<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03269877</url>
  </required_header>
  <id_info>
    <org_study_id>HSLC</org_study_id>
    <nct_id>NCT03269877</nct_id>
  </id_info>
  <brief_title>Hypersplenism in Patients With Liver Cirrhosis and Portal Hypertension</brief_title>
  <official_title>Hypersplenism in Patients With Liver Cirrhosis and Portal Hypertension: Prevalence, Pattern, Correlations, and Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assiut University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assiut University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The spleen could be considered a neglected organ. To date, it has been deemed an ancillary&#xD;
      organ in portal hypertension or an organ localization in lymphoproliferative diseases.&#xD;
      Hypersplenism is a common disorder characterized by an enlarged spleen which causes rapid and&#xD;
      premature destruction of blood cells. It can result from any splenomegaly. It is most common&#xD;
      with splenomegaly secondary to portal hypertension and hematological disorders. Portal&#xD;
      Hypertension is an important cause of splenomegaly in most tropical countries This work will&#xD;
      involve a series of studies aiming to:&#xD;
&#xD;
        1. Assess the prevalence and pattern of hypersplenism, and grade the severity of cytopenias&#xD;
           in patients with cirrhosis and portal hypertension.&#xD;
&#xD;
        2. Elucidate the relationship between hypersplenism, in these patients, and:&#xD;
&#xD;
             1. The severity of liver cirrhosis as assessed by Child's and the Model of End-stage&#xD;
                Liver Disease (MELD) scores.&#xD;
&#xD;
             2. The presence and grade of gastroesophageal varices as assessed by upper endoscopy.&#xD;
&#xD;
             3. The presence of hepatocellular carcinoma&#xD;
&#xD;
             4. Portal hemodynamics and portal vein thrombosis as assessed by Doppler Ultrasound.&#xD;
&#xD;
        3. Test the hypothesis that leucopenia in cirrhotic patients may be caused, at least in&#xD;
           part, by apoptosis of polymorphnuclear leucocytes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hypersplenism is a clinical syndrome characterized by: (1) Splenomegaly (2) Pancytopenia or a&#xD;
      reduction in the number of one or more types of blood cells (3) Normal production or&#xD;
      hyperplasia of the precursor cells in the marrow or a so called maturation arrest (4)&#xD;
      Decreased red blood cells survival (5) Decreased platelet survival. In hypersplenism, its&#xD;
      normal function accelerates, and begins automatically to remove cells that may still be&#xD;
      normal in function. It can be classified into three categories: I) Primary hypersplenism; II)&#xD;
      Secondary hypersplenism; III) Occult hypersplenism. A number of mechanisms causing&#xD;
      hypersplenism have been identified, and mainly involve retention in the spleen, phagocytosis,&#xD;
      and autoimmunity.&#xD;
&#xD;
      PMN have a short life-span and spontaneously undergo apoptosis in the living body. Although&#xD;
      neutropenia in cirrhotic patients is associated with the presence of splenomegaly and&#xD;
      increased clearance of granulocytes in the spleen, the complete sequence of events leading to&#xD;
      neutropenia in cirrhosis is at present unknown. Although neutrophils are programmed to&#xD;
      undergo apoptosis at the time of differentiation, the rate of apoptosis is under the&#xD;
      regulation of external factors. Therefore, changes in the rate of PMN apoptosis are likely to&#xD;
      occur in the setting of cirrhosis. The rate of apoptosis and its contribution in in cirrhotic&#xD;
      patients with or without neutropenia and hypersplenism need further evaluation.&#xD;
&#xD;
      Hypersplenism is a common complication in patients with chronic liver diseases, leading to&#xD;
      decreases in platelet and hemoglobin levels, and correlates with the severity of cirrhosis.&#xD;
      Splenomegaly is often used radiologically as an indicator of cirrhosis. Moreover, one study&#xD;
      has shown that hypersplenism is more frequent and more severe in younger cirrhotic patients,&#xD;
      and another one has addressed that platelet count to spleen diameter ratio non-invasively&#xD;
      identifies severe fibrosis and cirrhosis in patients with chronic hepatitis and cirrhosis.&#xD;
