effects of amiodarone, thyroid hormones and cyp2c9 and vkorc1 polymorphisms on warfarin metabolism:...

DOI:10.4158/EP13093.RA Endocrine Practice © 2013

ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. DOI:10.4158/EP13093.RA © 2013 AACE. Review Article EP13093.RA EFFECTS OF AMIODARONE, THYROID HORMONES AND CYP2C9 AND VKORC1

POLYMORPHISMS ON WARFARIN METABOLISM: A REVIEW OF THE LITERATURE

Running Title: AIT and Warfarin

Luca Tomisti, MD1; Marzia Del Re, PhD2; Luigi Bartalena, MD3; Maria L Tanda, MD3; Angelo Pucci, MD4; Franco Pambianco, MD4; Romano Danesi, MD, PhD2; Lewis E. Braverman, MD5;

Enio Martino, MD1 and Fausto Bogazzi, MD, PhD1

From the 1Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Pisa, Pisa, Italy, 2Division of Pharmacology, Department of Internal Medicine, University of Pisa, Pisa, Italy, 3Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy, 4Cardiology Unit, Hospital of Carrara, Carrara, Italy, and 5Department of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts. Address correspondence to Fausto Bogazzi, MD, PhD, Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Pisa, Ospedale Cisanello, Via Paradisa, 2, 56124 Pisa, Italy E-mail: [email protected]


ABSTRACT

Objective: To review the literature regarding the interaction between amiodarone therapy,

thyroid hormones and warfarin metabolism.

Methods: A 73-year-old man with type 2 amiodarone induced thyrotoxicosis (AIT) who

experienced a severe rise in the International Normalized Ratio (INR) values after starting

warfarin therapy, owing to an unusual combination of an excess of thyroid hormones,

amiodarone therapy and a genetic abnormality in warfarin metabolism.

Results: The genetic analysis showed that the patient was CYP2C9*2 wild-type,

CYP2C9*3/*3 homozygous mutant and VKORC1*3/*3 homozygous mutant. Review of the

literature revealed that booth mutations can independently affect warfarin metabolism. In

addition amiodarone therapy and the presence of thyrotoxicosis, per se, can affect warfarin

metabolism and reduce the warfarin dose needed to maintain the INR in the therapeutic range.

The association of the two genetic polymorphisms in a patient with AIT is extremely rare and

strongly impairs warfarin metabolism, exposing the patient to a high risk of overtreatment.

Conclusions: In patients with AIT, warfarin therapy should be gradually introduced,

starting with a very low dose, because of the significant risk of a warfarin overtreatment.

However, whether the genetic analysis of CYP2C9 and VKORC1 polymorphisms should be

routinely performed in AIT patients remains conjectural.

Key words: Amiodarone; Thyroid; Warfarin; INR control; VKORC1; CYP2C9


Abbreviations:

AIT = amiodarone-induced thyrotoxicosis; APTT = Activated Partial Thromboplastin Time;

CYP2C9 = cytochrome P450, family 2, subfamily C, polypeptide 9 gene; DEA = desetyl-

amiodarone; EF = ejection fraction; FT3 = free-triiodothyronine; FT4 = free-thyroxine; INR =

International Normalized Ratio; PCR = Polymerase Chain Reaction; PT = Prothrombin Time;

VKORC1 = vitamin K epoxide reductase subunit 1 gene


INTRODUCTION

Warfarin is the most used anticoagulant agent for the primary and secondary prevention of

thromboembolic disease and for the prevention of systemic embolism in patients with prosthetic

heart valves or atrial fibrillation (1).

A major problem in patients treated with warfarin is the large inter individual variation in the

dose required for an adequate anticoagulant effect. The warfarin dose can be affected by several

factors, including dietary, clinical and demographic factors, drugs and several pathophysiological

conditions (2).

