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ORIGINAL ARTICLE
Year : 2021  |  Volume : 14  |  Issue : 1  |  Page : 21-25  

Abnormalities of liver function tests in acute malaria with hepatic involvement: A case–control study in Eastern India


1 Department of Biochemistry, IPGME and R and SSKM Hospital, Kolkata, West Bengal, India
2 Department of Microbiology, ID and BG Hospital, Kolkata, West Bengal, India
3 Department of Microbiology, Purulia Government Medical College, Purulia, West Bengal, India
4 Department of Biochemistry, Burdwan Medical College and Hospital, Burdwan, West Bengal, India

Date of Submission05-Mar-2020
Date of Decision15-Jun-2020
Date of Acceptance07-Jul-2020
Date of Web Publication22-Jan-2021

Correspondence Address:
Kheya Mukherjee
39, Russa Road, South First Lane, Kolkata - 700 033, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_84_20

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  Abstract 


Context: Malaria is one of the major public health problems worldwide with increased morbidity and mortality. India has the fourth highest malaria burden in the world. Malaria parasite affects multiple organs of the body including liver, spleen, brain, kidney, blood vessels etc. Organ dysfunction predominantly seen in Plasmodium falciparum malaria, is not in Plasmodium vivax infections. Aims: The present study investigated the abnormalities of liver function test in acute cases of Plasmodium Falciparum infection. Settings and Design: A hospital-based case–control study conducted in a tertiary care center in West Bengal, India, for a duration of 7 months and included 53 acute falciparum malaria cases attending the outpatient department (OPD) and 47 age and sex matched patients, with complaints unrelated to the present study, as controls. Materials and Methods: Serum levels of bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), alkaline phosphatase, total protein and albumin were assayed using autoanalyzer (Konelab 60i autoanalyser). Statistical analysis used: SPSS software version 20 (IBM, New York, USA). Results: In this study serum bilirubin (total, conjugated and unconjugated ) SGOT, SGPT, alkaline phosphatase levels were highly significantly raised in cases with respect to controls. Levels of total protein, albumin and globulin in cases was not significantly different from the corresponding levels in controls. Conclusions: Hepatic function impairment in malaria is an important and potentially dangerous complication. Data from the present study can be useful for future research and also help in determining the prognosis and treatment.

Keywords: Hepatitis, liver function test, malaria, Plasmodium falciparum


How to cite this article:
Bhattacharjee D, Mukherjee K, Sarkar R, Chakraborti G, Das O. Abnormalities of liver function tests in acute malaria with hepatic involvement: A case–control study in Eastern India. Med J DY Patil Vidyapeeth 2021;14:21-5

How to cite this URL:
Bhattacharjee D, Mukherjee K, Sarkar R, Chakraborti G, Das O. Abnormalities of liver function tests in acute malaria with hepatic involvement: A case–control study in Eastern India. Med J DY Patil Vidyapeeth [serial online] 2021 [cited 2021 Feb 28];14:21-5. Available from: https://www.mjdrdypv.org/text.asp?2021/14/1/21/307691




  Introduction Top


Malaria parasites cause human disease by invasion and replication inside red blood cells. Plasmodium falciparum infection can lead to severe forms of malaria.[1],[2] Each year, malaria accounts for death of about 1 million children and causes debilitating illness in more than 500 million people.[3] Of the four species of Plasmodium malaria parasite causing the disease (falciparum, vivax, malaria, and ovale), falciparum is the foremost in causing organ dysfunction.[4] This is uncommon in Plasmodium vivax infections.[5] Malaria is prevalent in underdeveloped countries.[6] Severe malaria, caused by P. falciparum, is a complex multisystem disorder presenting with a range of clinical features[7] that vary according to the intensity of P. falciparum transmission.[8] The diagnosis of malaria is done by the presence of clinical signs and symptoms of fever (≥38°C), headache, myalgia and arthralgia, anemia, and hepatosplenomegaly.[9] Liver injury, a known feature of severe malaria, is only incidentally investigated in uncomplicated disease. We investigated liver function test abnormalities in early diagnosed patients with uncomplicated falciparum malaria.