      Many studies also investigated the relationship between size of gastroesophageal varices and&#xD;
      platelet count/spleen diameter ratio in cirrhotic patients which was found that it could be&#xD;
      used as also a non-invasive indicator of esophageal varices. Indeed, there is little&#xD;
      published on the actual frequency of hypersplenism.&#xD;
&#xD;
      Hypersplenism is correlated with increased risk of hepatocellular carcinoma in post-hepatitis&#xD;
      cirrhosis. One study addressed that several factors including hypersplenism in post hepatitis&#xD;
      cirrhosis may contribute to hepatocellular carcinoma development. It also addressed the&#xD;
      efficiency of splenectomy in reducing hepatocellular carcinoma risk. Another study concluded&#xD;
      that microwave ablation of the spleen combined with partial hepatectomy is a safe and&#xD;
      effective technique for treatment of hepatocellular carcinoma and hypersplenism.&#xD;
&#xD;
      It has been shown that portal venous pressure positively correlates with spleen size.&#xD;
      Duplex-Doppler has been employed in pathophysiological investigations of portal hemodynamics&#xD;
      and is accepted as the first-line imaging technique in patients with suspected portal&#xD;
      circulation disorders, particularly in portal hypertension. The measurement of the hepatic&#xD;
      venous pressure gradient has served as the gold standard for assessing the degree of portal&#xD;
      hypertension, however, due to its invasive nature and the requirements for skilled expertise&#xD;
      and special equipment, some Ultrasound indices, such as Hepatic Vein and Portal Vein indices,&#xD;
      exhibited an increased accuracy for diagnosing portal hypertension. These indices may be&#xD;
      useful in clinical practice for the detection of significant portal hypertension.&#xD;
&#xD;
      To date, no studies have fully assessed these correlations of hypersplenism in the same&#xD;
      cirrhotic patients, which can be useful in diagnostic aspects, assessment, grading of&#xD;
      severity, therapeutic interventions or even leading to the development of a new scoring&#xD;
      system for hypersplenism.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">September 1, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2018</completion_date>
  <primary_completion_date type="Anticipated">October 1, 2018</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Crossover</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Prevalence</measure>
    <time_frame>6 months</time_frame>
    <description>Percentage of hypersplenism in patients proven to have liver cirrhosis and portal hypertension</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Severity</measure>
    <time_frame>1 year</time_frame>
    <description>Depending mainly on the severity of cytopenia of the blood elements (RBCs, WBCs, and platlets), hypersplenism will be graded as mild, moderate, or severe, and given a total score of &lt;2 points, 2-3 points, and &gt;3 points, respectively</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Correlations with severity of liver disease</measure>
    <time_frame>1 year</time_frame>
    <description>Percentage of hypersplenism patients, falling into each category of the Child-Pugh score for assessment of severity of liver disease (A, B, or C)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation with Eosophageal varices</measure>
    <time_frame>1 year</time_frame>
    <description>Percentage of hypersplenism patients in each category of grades of oesophageal varices (small, moderate, or large)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlations with hepatocellular carcinoma</measure>
    <time_frame>1 year</time_frame>
    <description>Percentage of hypersplenism patients having hepatocellular carcinoma</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">400</enrollment>
  <condition>Hypersplenism</condition>
  <arm_group>
    <arm_group_label>Liver cirrhosis and hypersplenism</arm_group_label>
    <description>Patients proven to have Liver Cirrhosis and Hypersplenism based on clinical examination, Laboratory findings, and abdominal ultrasound examinaton</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        All admitted patients who fulfill the inclusion criteria over a period of one year will be&#xD;
