European Journal of Cardiovascular Medicine

The liver is one of the most complex functioning organs with a wide array of functions in human body. It plays a major role in carbohydrate, protein, lipid metabolism, synthesis of plasma proteins and maintenance of immunity (Kupffer cells), inactivation of various toxins, metabolism of drugs, and hormones. The liver has an extremely important role in maintenance of blood homeostasis as it functions as a storage depot for iron, folic acid, and Vitamin B12, secretes clotting factors and inhibitors. Hence, it is not surprising that, in liver diseases, a wide range of hematological abnormalities can be seen.

 CLD in the clinical context is a disease process of the liver that involves progressive destruction and regeneration of the liver parenchyma, leading to fibrosis and cirrhosis.1Cirrhosis is currently the 11th most common cause of death globally and liver cancer is the 16th leading cause of death; combined, they account for 3.5% of all deaths worldwide. 1 Cirrhosis is within the top 20 causes of disability-adjusted life years and years of life lost, accounting for 1.6% and 2.1% of the worldwide burden. About 2 billion people consume alcohol worldwide and upwards of 75 million are diagnosed with alcohol-use disorders and are at risk of alcohol-associated liver disease. Approximately 2 billion adults are obese or overweight and over 400 million have diabetes; both of which are risk factors for non-alcoholic fatty liver disease and hepatocellular carcinoma. The global prevalence of viral hepatitis remains high, while drug-induced liver injury continues to increase as a major cause of acute hepatitis. Liver transplantation is the second most common solid organ transplantation, yet less than 10% of global transplantation needs are met at current rates. 2

Cirrhosis is a condition that is defined histopathologically and has a variety of clinical manifestations and complications, some of which can be life threatening. Liver fibrosis is characterized by the accumulation of extracellular matrix, resulting from its increased production and decreased degradation and leading to distorted reconstruction of the liver parenchyma that accompanies liver function impairment during most chronic liver disease. 3

In chronic liver disease the presence of jaundice, liver cell failure, portal hypertension and hypersplenism, reduced red cell half- life all influence peripheral blood picture. 4Both Liver cell failure & cholestasis can derange the coagulation system. Dietary deficiencies, bleeding, alcoholism and abnormalities in hepatic synthesis of proteins used for blood formation or coagulation add to the problem of liver disease. 5

This study was undertaken to describe the hematological abnormalities in decompensated chronic liver disease so that measures could be taken to correct them and reducemorbidity.

The prospective cross sectional observational study was performed at the General Medicine department in a Tertiary Care Urban Teaching Hospital in Ahmedabad, Gujarat, India with inpatient cases of decompensated liver disease

Study design: Prospective Cross-Sectional Observational Study

Study area: The study was conducted at the General Medicine department in a Tertiary Care Urban Teaching Hospital in Ahmedabad, Gujarat, India.

Study population: Only inpatient cases of decompensated liver disease( Deterioration in liver function in patient with cirrhosis and is characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome or varicealhemorrhage) evaluated within the hospital.

Study subjects were enrolled as per inclusion and exclusion criteria. A total of 100 patients were included in this study.

Duration: 1 years

Inclusion criteria

All liver disease patients whose symptoms and signs persist more than 6 months.

Age >18 years

Alcoholic and post-infective, metabolic, auto-immune causes of liver diseases are taken for study.

Exclusion disorder

Patients with primary coagulation disorder.

Patients with known GIT malignancy or known primary hepatocellular carcinoma.

Patients with known hematological malignancy like leukemia lymphoma.

Patients with bone marrow disorders like MDS.

Patients with acute liver cell failure.

Patients with other causes of septicemia or endotoxemia other than primary liver causes.

Method:

To Assess the hematological abnormalities in chronic liver disease, the prevalence study was conducted in tertiary care hospital, during the period from June 2021 to August 2022. About one hundred patients were selected in random for this study.

All cases in the study were admitted in the hospital ward and evaluated for chronic liver disease and for the study to assess the hematological abnormalities. Oral consent of the patients got for the clinical examination and for the lab investigations. Written consent also got for the special procedures such as liver biopsy, upper GI endoscopy and viral markers study.

All the patients were interrogated regarding the presenting complaints, examination and all as per the Proforma.

Patients were submitted to a number of blood investigations. Blood samples obtained from the patients were personally handed over to laboratory. The results were got in person and was noted. Blood sample were anticoagulated with EDTA.

