Liver Function Biomarker in Patients on Anticoagulant Therapy at Usmanu Danfodiyo Unversity Teaching Hospital, Sokoto, Nigeria

Oduola Taofeeq; Bature Farida; Ndakotsu Mohammed Alhaji; Yakubu Abdulmumini; Dallatu Mohammed Kabiru; Mainasara Abdullahi Suleiman

doi:10.12691/ajcmr-3-3-1

American Journal of Clinical Medicine Research

Vol. 3, No. 3, 2015, pp 37-41. doi: 10.12691/ajcmr-3-3-1 | Research Article

OPEN ACCESS

PEER-REVIEWED

Liver Function Biomarker in Patients on Anticoagulant Therapy at Usmanu Danfodiyo Unversity Teaching Hospital, Sokoto, Nigeria

Oduola Taofeeq^1,, Bature Farida¹, Ndakotsu Mohammed Alhaji², Yakubu Abdulmumini³, Dallatu Mohammed Kabiru¹, Mainasara Abdullahi Suleiman⁴

¹Faculty of Medical Laboratory Sciences, Department of Chemical Pathology, Usmanu Danfodiyo University, Sokoto, Nigeria

²Department of Haematology and Blood Transfusion, College of Health Sciences, Usmanu Danfodio University, Sokoto, Nigeria

³Department of Medicine, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria

⁴Department of Chemical Pathology, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria

	Abstract
1.	Introduction
2.	Subjects and Methods
3.	Results
4.	Discussion
	Acknowledgement
	Conflict of Interest
	Source of Funding
	References

Abstract

Background: Drug induced hepatotoxicity have been known to be a common cause of liver failure. Drugs can either have a short-term or long-term adverse effect. The risk of side effect varies from drug to drug and from patient to patient. Most of the patients that need anticoagulant therapy are on the drugs for a long period, hence liver function may be impaired during the course of therapy this study was designed to investigate the effect of anticoagulant drugs on liver function. Methods: Thirty patients who have been on anticoagulant therapy between 1to 20 years (X5.8years), 30 patients that were yet to commence anticoagulant therapy but with the same clinical condition and 30 apparently healthy subjects were recruited for the study. Effect of duration of therapy on liver function were also assessed. Patients with background liver disease from any cause were excluded from the study. Five ml of blood were collected from each of the participant and liver function biomarkers estimated using standard techniques. Result: Therewere statistically significant increases (P<0.001) in values of aspartate transaminase (AST), alanine transaminase (ALT), and gammaglutamyl transferase(GGT) in patients on anticoagulant therapy and patients that were not on anticoagulant therapy when compared with control subjects but the increases were within the reference range. There was no significant difference (P>0.001) in alkaline phosphatase (ALP), total protein (TP), albumin (ALB), total bilirubin (TB) and direct bilirubin (DB) values between the patients and the control group. Conclusion: The slight elevation in liver function biomarkers assessed in patients on anticoagulant therapy could not be linked to the effect of the drug because patients with the same clinical conditions that were not on anticoagulant therapy showed the same elevation of the biomarkers. We did not observe effect of duration of therapy on liver function. The liver function biomarkers assessed were within the reference range in both the patients on therapy and those not on therapy. From our findings, we did not observe hepatotoxicity among our subjects.

Keywords: liver function, biomarkers, anticoagulant therapy, patients, adverse effect

Received April 08, 2015; Revised June 01, 2015; Accepted June 24, 2015

Cite this article:

Oduola Taofeeq, Bature Farida, Ndakotsu Mohammed Alhaji, Yakubu Abdulmumini, Dallatu Mohammed Kabiru, Mainasara Abdullahi Suleiman. Liver Function Biomarker in Patients on Anticoagulant Therapy at Usmanu Danfodiyo Unversity Teaching Hospital, Sokoto, Nigeria. American Journal of Clinical Medicine Research. Vol. 3, No. 3, 2015, pp 37-41. https://pubs.sciepub.com/ajcmr/3/3/1

Taofeeq, Oduola, et al. "Liver Function Biomarker in Patients on Anticoagulant Therapy at Usmanu Danfodiyo Unversity Teaching Hospital, Sokoto, Nigeria." American Journal of Clinical Medicine Research 3.3 (2015): 37-41.

Taofeeq, O. , Farida, B. , Alhaji, N. M. , Abdulmumini, Y. , Kabiru, D. M. , & Suleiman, M. A. (2015). Liver Function Biomarker in Patients on Anticoagulant Therapy at Usmanu Danfodiyo Unversity Teaching Hospital, Sokoto, Nigeria. American Journal of Clinical Medicine Research, 3(3), 37-41.

