Pregnancy-related Liver Disease Research Articles

Enfermedades hepáticas relacionadas con el embarazo

Pregnancy-related liver diseases are an important cause of maternal and infant morbidity and mortality. The diagnosis should always be a diagnosis of exclusion (viral, autoimmune, or drug-related liver diseases or biliopancreatic diseases). Pregnancy-related liver diseases include hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, preeclampsia, eclampsia, HELLP syndrome, and acute fatty liver of pregnancy.

Liver imaging and pregnancy: what to expect when your patient is expecting.

Liver diseases in pregnancy can be specific to gestation or only coincidental. In the latter case, the diagnosis can be difficult. Rapid diagnosis of maternal-fetal emergencies and situations requiring specialized interventions are crucial to preserve the maternal liver and guarantee materno-fetal survival. While detailed questioning of the patient and a clinical examination are highly important, imaging is often essential to reach a diagnosis of these liver diseases and lesions. Three groups of liver diseases may be observed during pregnancy: (1) diseases related to pregnancy: intrahepatic cholestasis of pregnancy, pre-eclampsia, eclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, and acute fatty liver of pregnancy; (2) liver diseases that are more frequent during or exacerbated by pregnancy: acute herpes simplex hepatitis, Budd-Chiari syndrome, hemorrhagic hereditary telangiectasia, hepatocellular adenoma, portal vein thrombosis, and cholelithiasis; (3) coincidental conditions, including acute hepatitis, incidental focal liver lesions, metabolic dysfunction-associated steatotic liver disease, cirrhosis, hepatocellular carcinoma, liver abscesses and parasitosis, and liver transplantation. Specific knowledge of the main imaging findings is required to reach an early diagnosis, for adequate follow-up, and to avoid adverse consequences in both the mother and the fetus.Critical relevance statement Pregnancy-related liver diseases are the most important cause of liver dysfunction in pregnant patients and, in pregnancy, even common liver conditions can have an unexpected turn. Fear of radiations should never delay necessary imaging studies in pregnancy.Key points• Pregnancy-related liver diseases are the most frequent cause of liver dysfunction during gestation.• Fear of radiation should never delay necessary imaging studies.• Liver imaging is important to assess liver emergencies and for the diagnosis and follow-up of any other liver diseases.• Common liver conditions and lesions may take an unexpected turn during pregnancy.• Pregnancy-specific diseases such as pre-eclampsia and HELLP syndrome must be rapidly identified. However, imaging should never delay delivery when it is considered to be urgent for maternal-fetal survival.

Severe Early-Onset Intrahepatic Cholestasis of Pregnancy Following Ovarian Hyperstimulation Syndrome with Pulmonary Presentation after In Vitro Fertilization: Case Report and Systematic Review of Case Reports.

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disease, usually presented in the third trimester with pruritus, elevated transaminase, and serum total bile acids. Evidence shows that it can be developed in the first trimester, more commonly after in vitro fertilization (IVF) procedures, with the presence of ovarian hyperstimulation syndrome (OHSS). A literature search was conducted in the PubMed/MEDLINE database of case reports/studies reporting early-onset ICP in spontaneous and IVF pregnancies published until July 2023. Thirty articles on early-onset ICP were included in the review analysis, with 19 patients who developed ICP in spontaneous pregnancy and 15 patients who developed ICP in IVF pregnancies with or without OHSS. Cases of 1st and 2nd trimester ICP in terms of "early-onset" ICP were pooled to gather additional findings. Proper monitoring should be applied even before expected pregnancy and during IVF procedures in patients with known risk factors for OHSS and ICP development (patient and family history), with proper progesterone supplementation dosage and genetic testing in case of ICP recurrence.

