Molecular Enzymology and Drug Targets

Keywords

Non-Steroidal anti-inflammatory drugs (NSAIDS); Hepatotoxicity; Non traumatic musculoskeletal painful disorders; Liver Enzymes; Serum Bilirubin

INTRODUCTION

Nonsteroidal anti-inflammatory drugs (NSAIDs) which also includes selective Cyclooxygenase 2 inhibitors, have antiinflammatory and analgesic and some antipyretic properties. NSAIDs are more commonly used for the acute, recurring or chronic non traumatic musculoskeletal condition such as backache, arthritis, osteoarthritis, myalgias and other progressive non traumatic disorders [1,2]. NSAIDs are most frequently used by physician worldwide and especially by orthopedic surgeons and are even easily available as over-the-counter-analgesic in India. Non-steroidal anti-inflammatory drugs (NSAIDs) along with antimicrobial medications are most widely used and nevertheless are the most frequent causes of drug-induced liver injury (DILI) [1-3]. However, the present literature roughly states that 10% of total drug-induced hepatotoxicity is NSAIDs related, which is enormous considering the already high cost of medical treatment. The current policy concerning the use of NSAIDs recommends that patients take “the lowest effective dose for the shortest possible duration” needed to control pain symptoms, which may not be possible every time due to the nature of pain and its chronicity.

Mechanism of action of NSAIDs

All NSAIDs acts by inhibiting COX, an enzyme which converts arachidonic acid to prostaglandins, thereby mediating pain, inflammation, and fever. In this whole process, prostaglandin H2 gets converted to five primary prostaglandins, including thromboxane A2 (which is responsible for platelet aggregation and blood clot formation) in platelets and prostacyclin (a vasodilator inhibiting platelet aggregation) in the endothelium [4]. Two COX isoenzymes (COX-1 and COX-2) are commonly recognized. Generally, COX-1 is constitutively expressed and is involved in gastro protection from stomach acid and in thromboxane formation by platelets. COX-2 is inducible by inflammatory mediators in a wide range of tissues and has been associated with inflammation; however, it may also be constitutively expressed, whereby contributing to renal physiology, reproductive function, bone resorption, and neurotransmission [4]. In this particular setting evidence indicates that naproxen is associated with a lower thrombotic risk than coxibs, and that ibuprofen has a good thrombotic safety profile for daily doses of up to 1200 mg [5]. The efficiency of drug removal by the liver relies on hepatic blood flow, hepatic enzyme capacity, and plasma protein binding. Cirrhosis affects all these processes and may also lead to formation of portosystemic shunts by which a drug can circumnavigate hepatic elimination [2-4]. Advanced liver disease and cirrhosis alter the metabolism and effects of many drugs through a variety of mechanisms, including changes in pharmacokinetic behavior, altered accumulation of free drug in plasma, and end-organ response.

Mechanism of hepatotoxicity due to NSAIDs

The mechanism blamed for adverse liver effects by NSAIDs is thought to be due to NSAIDs induced Idiosyncratic liver damage and change in metabolism of liver which might be due to enterohepatic recirculation of NSAIDs. The relative damage from each type of access remains largely unknown. The toxicity of NSAIDs increases due to concomitant use of other hepatotoxic drugs. Metabolic aberration may occur as genetic polymorphism and difficult to assess and causes significant underreporting [6-10].

Materials and Methods

We prospectively reviewed and evaluated 2897 patients who were prescribed NSAIDs and who were treated in the orthopedic facility for non-traumatic musculoskeletal painful disorders between 2009 and 2014. Demographic profile of all the patients were recorded which included age, gender, addictions, and co morbidity. Type of NSAIDs, indications and duration of treatment were noted. Adverse drug reactions (ADRs) related to gastrointestinal effects and hepatotoxicity related to different liver enzymes were recorded. We have included all the patients with age 20 and above who fulfilled our inclusion criteria. For all patients a detailed history was obtained regarding antecedents upper or lower gastrointestinal or biliary disease, abnormal kidney and liver function test, previous chronic alcohol intake. A positive history of liver or kidney disorder in patient or family was excluded from the study. Only those patients who had abstained from alcohol and paracetamol (acetaminophen) 12 weeks prior to the start of NSAIDs therapy were included in the study. This was done to reduce drug-drug interactions and considering potential of acetaminophen and alcohol in contributing hepatotoxicity. In all the patients oral medications were used and at no time injectable NSAIDs were used. All the patients received gastro protective Proton Pump Inhibitors (PPIs) in appropriate dosage along with prescription of NSAIDs. Gastrointestinal Adverse Drug Reactions (ADRs) for NSAIDs were classified into mild, moderate and severe gastrointestinal ADRs. Liver function tests was done before the start of therapy, at 3 weeks, 6 weeks and the effect of different NSAIDs on liver enzymes were evaluated. Abnormal Liver function tests demanded another test at appropriate time or at 3 week interval and 3 months and thereafter whenever necessary. Liver function tests which were done include serum proteins, albumin, globulin, serum bilirubin. Serum Liver Enzyme assay include Serum Aspartate Transaminases (AST–SGOT), Serum Alanine Transaminase (ALT–SGPT), Lactate Dehydrogenase, 5?Nucleotidase (done whenever necessary), Alkaline Phosphatase, Cholinesterase (not routinely done due to cost constraints) and γ Glutamyl Transpeptidase (γ GT). Effect of NSAIDs on immunoglobulins was also noted.