Patients were evaluated for chronic liver disease to establish the diagnosis of cirrhosis. Liver biopsy with consent was done to confirm the diagnosis. In patients with defects in coagulation ie increased prothrombin time or decreased platelet count, there is increased bleeding tendency during liver biopsy. So in that case diagnosis is established with ultrasound.

In the setting of contraindication to liver biopsy, suspicious of cirrhosis with ultrasound is coupled with evidence of portal gastropathy or varices in upper GI endoscopy to gain more evidence of diagnosis. Above investigations were also supported with signs of liver cell failure, to establish diagnosis.

After establishing the diagnosis patients were evaluated for hematological abnormalities. All blood investigations regarding hematological profile were done in the clinical pathology laboratory in the hospital. Similarly, prothrombin time and activated partial thromboplastin time were done at a pathology laboratory.

This study was done in 100 patients of chronic liver disease admitted in tertiary care  hospital, Ahmedabad. Following results were found while studying haematological abnormalities in these patients.

Table 1: Distribution of  patients as per age.(n=100)

Most of the patients in the study were in the middle age group 41-50 years.(39%) Followed by 31% in 51-60 years. Only 4% of patients were below 30 years of age and 8% had age >60 years. The mean age of study participants was 42.9 + 12.7 years.

Table 2: Distribution of  patients as per gender(n=100)

Among the study participants, 79% were male and 21% were female.

Table 3: Etiology/Risk factors  in patients

In the present study, Alcohol emerged as the most common etiology followed by patients having history of jaundice. 12% patients turned out to be positive for HBsAg and only 4% showed positive for anti HCV antibody.

While coming to data analysis of investigations, among the 100 Chronic Liver Disease patient’s 11% of patients were positive for serological markers like ANA/AMA/ASMA.

Table 4: Distribution of patients according to signs and symptoms.

Among the 100 patients, the majority of patients had altered consciousness(55%), followed by 45% abdominal distension, followed by 43% jaundice and 29% hematemesis.

Analysis of RBCs

Patients in the study were assessed for the presence and types of anemia and the characteristics of anemia.

Table 5: Hemoglobin level in patients(n=100)

Majority of patients had anemia(95) with  44 patients being severely anemic with  Hemoglobin of <8gm/dL

Table 6: RBC count in patients.

Majority(41) had low RBC count(<3 cells/mcL) among 100 patients and only 11 patients had RBC count>4.5 cells/mcL.

Table 7: Type of Anemia in patients.(n=100)

Out of total, 41 patients had normocytic normochromic RBCs, 32 patients had macrocytic, 23 patients were microcytic and 4% had dimorphic picture.

Table 8: Blood parameters in Alcoholics and Non-alcoholics with or without UGI bleed

Alcoholic patient with UGI bleed had average HB of 7.08 gm/dL and those without bleed had 9.48 gm/dL and non-alcoholic patients with UGI bleed had average HB of 6.59 gm/dL and those without bleed had 9.38 gm/dL. There is a statistically significant  difference between average level of haemoglobin and RBC counts in alcoholic and non-alcoholic with bleed and alcoholic and non-alcoholic without bleed.

Table 9: Distribution of patients according to Modified child Pugh Score(CPS).(n=100)

In the study out of 100 patients, 7 patients had CPS class A,  47 patients had CPS class B, 46 patients had CPS class C. Thus, majority of patients had moderate to severe disease.

Table 10: Comparison of HB levels, RBC counts and  Modified Child Pugh Score(CPS)

  In study, males had average HB of 8.64gm/dL and females had 8.47gm/dL.On assessing, there was no statistically significant difference between Gender and various blood parameters. Average CPS was  higher in males then female and it was statistically significant.

Table 11:Association between Haemoglobin level and Modified Child Pugh Score(CPS)

In study, out of 47 patients of  Class B CPS,18 patients and out of 46 patients of Class C, 26 patients had severe anemia with HB<8gm/dL. Thus patients with severe anemia had severe disease. There was no association found between CPS Score and Haemoglobin level in study.

Table 12.Association between Hemoglobin level and Ascites grading.

In the study, 24 patients had mild ascites followed by 10 patients had moderate and 8 patients had severe ascites with severe anemia with HB of <8gm/dL. 2 patients had mild ascites without anemia. There  was no association found between haemoglobin level and ascites category

Table 13. Association between Hemoglobin level and Hepatic encephalopathy grading.