Screening for maternal cytomegalovirus infection during pregnancy and pregnancy outcome in patients with liver disease: an observational study

BackgroundCytomegalovirus (CMV) infection among pregnant females could induce CMV hepatitis with possible changes in liver stiffness measurement (LSM) which could be reversibly increased during normal pregnancies, particularly in the third trimester. This study aimed to detect the prevalence of CMV infection among pregnant females with and without chronic liver disease and to evaluate the effects of CMV infection on LSM and pregnancy outcomes in comparison to non-CMV-infected pregnant females.MethodsThis is an observational prospective study that included 201 pregnant ladies presented to the liver disease with pregnancy clinic, Cairo University from March 2018 to April 2019. We assessed the laboratory results, abdominal ultrasonography, LSM using ARFI elastography, and pregnancy outcomes.ResultsTwo hundred and one pregnant ladies were divided into ; group 1: pregnant ladies with normal pregnancy (n = 128), group 2: pregnant ladies with chronic liver diseases not related to pregnancy (n = 35), and group 3: pregnant ladies with pregnancy-related liver diseases (n = 38). Positive CMV serology (either/or, +ve CMV-IgM, IgG) was detected in 106/201 patients (52.74%), and fifteen of them had an active infection (IgG +, IgM+, PCR+). Pregnant females with chronic liver diseases not related to pregnancy had significantly higher serum levels of CMV IgM, IgG, and PCR. Moreover, LSM had a significant correlation with CMV IgG and CM_PCR in normal pregnant ladies. Maternal mortality occurred only in pregnant females with chronic liver diseases in 5.7% (2/35).ConclusionMaternal CMV infection carries a significant risk to pregnant females with chronic liver disease. Routine CMV screening for women planning to be pregnant, especially those with chronic liver disease could help to avoid bad maternal and fetal outcomes.

Imaging of pregnancy-related liver diseases

Imaging of pregnancy-related liver diseases

Utility of Doppler-Ultrasound and Liver Elastography in the Evaluation of Patients with Suspected Pregnancy-Related Liver Disease

Grayscale abdomen ultrasound (US) is routinely performed in pregnant women with suspected pregnancy-related liver dysfunction, but its diagnostic yield is very low. We aimed to investigate the association between Doppler-US findings, liver stiffness measurement (LSM) and different causes of pregnancy-related liver dysfunction. This is a prospective cohort study of pregnant women referred to our tertiary center for any suspected gastrointestinal disease between 2017 and 2019 and undergoing Doppler-US and liver elastography. Patients with previous liver disease were excluded from the analysis. For group comparisons of categorical and continuous variables, the chi-square test or Mann-Whitney test, and the McNemar test were used, as appropriate. A total of 112 patients were included in the final analysis, of whom 41 (36.6%) presented with suspected liver disease: 23 intrahepatic cholestasis of pregnancy (ICP), six with gestational hypertensive disorders and 12 cases with undetermined causes of elevated liver enzymes. Values of LSM were higher and significantly associated with a diagnosis of gestational hypertensive disorder (AUROC = 0.815). No significant differences at Doppler-US or LSM were found between ICP patients and controls. Patients with undetermined causes of hypertransaminasemia showed higher hepatic and splenic resistive indexes than controls, suggesting splanchnic congestion. The evaluation of Doppler-US and liver elastography is clinically useful in patients with suspected liver dysfunction during pregnancy. Liver stiffness represents a promising non-invasive tool for the assessment of patients with gestational hypertensive disorders.

IMPACT OF LIVER DISEASES ON PREGNANCY AND PUERPERIUM STAGE: A SYSTEMATIC REVIEW

Purpose: Changes in the liver function tests (LFTs) are a serious complication during pregnancy and require proper analysis in order to avoid the risk factors in the diagnosis. Pregnancy-specific diseases are the most common reason for abnormal liver function tests while pregnant, especially in the third trimester.
 Materials and Methods: In this review article, pregnancy-related liver disease articles indexed in various databases were used. The collection of articles was evaluated by using keywords including liver diseases, pregnancy, eclampsia, fatty liver, liver enzymes and puerperium stage.
 Results: Liver cirrhosis, autoimmune infections, primary biliary redness, Wilson’s unwellness are few examples of pre-existing liver diseases which are exceptionally rare because pregnant women are often young and healthy. Intrahepatic cholestasis of pregnancy, the HELLP syndrome (haemolysis, increased liver enzymes, low platelets), eclampsia and acute fatty liver are all liver conditions that are specific to pregnancy. These abnormalities may cause foetal distress, serious liver damage, and even hepatic failure; as a result, rapid diagnosis and treatment are required. Serum transaminases, alkaline phosphatase, bilirubin etc. are frequently used diagnostic procedures.
 Conclusion: This review mainly focuses on the pregnancy-associated liver disorders with several biochemical tests, and their pathophysiology to interpret the abnormal condition of the liver during pregnancy. It also highlights the current scenario of Maternal Mortality Ratio in India. The effects of alcohol on unsuccessful pregnancies in females are also discussed. In this, so far bleak situation, changes in lifestyle, early and timely collaborative care by the obstetric and medical teams can produce the best results.