Results

Total 2897 patients were analyzed in the study. The male preponderance 1477 (50.98%) was noted (Table 1). All the patients were divided into various age groups and maximum patients were in 40-50 years age group i.e., 768 and the lowest were in more than 70 years age group i.e. 151 (Table 2). The patients were given different types of NSAIDs via oral route according to the duration and intensity of pain and choice given to patients after counseling regarding the efficacy and probable adverse effects (Diclofenac, Ibuprofen, Aceclofenac, Etoricoxib, Indomethacin and Nimesulide) and out of this most patients were given oral Diclofenac sodium i.e., 1152 and the least no. of patients got oral Indomethacin (47) (Table 3). Oral Diclofenac sodium showed raised bilirubin in 32 patients (1152/32-2.77%) Oral Indomethacin showed raised bilirubin in 13 patients (47/13–27.65%), Nimesulide showed raised bilirubin in 13 patients (68/13–19.11%), Aceclofenac showed raised serum bilirubin in 12 patients (365/123.29%), Oral Ibuprofen showed raised bilirubin in 7 patients (1117/7–0.62%) and oral etoricoxib seemed to have no effect on serum bilirubin concentration in our study. There was no significant raise in mean values of liver enzymes due to different NSAIDs at 3 weeks but diclofenac group patients demonstrated more rise in liver enzymes (Mean Lactate Dehydrogenase-158.65, Serum Alanine Transaminase-52.76, Serum Aspartate Transaminases-27.9, Alkaline Phosphatase-175.23, γ Glutamyl Transpeptidase-58.65). We had no fatality due to hepatotoxicity or drug induced liver Injury (DILI) in any patient, because in patients who had a raise of enzyme or deranged liver function test the culprit medications were withdrawn and patient case chart was listed as CLASS WARNING for particular NSAIDs. All our patients during follow up had complete restoration of normal liver function and complete restoration of liver enzyme at 6 weeks.

Discussion

The potential for hepatoxicity due to NSAIDs is a major challenge to the medical fraternity and hepatology specialists and there are many studies in literature showing hepatotoxicity caused by NSAIDs in range is from 1 to 9 per 10,000 patients [10,11]. Whereas in our study total there were 77 patients out of 2897 who showed raised bilirubin levels. In our study group the patients who were administered oral diclofenac were more affected with raised liver enzymes. However, The Indomethacin group showed a higher percentage of raise in serum bilirubin in our studies. The literature revealed that diclofenac sodium causes increased hepatotoxicity [12,13]. In a study on effects of NSAIDs on liver enzymes showed Hypertransaminasemia >3 × ULN in 3% of patients and alanine transaminase (ALT) higher than 10 × ULN in 0.5% of cases [13], whereas our study showed raised ALT and AST levels in 10.35% of patients (Table 4). The risk of acute hepatotoxicity due to cytolytic, cholestatic and combined pattern associated with nimesulide was estimated in a study and found that nimesulide had a higher liver damage and higher hospitalization rate than with other NSAIDs [14] and in contrast we found that there was no significant raise in liver function tests and liver enzymes due to Nimesulide. This might be due to lower sample size of nimesulide.

Patients who were administered Ibuprofen showed raised mean levels of liver function tests and liver enzymes at 3 weeks [Lactate Dehydrogenase: 180.25, Serum Alanine Transaminase (ALT) SGPT: 56.28, Serum Aspartate Transaminases (AST) SGOT: 47.12, Alkaline Phosphatase: 149.35, γ Glutamyl Transpeptidase (γ GT): 64.23, Serum Bilirubin: 0.95, Serum Protein: 7.23 and in literature a large number of studies have been published showing association of ibuprofen with hepatotoxicity [15,16]. It has also been suggested that ibuprofen may increase the risk of liver injury when administered to patients with chronic hepatitis C. An ibuprofen associated increase of transaminases >5 × UNL was recently reported in three patients with chronic hepatitis C [17]. We found that etoricoxib had negligible effect on liver functions and the literature reported that hepatotoxicity is very less common and incidence is 1 in 10,000 patients of all coxibs [18]. A rise of transaminase level was also reported and associated with rofecoxib (2%) and with higher doses of lumiracoxib (3%) [19]. In our study etoricoxib was used in which 6.7% patients showed raised transaminases whereas in a study the reported patients were only 1% who were treated with etoricoxib for 1 year [10,20,21]. A study by Masubuchi et al in 1998 on structural requirements for the hepatotoxicity of nonsteroidal anti-inflammatory drugs in isolated rat hepatocytes showed significant LDH leakage [22] and in our study the LDH was raised after 3 weeks which was not significant. Advanced age in general has more likelihood for adverse hepatic function.