As per observation severe anemia(HB <8gm/dL) was found in 2 patients of Grade 4, 4 patients of Grade 3, 16 patients of Grade 2, 7 patients of Grade 1 and 7 patients of Grade o encephalopathy. only 1 patient of Grade 2 encephalopathy had normal HB level(>12gm/dL). Thus severe anemia was seen with severe disease. There was no association found between  haemoglobin level and hepatic encephalopathy grading in study.

Table 14: Iron Profile  in patients

In the study, 67 patients had ACD(anemia of chronic disease), 24 patients had Iron deficiency anemia and 4 patients had iron overload with a history of iron correction and blood transfusion.

Analysis of WBCs

The analysis of WBCs was done with the total count. The total count of WBCs ranges from 2750/mm3 to 21,000/mm3. Among the 100 patients Leukocytosis was observed in 16 patients. Leucopenia was present in 22% of patients.

Table 15: WBC count in patients.(n=100)

Table 16: Association between WBC counts with Modified Child Pugh Score(CPS).

In the study 1 patient with Class A, 11 patients with Class B and 10 patients with Class C had leucopenia. There were 16 patients of Class C had Leukocytosis, which was not seen with Class B and Class A. There is no statistically significance with leucopenia, leukocytosis and CPS.

Analysis of Platelets

Table 17: Platelet counts in patients and association with average spleen size.

Thrombocytopenia was found in 84 patients among 100 cases in the study. Severe thrombocytopenia of < 50,000 cell / mm3 was found in patients with large spleen(average size-5.47 cms).

Table 18. Association between Platelet count and Ascites grading

 As per observation,  platelet count less than 50,000 cells/mm3, 8 patients had mild ascites, 9 patients had moderate ascites and 2 patients had severe ascites. While in more than 1.5 lakh platelet count, 13 patients had mild ascites and 3 patients severe ascites.

There was significant association found between platelet count and ascites grading.

Table 19. Association between Platelet count and Hepatic encephalopathy grading.

In the study, 5 patients of Grade 0, 8 patients og Grade 2, 5 patients of Grade 3 and 1 patient of Grade 4 had severe thrombocytopenia with platelet count <50,000 cells/mm3. all 7 patients of hepatic encephalopathy Grade 3 had count <75000 cells/mm3. Thus, thrombocytopenia was seen with severe disease and it was statistically significant.

Analysis of Serum proteins

Patients were analysed for the estimation of serum proteins, which is the synthetic function of the liver and evaluated for albumin globulin ratio which will be altered in the chronic liver disease patients

Table 20: Total protein in patients. (n=100)

In the study majority patients had total protein in the range of 6.1-7.0 g/dL and only 1 patient had total protein <5g/dl.

Table 21: Total protein in patients.(n=100)

In the study, majority of patients had A/G ratio between 0.71-0.80 and only 4 patients had a ratio of >1.  60 patients  had a ratio <0.8. A/G reversal was seen in study patients.

Abnormalities in coagulation

In study, the patients were assessed for the coagulation profile by testing for prothrombin time, activated partial thromboplastin time and bleeding time. Among the 100 patients 87 patients had prolonged prothrombin time. Bleeding time was Prolonged in 19 patients and Among the 100 patients, aPTT was prolonged in 19 patients.

Table 21: Hemostatic parameters in patients.

Table 22: Association between INR level and Hepatic encephalopathy grading

In study, only 6 patients had normal INR value<1.3, which was seen with Grade 0, Grade 1, Grade 2. all 2 patients of Grade 4 had INR value>2.0 and 5 patients of Grade 3 had INR value>2.0. Thus, high INR seen with severe disease.there was statistically significance.

Most of the patients (39%) in the study were in middle age group 40-50 years. Followed by 31% in 50-60 years. Only 4% patients were below 30 years age. Those 4 patients were diagnosed as chronic decompensated liver disease with pathology as cirrhosis and were of variable etiology. The mean age of study participants was 42.9 + 12.7 years. While in study of Lahari J et al6  mean age of study participants was found  similar to our study findings. In study of Sahin A et al,7 study the mean age was 58.3 years which was more than this present study.Among the study participants, 79% were male and 21% were female.  Similar observations seen in study of  Anil Kumar sharma et al.8 while in study of sonal Singh et al 9male preponderance is more than females, cause of personal habits males were more prone to liver infection and diseases.Among all, 52% patients had history of alcohol, and all were male. Among 100 patients only 36 patients had past history of jaundice. Later serologic investigations for HBsAg., Anti HCV antibody showed 12% patients positive for HBS Ag and only 4% shows positive for anti HCV antibody. In study of Anil kumar Sharma et al,8 Thirty two patients had past history of jaundice, out of which 5 patients were reported positive for HBsAg and one patient for anti HCV antibody. Almost same findings were observed in comparable study.