The use of metformin in the treatment of Intrahepatic cholestasis of pregnancy

Introduction: Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disease. It is characterized by persistent pruritus, usually occurring after 30 weeks of pregnancy, and by elevated levels of bile acids and transaminases, which decrease over the course of 2-3 weeks postpartum. [1,2]The occurrence of ICP in the mother may be associated with significant complications in the fetus, such as: preterm labor, intrauterine asphyxia, or sudden fetal death. Currently, the treatment of choice is ursodeoxycholic acid (UDCA).[2,6] Recently, it was observed that the administration of metformin in cases not responding to standard therapy improved lipid disorders in pregnant women.
 
 The aim of the study: The aim of the study is to present the possibility of using metformin in the treatment of ICP in pregnant women not responding to standard treatment and to present a clinical case..
 Material and methods: The work is a review of the literature on the management of ICP and the use of metformin in the treatment of lipid metabolism disorders, as well as a brief case report of a patient with intrahepatic cholestasis of pregnancy.
 Description of the state of knowledge: Metformin is an oral antidiabetic drug belonging to the group of biguanides. However, the latest observations show that metformin also has a beneficial effect on the liver function and on the lipid metabolism in pregnant women. In these patients, the levels of bile acids and liver enzymes decreased after the use of metformin.
 Summary: The mechanism of action of metformin explaining its beneficial effect on the lipid metabolism in pregnant women with intrahepatic cholestasis is not fully understood.

Pregnancy and COVID-19 - liver damage.

This review examines information from systematic reviews and meta-analyses, research studies, and case reports to present current knowledge about liver damage in pregnant patients having Covid-19 during pregnancy. Problems with diagnosis and differential diagnosis are examined in the context of the need to rule out other causes of liver dysfunction, including pregnancy-related liver disease. In this paper we give an overview of COVID-19 liver problems during pregnancy. Mechanisms of liver involvement in COVID-19 infection are being examined. An overview of the assessment of abnormal liver biological syndromes in pregnant patients is provided. Differential diagnostic algorithms for primary liver damage established in a pregnant woman in the context of the Covid-19 pandemic are presented. Challenges in diagnosis and etiology assessment methods and customized management options are described. The management of pregnant women with hepatic dysfunction onset on the Covid-19 background and subsequently aggravated is discussed. The importance of anticoagulant therapy as an essential measure of symptomatic management of Covid-19 in pregnant women is emphasized, as both pregnancy and COVID-19 are thrombogenic. Hypercoagulability appears to adversely affect the pregnant women liver with Covid-19 and post Covid-19 and anticoagulant therapy has benefits in the management of liver damage associated with Covid-19. The COVID-19 liver problems in a 33-year-old woman who was not vaccinated for Covid-19, without a history of chronic liver disease, was tested positive for Covid-19 at 33 weeks of gestation is discussed. The report of the diagnostics, differential diagnosis, and management questions in the context of liver dysfunction manifested by a significant increase in alanine aminotransferase cytolysis syndrome. The positive effect of anticoagulant therapy in resolving cytolytic syndrome is emphasized. The good maternal and perinatal result is also mentioned.