Summary and Conclusions

All the NSAIDs had been associated with some form of liver toxicity, etoricoxib being the safest in the present study, followed by Ibuprofen which showed to have excellent safety profile. The liver toxicity is less often than the gastrointestinal adverse effects, but might have significant morbidity if overlooked. The usual underreporting is due to lack of understanding and physicians probable associate the liver effects more commonly with alcohol or with acetaminophen. Because of low frequency of liver toxicity it is virtually difficult to study the risk factors and etiology of the liver toxicity purely due to NSAIDs. Increased awareness and recognition will lead to better patient treatment and subsequent outcome in a timely intervention pattern. Timely intervention would lead to reversal of liver toxicity, considering the enormous capacity of liver to be regenerative. The risk factors cannot be termed of true risk factors due to NSAIDs alone as they do not represent the only population receiving NSAIDs and further studies and large sample size of each of subgroups of NSAIDs are required to establish toxicity on liver purely due to NSAIDs use. NSAIDs induced liver toxicity must be kept in mind by physicians in patients with isolated impaired function test in otherwise health individual who is on NSAIDs; Under reporting is common because many of the patients may not disclose the fact to their physicians as it is not prescription drug. Prompt recognition and withdrawal of culprit drug reduces the liver risk and avoids chronic consequences.

Conflicts of Interest

None declared

Tables at a glance

Table 1 Table 2 Table 3 Table 4

References

1. Orudis® (ketoprofen) Philadelphia, PA: Wyeth Pharmaceuticals Inc; 2007.
2. Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, et al. (2005) Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.Gastroenterology 129: 512-521.
3. Björnsson E (2010) Review article: drug-induced liver injury in clinical practice.Aliment PharmacolTher 32: 3-13.
4. Hussaini SH, Farrington EA (2007) Idiosyncratic drug-induced liver injury: an overview.Expert Opin Drug Saf 6: 673-684.
5. Davies NM, Saleh JY, Skjodt NM (2000) Detection and prevention of NSAID-induced enteropathy.J Pharm PharmSci 3: 137-155.
6. Verbeeck RK (2008) Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.Eur J ClinPharmacol 64: 1147-1161.
7. Tegeder I, Lötsch J, Geisslinger G (1999) Pharmacokinetics of opioids in liver disease.ClinPharmacokinet 37: 17-40.
8. O’connor N, Dargan PI, Jones AL (2003) Hepatocellular damage from non-steroidal anti-inflammatory drugs. Q J Med 96:787-791 doi:10.1093/qjmed/hcg138.
9. Rostom A, Goldkind L, Laine L (2005) Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients.ClinGastroenterolHepatol 3: 489-498.
10. García Rodríguez LA, Pérez Gutthann S, Walker AM, Lueck L (1992) The role of non-steroidal anti-inflammatory drugs in acute liver injury.BMJ 305: 865-868.
11. de Abajo FJ, Montero D, Madurga M, García Rodríguez LA (2004) Acute and clinically relevant drug-induced liver injury: a population based case-control study.Br J ClinPharmacol 58: 71-80.
12. Laine L, Goldkind L, Curtis SP, Connors LG, Yanqiong Z, et al. (2009) How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial.Am J Gastroenterol 104: 356-362.
13. Traversa G, Bianchi C, Da Cas R, Abraha I, Menniti-Ippolito F, et al. (2003) Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs.BMJ 327: 18-22.
14. Alam I, Ferrell LD, Bass NM (1996) Vanishing bile duct syndrome temporally associated with ibuprofen use.Am J Gastroenterol 91: 1626-1630.
15. Laurent S, Rahier J, Geubel AP, Lerut J, Horsmans Y (2000) Subfulminant hepatitis requiring liver transplantation following ibuprofen overdose.Liver 20: 93-94.
16. Riley TR 3rd, Smith JP (1998) Ibuprofen-induced hepatotoxicity in patients with chronic hepatitis C: a case series.Am J Gastroenterol 93: 1563-1565.
17. Boelsterli UA (2002) Mechanisms of NSAID-induced hepatotoxicity: focus on nimesulide.Drug Saf 25: 633-648.
18. Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M,et al. (2004) Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet364:665-674.
19. Baraf HS, Fuentealba C, Greenwald M, Brzezicki J, O'Brien K, et al. (2007)Gastrointestinal side effects of etoricoxib in patients with osteoarthritis: results of the Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) trial. J Rheumatol34: 408-420
20. Masubuchi Y, Saito H, Horie T (1998) Structural requirements for the hepatotoxicity of nonsteroidal anti-inflammatory drugs in isolated rat hepatocytes.J PharmacolExpTher 287: 208-213.