        included. We are expecting that a total of 400 patients will be recruited.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All patients with documented evidence of liver cirrhosis (of any etiology other than&#xD;
             alcoholic cirrhosis) and portal hypertension, based on clinical examination, abdominal&#xD;
             ultrasound examination, upper gastrointestinal endoscopy.&#xD;
&#xD;
          -  Male and female patients aged between 18-60 years.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with splenomegaly of any cause other than liver cirrhosis.&#xD;
&#xD;
          -  Patients with any lymphoproliferative disorders.&#xD;
&#xD;
          -  Patients with extrahepatic malignancy.&#xD;
&#xD;
          -  Patients younger than 18 years old.&#xD;
&#xD;
          -  Any associated cardiovascular disease.&#xD;
&#xD;
          -  Failure to obtain consent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Ramy M Elbarody, MSc</last_name>
    <phone>00201006486228</phone>
    <email>ramybarody@yahoo.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ahmed H Salem, PhD</last_name>
    <phone>00201066339195</phone>
    <email>ahsalem10@yahoo.com</email>
  </overall_contact_backup>
  <results_reference>
    <citation>Kim G, Cho YZ, Baik SK, Kim MY, Hong WK, Kwon SO. The accuracy of ultrasonography for the evaluation of portal hypertension in patients with cirrhosis: a systematic review. Korean J Radiol. 2015 Mar-Apr;16(2):314-24. doi: 10.3348/kjr.2015.16.2.314. Epub 2015 Feb 27.</citation>
    <PMID>25741193</PMID>
  </results_reference>
  <results_reference>
    <citation>Lv Y, Lau WY, Li Y, Deng J, Han X, Gong X, Liu N, Wu H. Hypersplenism: History and current status. Exp Ther Med. 2016 Oct;12(4):2377-2382. doi: 10.3892/etm.2016.3683. Epub 2016 Sep 7.</citation>
    <PMID>27703501</PMID>
  </results_reference>
  <results_reference>
    <citation>McCormick PA, Walker S, Benepal R. Hypersplenism is related to age of onset of liver disease. Ir J Med Sci. 2007 Dec;176(4):293-6. doi: 10.1007/s11845-007-0089-8. Epub 2007 Oct 18.</citation>
    <PMID>17943410</PMID>
  </results_reference>
  <results_reference>
    <citation>Orlando R, Lirussi F, Basso SM, Lumachi F. Splenomegaly as risk factor of liver cirrhosis. A retrospective cohort study of 2,525 patients who underwent laparoscopy. In Vivo. 2011 Nov-Dec;25(6):1009-12.</citation>
    <PMID>22021698</PMID>
  </results_reference>
  <results_reference>
    <citation>Ramirez MJ, Titos E, Claria J, Navasa M, Fernandez J, Rodes J. Increased apoptosis dependent on caspase-3 activity in polymorphonuclear leukocytes from patients with cirrhosis and ascites. J Hepatol. 2004 Jul;41(1):44-8. doi: 10.1016/j.jhep.2004.03.011.</citation>
    <PMID>15246206</PMID>
  </results_reference>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>August 28, 2017</study_first_submitted>
  <study_first_submitted_qc>August 30, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 1, 2017</study_first_posted>
  <last_update_submitted>August 30, 2017</last_update_submitted>
  <last_update_submitted_qc>August 30, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 1, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Assiut University</investigator_affiliation>
    <investigator_full_name>Ramy Mahmoud Fathy Elbarody</investigator_full_name>
    <investigator_title>Principal investigator at Tropical Medicine and Gastroenterology Department</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Cirrhosis</mesh_term>
    <mesh_term>Hypertension, Portal</mesh_term>
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Hypersplenism</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03269877
org study id: HSLC
nct id: NCT03269877
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The spleen could be considered a neglected organ. To date, it has been deemed an ancillary
      organ in portal hypertension or an organ localization in lymphoproliferative diseases.
      Hypersplenism is a common disorder characterized by an enlarged spleen which causes rapid and
      premature destruction of blood cells. It can result from any splenomegaly. It is most common
      with splenomegaly secondary to portal hypertension and hematological disorders. Portal
      Hypertension is an important cause of splenomegaly in most tropical countries This work will
      involve a series of studies aiming to:

