Etiopathogenesis of Anemia in Chronic Liver Disease

Study Overview
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Brief Summary
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Anemia is the most common complication of liver cirrhosis and is seen in 75% of cases. The etiology of anemia in liver disease is diverse and often multi-factorial. Given the diverse and sometimes multifactorial etiology of cirrhosis, it is difficult to determine the exact cause of anemia in these groups of patients. The most common type of anemia encountered in liver cirrhosis is normocytic normochromic anemia, attributable to the chronic inflammatory state. The key question in management of anemia in patients with liver disease which specific factor needs to be corrected to restore hemoglobin levels and improve overall clinical status and improve severity scores.

Detailed Description
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Common causes of anemia include acute and chronic blood loss due to upper gastrointestinal (GI) bleeding, malnutrition, hemolysis, hypersplenism secondary to portal hypertension, and impaired coagulation. Alcohol causes anemia by its direct bone marrow toxicity, vitamin B12 and folate deficiency due to poor oral intake, and intestinal malabsorption. Treatment related anemia is seen in patients with chronic hepatitis C virus infection receiving ribavirin and interferon. Hepatitis associated aplastic anemia, characterized by pancytopenia and hypocellular bone marrow, is an entity seen concurrently with or within 6 months of infection with hepatotropic viruses such as hepatitis B, hepatitis C and Epstein-Barr virus. Acute and chronic blood loss from varices, portal hypertensive gastropathy and gastric antral vascular ectasia can give rise to iron-deficiency anemia, in which the picture is one of microcytic hypochromic anemia. Another common hematological abnormality seen in liver cirrhosis is macrocytosis. The causes of macrocytosis in liver cirrhosis are also multi factorial. Vitamin B12 and folate deficiency is also frequently seen in liver cirrhosis, particularly of alcoholic origin, due to malnutrition and increased intestinal permeability, and gut dysbiosis. Patients with cirrhosis patients have a high incidence of sepsis which can trigger decompensation and may result in prolonged hospital stay and increased mortality. Many studies have estimated that about 30%-50% admissions of patients with cirrhosis have sepsis. Of those who don't have sepsis at presentation, about 15% patients admitted to hospital develop sepsis during the hospital stay. After infection develops, the patient may develop acute kidney injury (AKI), shock, encephalopathy or disseminated intravascular coagulation (DIC) further decreasing the chances of survival. Sepsis and the associated cytokines have a myelosuppressive effect and prevent the erythron from making blood cells. This results in an increase in ferritin as an inflammatory biomarker and alters iron metabolism by affecting the production of hepcidin in the liver. The worsening of anemia in patients with sepsis is well documented, and this is further impacted using drugs like antibiotics which trigger inflammation mediated suppression of the erythron and other hematopoietic precursors like megakaryocytes and leucoblasts. In the study, after taking informed consent, participants will be evaluated for etiology of chronic liver disease with proper history, clinical examination and investigations which will include viral markers (HbsAg, Anti-HCV, Total anti-Hbc, AIH markers (Anti-nuclear antibody/ anti-smooth muscle antibody/anti- liver kidney microsomal antibody), serum ceruloplasmin, non-alcoholic fatty liver disease (NAFLD) work up and radiological investigations for cirrhosis. The severity of cirrhosis will be determined by Child-Pugh's and MELD/MELD-Na score. To evaluate for anemia, following results would be noted: Complete hemogram with RBC indices, reticulocyte count and peripheral blood smear, RFT, LFT, INR, iron studies - serum iron, ferritin, total iron binding capacity and %transferrin saturation, serum vitamin B12, folate levels. Workup for hemolysis would include lactate dehydrogenase, serum haptoglobin, direct coombs test and plasma hemoglobin. Upper GI endoscopy findings will also be noted to evaluate the contribution of gastrointestinal blood loss in causing anemia.

Official Title
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Assessment of Role of Iron Metabolism, Nutritional Deficiency, Gastrointestinal Loss, and Chronic Inflammation in the Etiopathogenesis of Anemia in Chronic Liver Disease

Conditions
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Anemia, Chronic Liver Disease

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 years Either gender Patients with chronic liver disease with anemia (Hemoglobin in Non-pregnant women (18 years of age and above) <12g/dl and in men <13g/dl Exclusion Criteria: Those who do not consent to participate in the study Renal dysfunction (S. Creatinine ≥ 2mg/dL) Pregnancy/Lactation Post liver transplant patients HIV infection Patients who are on psychoactive drugs, like sedatives or antidepressants Patients with uncontrolled sepsis Patients who are too sick to carry out the protocol Patients with ongoing active bleeding Patients with known primary hematological disorders

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Chronic liver disease with anemia<br>All patients with anemia as diagnosed by WHO criteria in patients with liver disease of any etiology. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Etiologies of anemia in patients with liver disease | Determine the prevalence of various etiologies of anemia in patients with liver disease | 1 month | 
| Correlation with liver disease severity | Association of liver disease severity as measured by MELD, MELD Na and CTP scores with severity of anemia | 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastro Intestinal Bleeding, Iron Deficiency Anemia, Cirrhosis, Anemia of Chronic disease, Nutritional deficiency