  Subjects and Methods Top


The study was a hospital-based, case–control study conducted at a tertiary care center in West Bengal, India. The study was approved by the Institutional Ethical Committee of Institute of Postgraduate Medical Education And Research and SSKM Hospital, Kolkata (Memo No: IPGMERandR/IEC/2019/480 dated 08.07.2019). Before enrollment of the participants, informed consent was obtained from all the participants. The duration of the present study was 6 months and included 53 acute falciparum malaria cases attending the outpatient department (OPD) during the above-mentioned period. Similarly, 47 age- and sex-matched patients attending OPD, with complaints unrelated to the present study and characterized by the absence of any sign of malaria, served as controls. Patients attending the OPD and satisfying inclusion criteria were selected. It was assumed that they had attended OPD randomly. The inclusion criteria were cases attending the OPD on the 1st day of fever (buccal temperature >99.7°F) with the diagnosis of falciparum malaria confirmed by microscopic examination of Giemsa-stained peripheral smear. The exclusion criteria included participants who had acute or chronic infections, alcoholics, past history of hepatic problems such as chronic hepatitis, fatty liver, drug-induced hepatitis, and viral hepatitis. All the cases and controls were subjected to physical examination and proper documentation of present and past medical history.

5 ml of venous blood sample was collected aseptically from all the cases and controls after 12 h of fasting. All samples were coded and assayed in a blind fashion by an investigator who was unaware of the participant's clinical status. Biochemical parameters related to liver functions were assayed using fully automated biochemistry analyzer (EM 360, Tranasia) from serum obtained from blood samples following centrifugation (3500 rpm for 10 min). Lipemic, icteric, and hemolyzed samples were excluded from the biochemical analysis. Serum total and direct bilirubin were determined by Diazo method.[10],[11] Levels of bilirubin, serum glutamic oxaloacetic transaminase (SGOT), and serum glutamic pyruvate transaminase (SGPT) were estimated by modified IFCC method.[12],[13] Serum alkaline phosphatase was measured by p-nitrophenol phosphatase kinetic method.[14] Serum levels of total protein and albumin were estimated by biochemical end point methods, Biuret and Bromocresol Green, respectively.[15],[16]

Statistical analysis of data was performed using the SPSS software version 20 (IBM, New York, USA), and inferences were drawn. A value of P < 0.05 was considered to be statistically significant and P < 0.001 highly significant.


  Results Top


The authors drew blood from 53 cases and 47 controls and performed statistical analysis with their data [Table 1].
Table 1: Levels of serum parameters in cases and controls (as mean±standard deviation)

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  Discussion Top


In the present study, serum bilirubin (total, conjugated and unconjugated, all) levels were highly significantly raised in cases with respect to controls [Table 1] and [Figure 1]. The cause of jaundice in a patient of falciparum malaria is multifactorial. Multiple mechanisms have been proposed and include intravascular hemolysis due to destruction of parasitized red blood cells. Moreover, there is immune hemolysis involving the adherence of the circulating antigen-antibody complexes to the surface of the erythrocytes. The presence of malnutrition, shock, and disseminated intravascular coagulation can also lead to microangiopathic hemolysis. Hepatocyte dysfunction in malaria may also be because of alteration in vascular flow through the organ since parasitized red blood cells adhere to endothelial cells and cause obstruction to intrahepatic blood flow by blocking of sinusoids. There is evidence of focal hepatocyte necrosis, cholestasis, bile stasis, granulomatous lesion, or malarial nodules. The bile stasis is because of impairment of bilirubin transport due to endothelial blockage and disturbance of hepatocyte microvilli.[17] Liver is the primary organ involved in malarial complication by sporozoite form of falciparum malaria. It is well known that one of the key factors associated with inflammation-induced cholestasis is intrahepatic cytokine synthesis such as interleukin 1, 6, 8 and tumor necrosis factor α from Kuffer cells and other immunocompetent cells. Their increased local concentration affects hepatocyte function in falciparum malaria.[18] In addition, cytokines are also released by bile duct epithelial cells or cholangiocytes.[19] Inflammation-induced cholestasis results from the downregulation of hepatobiliary transporter gene expression systems for bile salts and nonbile salt biliary constituents (e.g., bilirubin) by inflammatory cytokines activated in falciparum malaria infection.[20] All these mechanism are implicated in the leakage of nonfunctional parenchymal transaminases and membranous alkaline phosphatase enzymes in circulation during the hepatic stage of the parasite's life cycle.[21]
Figure 1: Comparison of serum levels of liver function test parameters between cases and controls

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Mehta et al. in a study of 425 cases of falciparum malaria have reported jaundice in 2.58% cases.[22] In children, “hepatitis” was reported in 8% children with complicated falciparum malaria.[23] Seth et al. found jaundice in 7.7% cases of falciparum malaria.[24] Thus, the incidence of jaundice in falciparum malaria in the present study is in concordance with other workers.