Taofeeq, Oduola, Bature Farida, Ndakotsu Mohammed Alhaji, Yakubu Abdulmumini, Dallatu Mohammed Kabiru, and Mainasara Abdullahi Suleiman. "Liver Function Biomarker in Patients on Anticoagulant Therapy at Usmanu Danfodiyo Unversity Teaching Hospital, Sokoto, Nigeria." American Journal of Clinical Medicine Research 3, no. 3 (2015): 37-41.

Import into BibTeX

Import into EndNote

Import into RefMan

Import into RefWorks

At a glance: Figures

View all figures

Prev Next

1. Introduction

The liver, located between the absorptive surface of the gastrointestinal tract and drugtargets throughout the body, is central to the metabolism of virtually every foreign substance. Most drugs and xenobiotics are lipophilic, enabling them to cross the membranes of intestinal cells. Drugs are rendered more hydrophilic by biochemical processes in the hepatocyte, yielding water-soluble products that are excreted in urine or bile ^[1]. This hepatic biotransformation involves oxidative pathways, primarily by way of the cytochrome P-450 enzyme system ^[2]. After further metabolic steps, which usually include conjugation to a glucuronide or a sulfate or glutathione, the hydrophilic product is exported into plasma or bile by transport proteins located on the hepatocyte membrane, and it is subsequently excreted by the kidney or the gastrointestinal tract ^{[3, 4, 5]}. Metabolism of drugs by this enzyme system leads sometimes to more active and toxic compounds which produce liver injury ^[6]. Liver disease is one of the acquired disorders that occur more frequently in several blood coagulation defects such as deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, congestive cardiac failure, artificial heart valve replacement and genetic or acquired hypercoagulability ^{[5, 7]}.

Anticoagulant drug is used to control and prevent thromboembolic disorders, the goal of anticoagulant therapy is to administer the lowest possible dose of anticoagulant to prevent clot formation or expansion. The required degree of anticoagulation continues to evolve as studies provide more information about the efficacy and safety of lower doses [7-13]^[7].

2. Subjects and Methods

2.1. Subjects

A total of 60 patients, 30 of them were on anticoagulant therapy (Warfarin) and the remaining 30 with the same clinical conditions that were yet to commence anticoagulant therapy were recruited for this study. The patients on anticoagulant therapy were also categorized into 4 depending on the duration of therapy; group 1 (1-5 years), group 2(6-10 years), group 3 (11-15 years) and group 4 (16-20 years). Thirty apparently healthy individuals of the same age and gender were recruited as controls.

Five ml of blood samples were collected from each subject into clean dry test-tubes by clean venipuncture. The samples were allowed to clot at room temperature and then centrifuged at 3000rpm for 5 minutes to obtain the sera. The separated clear sera were transferred into sterile plain bottles and were used for the assays of ALT and AST ^[14], GGT ^[15], TP ^[16], ALB ^[17], using Agape reagent kit (Agappe Diagnostics, Switzerland GmbH); ALP ^[16] TB and DB ^[16] using Randox reagent kit (Randox Laboratories Limited, UK) spectrophotometrically.

2.2. Ethics

This study was conducted in accordance with the Declaration of Helsinki. The study participants gave their informed consent and the research protocol was approved by the Ethics and Research Committee of Usmanu Danfodiyo University Teaching Hospital, Sokoto.

2.3. Statistics

The data obtained from this study were analyzed using the Sigma plot version 11.0 for the mean and standard deviation. Differences were considered significant when p<0.001.

3. Results

The mean ± standard deviation of serum AST (U/L) in controls, patients on therapy and patients not yet on therapy were 15.5 ± 4.86, 28.0 ± 17.01 and 33.0 ± 12.96; and ALT (U/L)10.45 ± 4.15, 24.27 ±16.58 and 23.01 ± 11.36 respectively. The mean ± standard deviation of serum GGT (U/L) in controls, patients on therapy and patients not yet on therapy was found to be 10.42 ± 3.36, 31.70 ±11.63 and 25.40 ± 11.83 respectively, (Figure 1).

Download as

Veiw figureFigures index

Figure 1. Bar chart showing values of AST, ALT and GGT in controls, patients on therapy and patients not on therapy

The mean ± standard deviation of serum ALP (U/L) in controls, patients on therapy and patients not yet on therapy were 126.07 ± 31.67,144.47 ± 54.08 and 137.43 ± 55.99 respectively, (Figure 2).

The mean ± standard deviation of serum total bilirubin (mg%) in controls, patients on therapy and patients not yet on therapy were found to be 0.40 ± 0.27, 0.63 ± 0.35 and 0.99 ± 0.68 and conjugated bilirubin (mg%) 0.15 ± 0.06, 0.22 ± 0.11 and 0.38 ± 0.33 respectively, (Figure 3).