Amiodarone is one of the most potent antiarrhythmic drugs, used in the prevention and treatment

of ventricular and supraventricular arrhythmias. This agent inhibits the plasma clearance of

warfarin, thereby increasing its anticoagulant action. This effect seems to be related to a

pharmacokinetic interaction of amiodarone with hepatic warfarin metabolism, mediated by the

competitive inhibition of cytochrome P450, family 2, subfamily C, polypeptide 9 gene

(CYP2C9) and the vitamin K epoxide reductase subunit 1 gene (VKORC1) (3). In addition,

about 10-15% of patients receiving amiodarone treatment develop thyrotoxicosis (amiodarone-

induced thyrotoxicosis, AIT) or hypothyroidism that can strengthen or reduce warfarin action,

respectively. AIT represents a complex diagnostic and therapeutic problem, and may require,

depending on the pathogenesis, treatment with thionamides, glucocorticoids or thyroidectomy (4-

7).

Recently, several studies have shown that genetic factors play a relevant role in the

individual variability of the warfarin dose. In particular, several single nucleotide polymorphisms

of CYP2C9 and VKORC1 genes can influence the warfarin dose requirement (8). For this

reason, in 2007, the Food and Drug Administration added pharmacogenetic information to the


warfarin product label.

We herein report a patient in whom the concomitant presence of rare genetic abnormalities,

amiodarone treatment and thyrotoxicosis interacted to cause a marked increase in the INR values

and the risk of bleeding.


METHODS

DNA sequencing and analysis

Genomic DNA was extracted from EDTA blood samples using QIAamp® DNA Blood

Mini Kit (Qiagen) and quantified with a NanoDrop ND-1000 spectrophotometer (Thermo

Scientific). The DNA samples were analyzed by Real Time Polymerase Chain Reaction (PCR)

assays C__25625805_10, C__27104892_10, and C__30429388_10 for genotyping the

CYP2C9*2, CYP2C9*3 and VKORC1*3 polymorphisms, respectively. The analysis was

performed using the 7300 Real Time PCR system (Applied Biosystems). Amplification was

performed with 1,250 µl Assay mix 20X (Applied Biosystems), 12,5 µl PCR Master Mix 2X and

20 ng genomic DNA in a total volume of 25 µl. Before the amplification, a pre-read run was

performed at 60°C for 1 min. The amplification protocol was an initial step at 95°C for 10 min

followed by the amplification step at 92°C for 15 sec and 60°C for 60 sec for 50 cycles.

CASE REPORT

A 73-yr-old Caucasian man was referred to the Department of Endocrinology of the

University of Pisa because of severe type 2 AIT. At the ages of 40 and 43, the patient had two

lateral myocardial infarctions treated with triple coronary artery bypass grafting. At the age of 69

he was treated with the implantation of a single-chamber defibrillator in primary prevention

because of dilated cardiomyopathy with severe left ventricular dysfunction. Over the last two

years he experienced recurrent episodes of ventricular tachycardia treated with beta-blockers

(bisoprolol 1.25 mg/day) and amiodarone (400 mg per day) and, subsequently, with

radiofrequency catheter ablation. One month before admission, the patients experienced a new

episode of ventricular tachycardia treated with amiodarone i.v., beta-blockers and mexiletine.

Echocardiography showed the presence of dilated cardiomyopathy with severe impairment of


left ventricular function (EF 25%) due to anterior septal akinesia and hypokinesis of the

remaining segments; no signs of right ventricular dysfunction were found. Thyroid function tests

revealed thyrotoxicosis. The clinical and biochemical features of the patient on admission are

summarized in Table 1.

Diagnosis of type 2 AIT was made on the basis of a low thyroid radioactive iodine uptake

and the marked decrease in thyroid blood flow on echo color flow doppler, and prednisone

treatment was started (initial dose, 40 mg per day po) while amiodarone therapy (400 mg/day)

was continued. In addition, the patient was also treated with rosuvastatin (5 mg/day) and low-

dose cardioaspirin (100 mg/day) therapy; no other drugs inhibiting CYP2C9 action were

admistered during the study period.