SGOT and SGPT levels were increased significantly in cases in the present study when compared to the respective levels in controls [Table 1]. Kochar et al. found that many patients of malaria with jaundice had significantly higher levels of SGOT and SGPT and increased serum alkaline phosphatase.[25] In a similar study, the mean serum SGPT in a group of patients was 41 ± 16 IU/L as compared to 53.46 ± 31.24 IU/L in another group of patients.[26] The observation of linear elevation of SGOT and SGPT levels in patients with different bilirubin levels, hepatomegaly with low echogenicity in hepatic imaging, and increased gallbladder wall thickness on ultrasound examination. These were important evidence of widespread hepatocyte dysfunction in the absence of other causes of liver dysfunction.[27] In the present study, alkaline phosphatase levels were also increased significantly in cases in the present study when compared to the respective levels in controls [Table 1]. The causes might be attributed to hepatic dysfunction due to intrahepatic cholestasis because of reticuloendothelial blockage and disturbance of hepatic microvilli by sporozoites form of falciparum.[28],[29] Although the hepatocellular dysfunction is labeled as “malarial hepatitis,” biochemical and histological evidence of hepatocellular injury is often minimal in these patients.[30] In cases, higher level of unconjugated bilirubin is suggestive of the presence of extrahepatic hemolysis as the primary cause of jaundice. Increased liver enzymes, including alkaline phosphates on the other hand, refer to the structural and obstructive changes in the hepatobiliary system that occurs as infection progresses depicting the changing spectrum of clinical presentation and complication.

Half-life of albumin, the main component of total protein, is almost 1 month; so, changes in levels of albumin occur only after a few days of decreased synthesis in the liver when hepatic function is deranged. Hence, in the opinion of authors, levels of total protein, albumin, and globulin in cases were not significantly different from the corresponding levels in controls [Table 2] because these parameters were assayed in acute cases, on the 1st day of fever, and albumin levels did not get time to become lowered. Falciparum malaria leads the list among malaria-associated dreaded complications, coagulopathy being one of the major determinants. However, it is not evaluated in clinical practice. Royal Society of Tropical Medicine and Hygiene in 2000 reported the incidence of bleeding in falciparum malaria cases to be fewer than 10%. On the contrary, Kochar and Rawat[31] found bleeding manifestations to be as high as 25.52% in his observed cases. In the present study, 4 (7.5%) cases had mild bleeding symptoms in the form of nasal or gum bleeding. The platelet count, prothrombin time, activated partial thromboplastin time and D-dimer levels were significantly raised in these four cases compared to controls (P < 0.05). If untreated, it may lead to dreaded complications such as subconjunctival, retinal, or gastrointestinal bleeding.
Table 2: Level of significance (t-test results) for various parameters

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In acute malaria, hepatic dysfunction is reversible in all the patients developing malarial hepatopathy who respond favorably to antimalarial therapy and no residual effects have been documented in survivors.[32] Evidence exists that the underlying pathogenesis of liver injury in uncomplicated malaria is not related to hepatotoxicity of antimalarials or supportive agents like paracetamol. Induced inflammation per se may be a major driver of liver injury in controlled human malarial infection because parasite load in these cases is extremely low but sufficient to affect systemic inflammation and oxidative stress.[33] The awareness about the changing spectrum of severe malaria is of great importance to every level health-care provider as the study specifically advocates relevance in relation to potential clinical implications in uncomplicated disease, which constitutes the vast majority of clinical malaria cases in India. With any level of transmission, the possibility of falciparum malaria should always be suspected in a patient presenting with fever along with jaundice.[34]

This study has limitations that should be considered. Patients were taking a number of medications (other than hepatotoxic drugs) to control symptoms. However, these treatments are characteristic of patients with malaria and do not affect the serum parameter levels of the present study. Since the number of patients in the study group was not large, one should be cautious to extrapolate the present findings to any other population. Our present study was conducted in a tertiary care hospital. In our country, a huge section of the population visit district, subdivisional, and lower-tier hospitals for treatment. For this reason, our study results might not reflect the true picture of the entire population. Hence, a multicentric study on a larger population would be required to reveal a more robust statistics. Despite these limitations, we believe that our study results will help researchers in further works. Still, the authors believe that the problem of hepatic involvement in malaria should be further investigated, and other similar biological parameters should also be assessed. All the cases in the study had been diagnosed and treated promptly with antimalarial agents. Although the percentage of involved patients is low, hepatic function impairment is an important and well-known feature of severe malaria contributing to clinically significant complications such as hypoglycemia, metabolic acidosis, impaired drug metabolism, and finally organ failure.[35] Data from the present study can be useful for future research, but more work should be done to supplement the information derived from the present study to confirm the findings and help in determining the prognosis and treatment.


  Conclusion Top


Abnormalities in liver function are an important and potentially dangerous complication of malarial infection. Regular biochemical analysis of patients suffering from malaria is absolutely necessary especially in falciparum malaria cases undergoing treatment.

Acknowledgment

The authors express their acknowledgment to all the laboratory staff who have helped immensely in sample separation and estimation of various biochemical parameters.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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