Download as

Veiw figureFigures index

Figure 2. Bar chart showing values of ALP in controls, patients on therapy and patients not on therapy

Download as

Veiw figureFigures index

Figure 3. Bar chart showing values of total bilirubin and conjugated bilirubin in controls, patients on therapy and patients not on therapy

The mean ± standard deviation of serum total protein (mg/dl) in controls, patients on therapy and patients not yet on therapy were 6.61 ± 0.78,6.78 ± 0.84 and 6.46 ± 1.24 and albumin (mg/dl)4.15 ± 0.60,4.33 ± 1.07 and 3.98 ± 0.84 respectively, (Figure 4).

Download as

Veiw figureFigures index

Figure 4. Bar chart showing values of total protein and albumin in controls, patients on therapy and patients not on therapy

TABLE 1. Effect of duration in therapy on liver biomarkers

Download as

Veiw tableTables index

NEW
View table in a new window

4. Discussion

Hepatotoxicity have been reported to be a rare complication of coumarin anticoagulants ^[18], except for bleeding complications, relevant adverse effects of coumarin anticoagulants are comparatively rare considering the widespread use of these substances ^[19].

From the present study, the values obtained for AST and ALT in patients on drug and those that were not on drug were significantly higher (p<0.001) than values obtained for the control groups, however there was no significant difference (p=0.130) in the values obtained for patients on drug and those not on drug. Nipun et al ^[20] has previously described elevated levels of transaminases in patients on anticoagulant therapy;association of anticoagulants with asymptomatic elevation of serum transaminases, clinically significant hepatitis, and fatal liver failure have also been reported ^{[21, 22, 23, 24]}. Levels of transaminases, ALT and (AST) are sensitive indicators of drug-induced hepatocellular injury. Elevations in ALT and AST can occur from conditions other than liver injury, but ALT is relatively more specific because it is synthesized primarily by the liver ^[20]. In this study, we could not associate increased level of transaminases to drug intake because our observations in both categories of patients were similar. The elevations in AST and ALT in patients on drug could also be due to their clinical state since this elevation was also observed in patients not on drug. The specific mechanism of transaminase elevation after anticoagulant use has not been identified ^[20], but coumarin drugs can be linked with direct damage of hepatocytes by reactive metabolites, which may result in augmented antigenicity and consequent immunoallergic reaction. It can also be associated with high-energy reactions involving cytochrome P-450 enzymes, causing decline of adenosine triphosphate levels, loss of ionic gradients, cell swelling, and rupture ^[25].

The values obtained for GGT in patients on drug and those not on drug were significantly higher (P<0.001) than values obtained for the control groups. Also the GGT values of patients on drug were significantly higher (P<0.001) than those not on drug. These elevations may be due to anticoagulant therapy because anticoagulant drugs are known to be enzyme-inducing ^[20].

Although the values obtained for serum ALP in patients on drug and those not on drug were higher than that of the control group, the values were not statistically significant (p= 0.338), hencewe did not observe cholestatic reaction to anticoagulant drug in our subjects, however a case of cholestasis following exposure to warfarin therapy has been reported ^[26].

The values obtained for total protein and albumin in patients on drug and those not on drug were not statistically different from the control groups. This observation might be that the drug has no adverse effect on synthetic function of the liver. The values obtained for total and direct bilirubin in patients on drug and those not on drug were higher than the control groups, although the increases were not statistically significant. The values obtained for all the groups were within the reference range.

In conclusion, our study did not reveal any adverse effect of anticoagulant therapy on liver function and we did not observe association between duration of exposure to therapy and liver function. Our observations may be due to small sample size of our subjects, it is recommended that this study is conducted on large number of patients.

Acknowledgement

The authors are grateful to all our study participants.

Conflict of Interest

There was no conflict of interest in any form.

Source of Funding

The authors did not receive financial support from any source.

References

[1]	Weinshilboum, R, Inheritance and drug response. N Engl J Med, 348:529-37, 2003.
	In article	View Article PubMed

[2]	Guengerich, F.P. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol, 14:611-50, 2001.
	In article	View Article PubMed

[3]	Lee, W.M. Drug Induced Hepatotoxicity.N Eng J Med, 349: 474-485, 2003.
	In article	View Article PubMed

[4]	Bishop,M.L, Fody,E.B, Schoeff, L.E. The liver function In: Clinical chemistry, Techniques, Principle and Correlations, Lippincott Williams & Wilkins, Philadelphia, USA, 6thed.516-529, 2010.
	In article