        1. Assess the prevalence and pattern of hypersplenism, and grade the severity of cytopenias
           in patients with cirrhosis and portal hypertension.

        2. Elucidate the relationship between hypersplenism, in these patients, and:

             1. The severity of liver cirrhosis as assessed by Child's and the Model of End-stage
                Liver Disease (MELD) scores.

             2. The presence and grade of gastroesophageal varices as assessed by upper endoscopy.

             3. The presence of hepatocellular carcinoma

             4. Portal hemodynamics and portal vein thrombosis as assessed by Doppler Ultrasound.

        3. Test the hypothesis that leucopenia in cirrhotic patients may be caused, at least in
           part, by apoptosis of polymorphnuclear leucocytes.
Hypersplenism is a clinical syndrome characterized by: (1) Splenomegaly (2) Pancytopenia or a
      reduction in the number of one or more types of blood cells (3) Normal production or
      hyperplasia of the precursor cells in the marrow or a so called maturation arrest (4)
      Decreased red blood cells survival (5) Decreased platelet survival. In hypersplenism, its
      normal function accelerates, and begins automatically to remove cells that may still be
      normal in function. It can be classified into three categories: I) Primary hypersplenism; II)
      Secondary hypersplenism; III) Occult hypersplenism. A number of mechanisms causing
      hypersplenism have been identified, and mainly involve retention in the spleen, phagocytosis,
      and autoimmunity.

      PMN have a short life-span and spontaneously undergo apoptosis in the living body. Although
      neutropenia in cirrhotic patients is associated with the presence of splenomegaly and
      increased clearance of granulocytes in the spleen, the complete sequence of events leading to
      neutropenia in cirrhosis is at present unknown. Although neutrophils are programmed to
      undergo apoptosis at the time of differentiation, the rate of apoptosis is under the
      regulation of external factors. Therefore, changes in the rate of PMN apoptosis are likely to
      occur in the setting of cirrhosis. The rate of apoptosis and its contribution in in cirrhotic
      patients with or without neutropenia and hypersplenism need further evaluation.

      Hypersplenism is a common complication in patients with chronic liver diseases, leading to
      decreases in platelet and hemoglobin levels, and correlates with the severity of cirrhosis.
      Splenomegaly is often used radiologically as an indicator of cirrhosis. Moreover, one study
      has shown that hypersplenism is more frequent and more severe in younger cirrhotic patients,
      and another one has addressed that platelet count to spleen diameter ratio non-invasively
      identifies severe fibrosis and cirrhosis in patients with chronic hepatitis and cirrhosis.
      Many studies also investigated the relationship between size of gastroesophageal varices and
      platelet count/spleen diameter ratio in cirrhotic patients which was found that it could be
      used as also a non-invasive indicator of esophageal varices. Indeed, there is little
      published on the actual frequency of hypersplenism.

      Hypersplenism is correlated with increased risk of hepatocellular carcinoma in post-hepatitis
      cirrhosis. One study addressed that several factors including hypersplenism in post hepatitis
      cirrhosis may contribute to hepatocellular carcinoma development. It also addressed the
      efficiency of splenectomy in reducing hepatocellular carcinoma risk. Another study concluded
      that microwave ablation of the spleen combined with partial hepatectomy is a safe and
      effective technique for treatment of hepatocellular carcinoma and hypersplenism.

      It has been shown that portal venous pressure positively correlates with spleen size.
      Duplex-Doppler has been employed in pathophysiological investigations of portal hemodynamics
      and is accepted as the first-line imaging technique in patients with suspected portal
      circulation disorders, particularly in portal hypertension. The measurement of the hepatic
      venous pressure gradient has served as the gold standard for assessing the degree of portal
      hypertension, however, due to its invasive nature and the requirements for skilled expertise
      and special equipment, some Ultrasound indices, such as Hepatic Vein and Portal Vein indices,
      exhibited an increased accuracy for diagnosing portal hypertension. These indices may be
      useful in clinical practice for the detection of significant portal hypertension.