Acoustic radiation force impulse to measure liver stiffness and predict hepatic decompensation in pregnancy with cirrhosis: A cohort study

Background and study aimsPregnancy in association with cirrhosis is a rather uncommon and highly risky situation for both mother and child. We aim to study all factors and the utility of liver stiffness (LS) measurement by Acoustic Radiation Force Impulse elastography (ARFI) to predict hepatic decompensation in pregnant cirrhotic patients. Patients and methodsWe prospectively recruited 224 pregnant women at the multidisciplinary clinic of liver disease with pregnancy, Cairo University. LS was measured using ARFI (Siemens ACUSON S3000 ultrasound system) during the second trimester and 8–12 weeks post-delivery. The outcome of pregnancy and the incidence of hepatic decompensation were assessed. ResultsOur cohort comprised 128 normal pregnancies, 37 patients with pregnancy-related liver disease (Intrahepatic cholestasis (n = 6), preeclampsia (n = 23), and hyperemesis gravidarum (n = 8)) and 59 patients with an established chronic liver disease not related to pregnancy. In all patients, LS significantly decreased after delivery from 1.19 m/s to 0.94 m/s (P < 0.001). In multivariate analysis, LS was an independent predictor for the outcome of pregnancy in all patients (odds ratio (OR) = 5.442 (3.01–6.82), cut-off = 1.21 m/s). Patients with cirrhosis, mean LS was 1.57 ± 0.66 m/s and 26 (44%) patients had hepatic decompensation (hepatocellular jaundice (n = 8), ascites (n = 9) and variceal bleeding (n = 6)). In multivariate analysis; LS, platelets, albumin, and bilirubin were independent predictors of decompensation post-delivery and the OR for LS was 6.141(4.32–7.98). The optimal cut off value of LS to predict decompensation was 1.46 m/s (8.4 kPa) with AUROC of 0.827. ConclusionLS can be used to predict hepatic decompensation after delivery in pregnant women with manifest cirrhosis.

Study of fetomaternal outcomes in a tertiary care hospital related to liver disorders during pregnancy

Introduction: Pregnancy-related liver diseases are significant medical conditions with a poor prognosis that present a challenge to both obstetricians and hepatologists. Around 3% of pregnancies worldwide and 3-5% of pregnancies in India are impacted by it. Numerous symptoms, including a yellowish discoloration of the sclera, black urine, anorexia, nausea, vomiting, and stomach pain, can be present. Hyperemesis gravidarum, preeclampsia, eclampsia with liver dysfunction, hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, intrahepatic cholestasis of pregnancy (IHCP), and acute fatty liver of pregnancy are among the specific liver illnesses associated with pregnancy. Methods: This prospective observational study was carried out at the SCB Medical College and Hospital in Cuttack, Department of Obstetrics and Gynecology. On the basis of the inclusion criteria, 85 prenatal cases were prospectively investigated. Those who underwent a thorough history and examination, clinical symptoms suggestive of liver disorders, all available LFTs, including LDH, as well as some more conclusive tests to help identify the underlying cause, were then monitored up until delivery in terms of the outcome for the maternal and the foetus. Results: There were 0.86% cases of hepatic problems during pregnancy. In the study group, 76.5% of cases appeared in the third trimester of pregnancy, 72.9% of cases were primigravida, and 90.59% of cases were between 20 and 30 years old. 76.4% of the participants in this study had a liver condition unique to pregnancy, of which 32.9% had pre-eclampsia, 11.7% had eclampsia, and 11.7% had HELLP syndrome. 16.4% had ICP, 2.3% had AFLP, and 1.1% had hyperemesis gravidarum. Morbidity was 34.12% and maternal mortality was 10.58%. Preterm 21.1%, stillbirth 38.82%, live birth 61%, and IUGR 24.7%. In 28.57% of cases, NICU admission is necessary. Conclusion: Poor outcomes for the maternal and the foetus are linked to abnormal liver function during pregnancy. Many pregnant women and their unborn children can be saved by routine prenatal screenings, liver problem diagnosis, and treatment.

Evaluation of G-Protein-Coupled Bile Acid Receptor 1 (TGR5) Levels in Intrahepatic Cholestasis of Pregnancy.