[5]	Parveen, K., Clark, M. Gastrointestinal diseases:In:Clinical Medicine, 6thed. P: 318-384, 2006.
	In article

[6]	Remmer, H. The role of liver in drug metabolism. American J of Medicine. 49: 617-629, 1970.
	In article	View Article

[7]	Rang, H., P., Dale, M., M., Ritter, J., M., Flower, R., J. Homeostasis and Thrombosis. In: Pharmacology 6thed. 331-344, 2007.
	In article

[8]	Hirsh, J,Dalen, J.E, Deykin, D, Poller L, Bussey H. Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest, 108(4 Suppl):231S-46S, 1995.
	In article	View Article PubMed

[9]	Stein, P.D,, Alpert, J.S., Copeland, J., Dalen J.E., Goldman, S., Turpie, A.G. Antithrombotic therapy in patients with mechanical and biologic prosthetic heart valves. Chest, 108(4 Suppl):371S-9S[Published erratum in Chest 1996;109:592], 1995.
	In article

[10]	Levine, H.J, Pauker S.G, Eckman M.H. Antithrombotic therapy in valvular heart disease. Chest, 108(4 Suppl):360S-70S, 1995.
	In article	View Article PubMed

[11]	Schulman, S., Granqvist S., Holmstrom M., Carlsson A., Lindmarker P., Nicol P, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med, 336: 393-8, 1997.
	In article	View Article PubMed

[12]	Laupacis, A., Albers G., Dalen J, Dunn M, Feinberg W, Jacobson A. Antithrombotic therapy in atrial fibrillation. Chest, 108(4 Suppl): 352S-9S, 1995.
	In article	View Article PubMed

[13]	Levine M.N, Hirsh J, Gent M, Turpie AG, Weitz J, Ginsberg J, et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost, 74: 606-11, 1995.
	In article	PubMed

[14]	Reitman S.S., Frankel S. A coulorimetric method for the determination serum transaminase activity. Amer. J. Clin. Path., 28: 56-68, 1957.
	In article	PubMed

[15]	Recommendation of German Society of Clinical Chemistry (Rec. Gscc). Optimised standard colorimetric methods. Journal of Clinical Chemistry and Clinical Biochemistry 10: 182, 1972.
	In article

[16]	Tietz N.W. Clinical Guide on Laboratory Tests. 3rd ed. Philadelphia Pa WB Saunders Company, 286, 1995.
	In article

[17]	Henry F.R, Canon D.C, Winkelman J.W. Clinical Chemistry, Principles and Techniques, 2nd ed. Harper and Row Publishers, New York, 1974.
	In article

[18]	18. Höhler T, Schnütgen M, Helmreich-Becker I, Mayet W.J, Mayer Z.U.M, Büschenfelde K.H.Drug-induced hepatitis: a rare complication of oral anticoagulants. J Hepatol. Sep; 21(3): 447-9, 1994.
	In article

[19]	Ehrenforth S, Schenk J.F, Scharrer I.Liver damage induced by coumarin anticoagulants. Semin Thromb Hemost. 25(1): 79-83, 1999.
	In article	View Article PubMed

[20]	Nipun A., Samuel, Z. G.Anticoagulants and transaminases elevation. Circulation; 113:e698-e702, 2006.
	In article	View Article PubMed

[21]	Bamanikar A, Hiremath S. Hepatotoxic reaction to warfarin in a recovering hepatitis patient with hypoalbuminemia. J Assoc Physicians India, 50: 1456, 2002.
	In article	PubMed

[22]	Chaudhry S, Oelsner D. Cholestatic reaction to warfarin. Am J Gastroenterol. 90: 853, 1995.
	In article	PubMed

[23]	Bux-Gewehr I, Zotz R.B, Scharf R.E. Phenprocoumon-induced hepatitis in a patient with a combined hereditary hemostatic disorder. Thromb Haemost. 83: 799–800, 2000.
	In article	PubMed

[24]	Hinrichsen H, Luttges J, Kloppel G, Folsch UR, Schmidt WE. Idiosyncratic drug allergic phenprocoumon-induced hepatitis with subacute liver failure initially misdiagnosed as autoimmune hepatitis. Scand J Gastroenterol. 36: 780–783, 2001.
	In article	View Article PubMed

[25]	Schimanski C.C, Burg J, Mohler M, Hohler T, Kanzler S, Otto G, Galle P.R, Lohse A.W. Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure. J Hepatol,41: 67-74, 2004.
	In article	View Article PubMed

[26]	Adler E, Benjamin SB, Zimmerman HJ.Cholestatic hepatic injury related to warfarin exposure. Arch Intern Med.146(9):1837-9, 1986.
	In article	View Article PubMed