After 10 days, serum free-thyroxine (FT4) and serum free-triiodothyronine (FT3) decreased

from 52.5 to 39.5 pg/ml and from 6.0 to 4.5 pg/ml, respectively (normal values, FT4 7-17 pg/ml,

FT3 2.7-5.7 pg/ml). Serum thyroid hormone concentrations increased again when the

glucocorticoid daily dose was tapered to 20 mg/day. After four days, indeed, FT4 and FT3 raised

to 62.3 pg/ml e 8.35 pg/ml, respectively. The physical status of the patient and his cardiac

condition worsened and we considered the possibility of performing a total thyroidectomy.

A pre-operative echocardiography showed the presence of a large, stalked and floating,

apical left ventricular thrombus. The patient was transferred on to the Cardiac Intensive Care

Unit where high dose i.v. heparin therapy was started. After one day, because of a macular vision

loss, a cerebral CT scan (without any contrast medium injection) was performed, revealing an

ischemic lesion in the occipital and back trigonal left region. Echocardiography, performed after

5 days of heparin therapy, showed the disappearance of the left ventricular thrombus. Warfarin

therapy (5 mg/day) was added, monitoring the INR values daily (basal INR 1.02). After 3 days,


INR markedly increased to 10.7. This increase persisted 24 hours after withdrawal of warfarin,

and required phitomenadione (20 mg po) and plasma infusion.

After restoring INR values to normal, low-dose warfarin therapy (2.5 mg/day) was

reinstituted. This led again to a sharp increase in the INR (6.8) which persisted for the following

4 days (Figure 1).

The patient underwent genetic analysis and proved to be CYP2C9*2 wild type, CYP2C9*3/*3

homozygous mutant and VKORC1*3/*3 homozygous mutant.

DISCUSSION

We have observed an unusual case of type 2 AIT in which the beginning of warfarin therapy

caused a dangerous and unexpected elevation of the INR value.

From a clinical point of view, several factors can influence the response to warfarin therapy

(Table 2).

Warfarin Metabolism

Warfarin consists of two isoforms: R-isomer and the more potent S-isomer. It is given orally,

absorbed by the gastrointestinal system and metabolized by liver enzymes (9). The CYP2C9

gene, one of the cytochrome P450 genes, is implicated in the pharmacokinetic metabolism of

warfarin, encoding a liver enzyme (CYP2C9) that metabolizes S-Warfarin into inactive products.

Several polymorphisms of this gene can decrease the enzyme activity and extend the warfarin

effect (9, 10).

Warfarin pharmacodynamic metabolism, instead, involves the VKORC1 gene. In the

coagulation process, factors II, VII, IX and X need �-glutamyl carboxylation to be activated and

�-glutamyl carboxylation requires the presence of the reduced form of Vitamin K. The

VKORC1 gene encodes for Vitamin K reductase (VKORC1), an enzyme that replenishes the


reduced vitamin K (Figure 2) (11). Warfarin exerts its anticoagulant effect inhibiting VKORC1

activity and causing a decreased level of functional, vitamin K-dependent, coagulation factors

(11).

Thyrotoxicosis.

It has been reported the overt hyperthyroidism exerts a procoagulant effect modifying the

balance between coagulation and fibrinolysis and increases the risk of thromboembolic events

(12-15).

In contrast, in patients receiving warfarin, thyrotoxicosis has been associated with an

increased sensitivity to the drug, irrespective of the nature of the underlying thyroid disease (16).

Several case reports, indeed, have reported a potentiation of warfarin-induced

hypoprothrombinemia in hyperthyroid patients (17, 18) with an increased risk of bleeding (19).

Thyrotoxic patients exhibit an exaggerated depression in functional clotting factors (II and

VII) in response to warfarin and, accordingly, an accentuation in the prothrombin time (13, 17).

Furthermore, the degradation rate of coagulation factors is increased in thyrotoxicosis, leading to

their higher plasma clearance and shorter plasma half-life (16).