Background and objectiveIntrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disease. G-protein-coupled bile acid receptor 1 (TGR5) agonists might be beneficial in ICP treatment. In this study, we aimed to investigate the relationship of serum TGR5 levels with ICP and associated itching.MethodsSixty-three pregnant women diagnosed with ICP based on a serum bile acid level of >10 µmol/L (patient group) and 47 healthy pregnant women as a control group were included in the study. In the patient group, ursodeoxycholic acid (UDCA) therapy was given at a dose of 15 mg/kg from the time of diagnosis until the termination of pregnancy. Serum transaminase levels were measured at the beginning and within 15 days after the onset of treatment, and the dose was increased in patients who were unresponsive to treatment.ResultsBile acid level was found to be between 10-39 µmol/L in 61.9% of the ICP patients, and it was ≥40 µmol/L in 38.1% of the patients. The majority of the patients responded well to the treatment with UDCA. The mean TGR5 level was significantly higher in the patient group compared to the control group (0.98 ±0.95 ng/mL vs. 0.74 ±0.23 ng/mL, p=0.032). In the patient group, TGR5 level showed negative correlations with age and red cell distribution width and a positive correlation with lactate dehydrogenase level and lymphocyte count.ConclusionsBased on our findings, it can be suggested that TGR5 may have a role in the pathogenesis but has no impact on the prognosis of the condition.

Early-stage clinical features, diagnosis and treatment progress of pregnancy-related liver disease

Pregnancy-related liver disease is a group of severe diseases that usually resulting in worsening clinical outcome in pregnant women and fetuses. Therefore, diagnosis and treatment at early-stage are essential. This paper reviews the early-stage clinical features, pathogenesis, diagnosis and treatment key points of common pregnancy-related liver diseases such as hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, hemolysis, elevated liver enzymes and low platelet syndrome, and acute fatty liver of pregnancy, in order to help clinicians, improve their understanding of pregnancy-related liver disease.

Special liver disease in adult: rare, complicated, and new understanding

Clinically, chronic hepatitis B and C are the main common chronic liver diseases that lead to cirrhosis and liver cancer, followed by drug-induced liver injury, alcohol and metabolic-associated fatty liver disease, and autoimmune liver disease in adult, but, by contrast, some special liver diseases, including pregnancy-related liver disease, liver injury related to abnormal liver endocrine function, adult hereditary liver disease, and hepatitis caused by non-hepatotropic viruses are also gradually increasing. Early identification and diagnosis are the only accurate and timely manner treatment for these special liver diseases.

Spectrum of liver diseases occurring solely in pregnancies carrying male fetuses: A case series

Liver disease affects nearly 3% of pregnancies. It is a challenging topic for obstetricians as it can be fatal for both, the mother and the fetus. They carry a high mortality rate reaching 25%. Sex-specific effect on the expression of pregnancy-related liver diseases is largely unknown. We present several cases of familial pregnancy-related liver diseases that were expressed solely when the mothers had male fetuses, ending with deleterious outcomes. Liver disease was not expressed when they had female fetuses. These cases provide a novel insight into the diversity of pregnancy-related liver disease complications expression among sex.

SERUM BILE ACIDS LEVEL IN CASES OF MECONIUM STAINED LIQUOR IN ELECTIVE CESAREAN SECTIONS AT EL-SHATBY MATERNITY UNIVERSITY HOSPITAL

Hepatic disorders of pregnancy comprise an impressive list of diseases and complications. Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, is considered the most common pregnancy-related liver disease. It takes place in the second or third trimester of gestation and it spontaneously disappears after delivery.The condition of asymptomatic hypercholanemia of pregnancy (AHP) has recently been reported. AHP is defined as increased serum bile acids in pregnancy in the absence of symptoms and other biochemical markers of ICP or any other hepatobiliary disease.The prevalence of this condition usually increases with gestational ageBile acids can pose a highly significant risk for the fetus resulting in several adverse perinatal outcomes such as meconium stained amniotic fluid (MSAF), prematurity, fetal distress and stillbirth. In ICP, MSAF has been reported in 16%-58% of all cases and up to 100% of cases affected by intrauterine death. It has been found that the risk of MSAF is associated not only with the magnitude of hypercholanemia at diagnosis but also with the early gestational onset of raised maternal serum bile acids. The frequency of MSAF is greater in pregnancies with higher reported levels of maternal serum bile acids.

Liver diseases in pregnancy and outcomes: A retrospective study from Saudi Arabia.