 Total, 95 patients had anemia and only 5 patients had normal hemoglobin above 12 gm%. About 44 patients had severe anemia less than 8 gm%. Out of total, 41 patients had normocytic normochromic RBCs. Among the study participants, 32 patients had macrocytic, 23 patients were microcytic and 4% had dimorphic picture.  In our study majority patients had severe anemia, in contrast other studies E Halleys Kumar et al, 10 Anil Sharma et al,8 and G. Anbazhabag et al,11  In which Moderate anemia was more observed than other category. It was due to variety of dietary pattern and other factors affecting anemia level.

In current research, Alcoholic patient with UGI bleed had average HB of 7.08 g% and those without bleed had 9.48 g% and non-alcoholic patients with UGI bleed had average HB of 6.59 g% and those without bleed had 9.38 g%. There is statistically significant  difference between average level of haemoglobin in alcoholic with bleed and alcoholic without bleed. There is no statistically significant  difference between average level of RBC Count in nonalcoholic with bleed and nonalcoholic without bleed.  In research of Gundling F et al, 12total 417 patients with high alcohol consumption from Leipzig (n = 277) and Munich (n = 140) with an average alcohol consumption of 660 g/week about their behavior when faced with symptoms of acute upper gastrointestinal bleeding.71% or 51% said they would call the emergency physician if they were to vomit blood or black liquid. Only 32% would call emergency medical aid if they were to pass black stools, and only 25% of those surveyed thought urgent medical attention necessary in any of the three scenarios.In this study out of 100 patient, 7 patients had CPS class A,  47 patients had CPS class B, 46 patients had CPS class C.  while in study of sonalsingh et al, 9 there was 35.4% cases had Class C CPS  followed by 34.8% cases had Class A CPS Category. In contrast Study of Liangpunsakl S et al,13 majority patients had Class B CPS Category. The total count of WBCs ranges from 2750/mm3 to 21,000/mm3. Among the 100 patients Leukocytosis were observed in 16 patients. Leucopenia was present in 22% of patients. Although in study of Hegde et al 14 there was more leucocytosis seen in 38% patients followed by 25% cases had normal range of total leuocyte count. This difference was due to Higher and low rate of infection and immunity of individuals.In this study, thrombocytopenia was found in 84 patients among 100 cases is the study. Severe thrombocytopenia of < 50,000 cell / mm3 was found in patients with large spleen(average size-5.47 cms) and had a history of massive hematemesis. Thrombocytopenia was associated with history of at least an episode of hematemesis. While in study ofBibh Prasad Behera  et al, 15 68.12% cases had   thrombocytopenia, and in study of Anil Sharma et al [39]  total 74% cases had  thrombocytopenia.

Among the patients with severe thrombocytopenia 5 patients were found to have disseminated intravascular coagulation, later confirmed by the raised value of APTT and PT. Among the 100 patients 87 patients had prolonged prothrombin time. There was no correlation between the severity of jaundice and the prolongation of prothrombin time. Among the 87 patients with prolonged prothrombin time majority patients had history of at least one episode of hematemesis. Bleeding time was Prolonged in 19 patients who had platelet counts less than 1,00,000 / mm. In present study, 25 patients had high INR(>2.0) , 20 patients having INR ranges from 1.3-2.0 and only 1 patient had INR <1.3 among CPS class C patient. Thus high INR associated with severe disease( CPS class C). there      was no association found between  CPS score and   INR level.

The most common anemia in cirrhotics is normochromic normocytic anemia attributable to chronic inflammatory state. Microcytosis occur in patients with bleeding tendencies and macrocytosis occurs mostly in alcoholics.

Leucopenia occurs in a small fraction of patients and Leukocytosis occurs in patients with history of repeated paracentesis and peritonitis.

Thrombocytopenia is present in most of the cirrhosis patients and is associated with increased bleeding tendencies.

Increased prothrombin time and APTT due to decreased synthesis of clotting factors.

All the cirrhosis patients must be evaluated for hematological and hemostatic abnormalities. Early treatment to correct these co morbidities can decrease the mortality.

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