      To date, no studies have fully assessed these correlations of hypersplenism in the same
      cirrhotic patients, which can be useful in diagnostic aspects, assessment, grading of
      severity, therapeutic interventions or even leading to the development of a new scoring
      system for hypersplenism.
observational model: Case-Crossover
time perspective: Cross-Sectional
measure: Prevalence
time frame: 6 months
description: Percentage of hypersplenism in patients proven to have liver cirrhosis and portal hypertension
measure: Severity
time frame: 1 year
description: Depending mainly on the severity of cytopenia of the blood elements (RBCs, WBCs, and platlets), hypersplenism will be graded as mild, moderate, or severe, and given a total score of <2 points, 2-3 points, and >3 points, respectively
measure: Correlations with severity of liver disease
time frame: 1 year
description: Percentage of hypersplenism patients, falling into each category of the Child-Pugh score for assessment of severity of liver disease (A, B, or C)
measure: Correlation with Eosophageal varices
time frame: 1 year
description: Percentage of hypersplenism patients in each category of grades of oesophageal varices (small, moderate, or large)
measure: Correlations with hepatocellular carcinoma
time frame: 1 year
description: Percentage of hypersplenism patients having hepatocellular carcinoma
arm group label: Liver cirrhosis and hypersplenism
description: Patients proven to have Liver Cirrhosis and Hypersplenism based on clinical examination, Laboratory findings, and abdominal ultrasound examinaton
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Ramy M Elbarody, MSc
phone: 00201006486228
email: ramybarody@yahoo.com
last name: Ahmed H Salem, PhD
phone: 00201066339195
email: ahsalem10@yahoo.com
citation: Kim G, Cho YZ, Baik SK, Kim MY, Hong WK, Kwon SO. The accuracy of ultrasonography for the evaluation of portal hypertension in patients with cirrhosis: a systematic review. Korean J Radiol. 2015 Mar-Apr;16(2):314-24. doi: 10.3348/kjr.2015.16.2.314. Epub 2015 Feb 27.
PMID: 25741193
citation: Lv Y, Lau WY, Li Y, Deng J, Han X, Gong X, Liu N, Wu H. Hypersplenism: History and current status. Exp Ther Med. 2016 Oct;12(4):2377-2382. doi: 10.3892/etm.2016.3683. Epub 2016 Sep 7.
PMID: 27703501
citation: McCormick PA, Walker S, Benepal R. Hypersplenism is related to age of onset of liver disease. Ir J Med Sci. 2007 Dec;176(4):293-6. doi: 10.1007/s11845-007-0089-8. Epub 2007 Oct 18.
PMID: 17943410
citation: Orlando R, Lirussi F, Basso SM, Lumachi F. Splenomegaly as risk factor of liver cirrhosis. A retrospective cohort study of 2,525 patients who underwent laparoscopy. In Vivo. 2011 Nov-Dec;25(6):1009-12.
PMID: 22021698
citation: Ramirez MJ, Titos E, Claria J, Navasa M, Fernandez J, Rodes J. Increased apoptosis dependent on caspase-3 activity in polymorphonuclear leukocytes from patients with cirrhosis and ascites. J Hepatol. 2004 Jul;41(1):44-8. doi: 10.1016/j.jhep.2004.03.011.
PMID: 15246206
responsible party type: Principal Investigator
investigator affiliation: Assiut University
investigator full name: Ramy Mahmoud Fathy Elbarody
investigator title: Principal investigator at Tropical Medicine and Gastroenterology Department
mesh term: Liver Cirrhosis
mesh term: Hypertension, Portal
mesh term: Hypertension
mesh term: Hypersplenism