Liver diseases unique to pregnancy are common causes of both maternal and fetal mortality and morbidity. We retrospectively studied liver diseases unique to pregnancy, including hyperemesis gravidarum (HG); intrahepatic cholestasis of pregnancy; eclampsia; preeclampsia; hemolysis, elevated liver enzymes, and a low platelets (HELLP) syndrome; and acute fatty liver of pregnancy. We collected data including maternal age, gestational weeks at presentation and at delivery, mode of delivery, number of parity, and laboratory markers at 0, 1 week, and within 24 hours after delivery; from 112 patients (mean age, 29.8 years) from April 2015 - March 2017. SPSS 22 was used for statistical analysis. We The commonest liver disease in pregnancy was pre-eclampsia followed by HG. HG patients were younger compared with those with eclampsia and preeclampsia (P=0.025). Gestational week at presentation and the week of delivery were significantly greater for preeclampsia/eclampsia and HELLP patients compared to HG. Primigravida represented 42.9% of our patients. Fetal complications were reported in 29 (26%) of cases. Of those, 17 had fetal or neonatal death. Fourteen mothers (12.5%) had ICU admission. Pregnancy related liver diseases are important causes for fetal mortality and morbidity. Maternal age and gestational weeks are important predictors of fetal and maternal outcomes.

Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy is the most common pregnancy-related liver disease that occurs during pregnancy. It causes mortality and morbidity. In this review, the intrahepatic cholestasis of pregnancy (ICP) is discussed with the current literature.

Intrahepatic Cholestasis of Pregnancy and Associated Adverse Maternal and Fetal Outcomes: A Retrospective Case-Control Study.

Objective Intrahepatic cholestasis of pregnancy (ICP) is a common pregnancy-related liver disease and is associated with an increased risk of adverse neonatal outcomes. Ursodeoxycholic acid (UDCA) is the most effective treatment. This study was aimed at investigating the adverse outcomes of ICP and evaluating the effects of treatment with UDCA in patients with ICP. Methods We included 114 women with ICP and 3725 women without ICP (no-ICP group) who delivered in our hospital between September 2017 and August 2019. The prevalence of ICP in this study was 3.15%. We matched each woman with ICP to five controls. Of all the 114 women with ICP, 73 (64.04%) received UDCA while 41 (35.96%) did not. Logistic multivariate regression analysis was used to compare the adverse outcomes between those with ICP and matched controls as well as between those who received UDCA (UDCA group) and those who did not (non-UDCA group). Results Compared with controls, women with ICP were more likely to have preeclampsia (adjusted odds ratio, aOR = 16.74, 95% CI 5.29–52.98), cesarean section (aOR = 1.76, 95% CI 1.10–2.81), and preterm birth (aOR = 24.35, 95% CI 2.74–216.67). Administration of UDCA reduced the rate of preterm birth (1.37% vs. 14.63%, aOR = 0.10, 95% CI 0.01–0.90). Conclusion ICP increased the risk of preeclampsia, cesarean section, and preterm birth. UDCA could reduce the rate of preterm birth.

The Alterations in Alcohol Dehydrogenase Activity in the Sera of Women With Intrahepatic Cholestasis of Pregnancy.

The liver of pregnant women undergoes physiological and pathological changes and the changes in liver enzyme activity and release reflect changes in serum enzymatic activity. We aimed to assess the activity of alcohol dehydrogenase (ADH) isoenzymes, and aldehyde dehydrogenase (ALDH) in the sera of women with intrahepatic cholestasis of pregnancy (ICP), the most common pregnancy-related liver disease. Serum samples were taken from 40 women with ICP in the second or third trimester of pregnancy. Serum samples were also obtained from 40 healthy pregnant women at the same time of pregnancy and 40 healthy non-pregnant women. Class I and II of ADH and ALDH activity was measured by a spectrofluorometric method. Class III, IV ADH and total ADH activity was measured by photometric methods. The total ADH activity was significantly higher in women with ICP than in healthy pregnant and non-pregnant women (about 42%). The median total activity of ADH was 1067 mU/l in women with ICP, 628 mU/l in healthy pregnant and 605 mU/l in non-pregnant women. A statistically significant increase in class I ADH isoenzymes was found in the sera of pregnant women with ICP. The median activity of this class in the ICP group increased about 62% and 80% in comparison to the healthy pregnant women and non-pregnant women, respectively. The activity of class I ADH isoenzymes in the sera of women with ICP is statistically significantly increased and may have a diagnostic significance.