controls (Table 3). Mean serum CCK levels were significantly lower in pregnant women with HG in comparison to those without HG (Table 4). There was no correlation between laboratory parameters, like ketonuria, TSH, fT3 and T4, and CCK concentration (Table 5).
Discussion Nausea and vomiting of pregnancy may be produced by visual, vestibular, olfactory, gustatory, psychogenic and emetogenic stimuli, which are modified in intensity by genetic variation, also by behavioral and psychological factors and triggered presumably by human
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Cholecystokinin in hyperemesis gravidarum
Table 1 Demographic and obstetric characteristics of hyperemesis gravidarum and control study populations Parameters
Normal pregnancy n = 40
Hyperemesis gravidarum n = 40
P
Age (years)
27.30 ± 5.49 27 (18–40) 162.95 ± 4.14 163 (155–171) 65.23 ± 13.09 61.5 (48–96) 1.65 ± 0.86 1 (1–5) 0.5 ± 0.68 0 (0–3) 0.48 ± 0.68 0 (0–3) 0.18 ± 0.38 0 (0–1)
27.40 ± 6.47 26.00 (17–40) 162.18 ± 4.62 161.50 (155–173) 61.63 ± 13.11 58 (40–94) 2.73 ± 2.22 2 (1–10) 0.83 ± 0.93 1 (0–4) 0.73 ± 0.75 1 (0–2) 0.35 ± 1.29 0 (0–8)
0.941*
Height (cm) Weight (kg) Gravidity (n) Parity (n) Live birth (n) Abortus (n)
0.432* 0.168** 0.008** 0.108** 0.107** 0.959**
Data are presented as mean ± standard deviation and median (min–max). *P-values are based on Student’s t-test. **P-values are based on Mann–Whitney U-test.
Table 2 Daily frequency of vomiting in pregnant women with hyperemesis gravidarum study population Frequency/day
n
%
3 4 5 6 7 8 12 Total
3 3 2 12 10 9 1 40
7.5 7.5 5.0 30.0 25.0 22.5 2.5 100.0
chorionic gonadotrophin and estrogens.2 Neuromuscular abnormalities of the stomach associated with nausea and vomiting have been described in women with HG. These patients do not have any mucosal or structural abnormalities in their stomach but rather have disorders of neuromuscular function, including gastric dysrhythmias, and in severe cases, gastroparesis.9 It has been shown that estrogen and progesterone administered to healthy women induce gastric dysrhythmias, particularly bradygastrias.10–12 Hyperthyroidism and hypothyroidism may also disrupt intestinal pacemaker activity.13–15 A correlation between levels of human chorionic gonadotrophin, estradiol, thyroxine hormones, and severity of nausea and vomiting of pregnancy have already been reported.16
Regardless of the type of stimuli, the emetic response is processed by a series of events, including marked reduction in gastric tone and motility followed by a retrograde strong contraction moving small intestinal contents into the stomach, followed by contractions of the diaphragm and abdominal muscles in combination with relaxation of the gastroesophageal sphincter to facilitate passage of gastrointestinal contents.17 These neuromuscular events are mediated by vagal and sympathetic nervous system inputs to the stomach, a variety of hormonal influences elicited by particular meals, and the activity of the wall of the stomach musculature.18,19 In accordance with these physiologic changes, a sudden increase in nausea and vomiting with meal ingestion, immediately triggering the release of CCK by enteroendocrine cells,20 correlates well with the changes in gastric activity.21 Duodenal CCK then increases the firing rate of vagus nerve afferents and information is conveyed to the nucleus of the solitary tract in the brainstem and also directly to the hypothalamus. This stimulus slows gastric emptying by increasing both the frequency and amplitude of contractions in the distal stomach.22–24 This is in harmony with the finding that the CCK1 antagonists have accelerated gastric emptying by increasing both the frequency and amplitude of contractions in the distal stomach, thereby reducing both exogenous and endogenous CCK-induced delay in gastric emptying of liquids and solids in healthy human subjects.25
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
507
E. Biberoglu et al.
Table 3 Biochemical, hematologic and hormonal parameters in hyperemesis gravidarum and control study populations Parameter
Normal pregnancy n = 40
Hyperemesis gravidarum n = 40
Hb (g/dL)
13.11 ± 1.36 13.00 (10.20–17.30) 8 631.50 ± 1 880.51 9 000 (5 000–13 000) 252 575.00 ± 51 762.22 247 000 (178 000–405 000) 7.15 ± 0.31 7.15 (6.50–8.10) 4.24 ± 0.29 4.30 (3.60–4.70) 89.18 ± 9.74 88.50 (72.00–112.00) 15.08 ± 3.38 14.00 (9.00–25.00) 13.46 ± 7.64 11.00 (4.00–34.00) 17.55 ± 4.25 17.00 (4.00–24.00) 0.55 ± 0.10 0.60 (0.30–0.70) 139.63 ± 2.37 139.50 (134.00–144.00) 3.99 ± 0.25 4.00 (3.40–4.50) 1.56 ± 1.07 1.45 (0.02–4.90) 1.12 ± 0.14 1.10 (0.80–1.50) 3.24 ± 0.44 3.20 (2.20–4.09)
12.74 ± 1.03 12.75 (9.90–15.00) 8 741.00 ± 2 358.48 8 000 (5 810–14 580) 259 325.00 ± 84 869.85 248 500 (143 000–539 000) 7.21 ± 0.51 7.20 (6.20–8.20) 5.10 ± 5.99 4.20 (3.60–42.00) 91.60 ± 12.68 90.50 (67.00–120.00) 17.30 ± 7.32 15.00 (9.00–41.00) 18.23 ± 15.65 14.00 (7.00–71.00) 26.06 ± 32.68 21.00 (11.00–224.00) 0.52 ± 0.09 0.50 (0.30–0.70) 136.80 ± 2.34 136.00 (134.00–144.00) 3.84 ± 0.34 3.90 (2.90–4.50) 1.01 ± 1.02 0.96 (0.02–5.80) 1.25 ± 0.30 1.25 (0.02–1.80) 3.37 ± 0.51 3.30 (2.26–4.90)
WBC (103/μL) PLT (103/ μL) TP (g/dL) Alb (g/dL) FBG (mg/dL) AST (IU/L) ALT (IU/L) BUN (mg/dL) CR (mg/dL) Na (mEq/L) K (mEq/L) TSH (μIU/mL) fT4 (ng/dL) fT3 (pg/mL)
P 0.172* 0.787** 0.904** 0.542* 0.423** 0.341* 0.315** 0.071** 0.016** 0.088**