Hypothyroidism, in contrast, has been associated with a reduction in factor VIII and Von

Willebrand factor activity and with a decrease in Prothrombin Time (PT) and Activated Partial

Thromboplastin Time (APTT), reversible after levothyroxine therapy (20). However a recent

study failed to found an association between levothyroxine therapy and hemorrhage risk in

patients treated with warfarin (21).

Amiodarone

Amiodarone increases the anticoagulant effect of warfarin. Indeed, a patient with stable

anticoagulation therapy requires, on average, a reduction of 6-65% of the warfarin dose after


starting amiodarone therapy (22). In addition, it has been reported that patients starting warfarin

and amiodarone therapy simultaneously had a higher enhanced pharmacodynamic response to

warfarin therapy than those treated with warfarin alone (23).

Amiodarone has its effect in the first 2-12 weeks (24-26) primarily through conversion to its

active metabolite, desethyl-amiodarone (DEA) which competitively inhibits CYP2C9, reducing

the metabolism of the warfarin (R)-enantiomer and, more so, of the (S)-enantiomer (3, 27-29).

This interaction has been shown to be dose and plasma concentration-dependent, decreasing

warfarin clereance and reducing the required daily dose of warfarin of 25-65% (25, 26, 28). It

has been calculated that, for an amiodarone maintenance dose of 100, 200, 300 and 400 mg/day,

the warfarin dose needs to be reduced by 25, 30, 35 and 40%, respectively (25). From a clinical

point of view, an empirical reduction in the warfarin dose by about 30% has been recommended

when amiodarone therapy is given to stably anticoagulated patients (16, 25). This problem

represents a large number of patients, since as many as 10% of patients receiving warfarin also

take amiodarone (16, 30).

Recently a rise in INR values has been reported in patients receiving warfarin, after the

addition of dronedarone, a new antiarrhythmic drug (31, 32). However, the underlying

mechanism is not completely understood and, currently, there is no evidence that a dose

reduction of warfarin is required when dronedarone is co-administered (33).

Amiodarone-induced thyrotoxicosis

Even though AIT represents an ideal model in which thyroid hormone excess and

amiodarone therapy coexist, only a few reports have evaluated the effects of AIT on warfarin

sensitivity. Woeber et al described a patient receiving chronic warfarin and amiodarone therapy

in which the onset of AIT resulted in a rise in INR values and a reduction in the warfarin dose by


about 28% (34). Kurnik et al reported three patients with AIT in whom the onset of

thyrotoxicosis reduced the warfarin dose by 12-40%. In one patient receiving a stable warfarin

dose, the onset of amiodarone therapy led to a reduction in the warfarin dose of about 25% and

the subsequent appearance of thyrotoxicosis further decreased the warfarin dose by 27%. These

changes were reversible following restoration of euthyroidism or after withdrawal of amiodarone

therapy (16).

Genetic factors.

Genetic factors may account for about 40-50% of warfarin dosing variability (8).

Two main genes are involved in warfarin metabolism: i) CYP2C9, a liver enzyme required

for the oxidative metabolism of a large number of clinically important drugs, including warfarin

(35), and ii) Polymorphisms of the target of warfarin, VKORC1, a critical component in the

vitamin K cycle essential for blood clotting (36).

Various polymorphisms have been identified within the CYP2C9 gene, but two gene

variants, a substitution of an arginine with a cysteine at position 144 within the exon 3

(CYP2C9*2, Arg144Cys) and a substitution of an isoleucine with a leucine at position 359

within the exon 7 (CYP2C9*3, Ile359Leu), impair the hydroxylation of warfarin in vitro (37, 38)

and are associated with decreased warfarin dose requirements of about 17% and 38% (39) and a

higher risk of early bleeding in vivo (40).

A potential pharmacodynamic mechanism underlying warfarin resistance has been ascribed

to VKORC1. This gene encodes for the enzyme that reduces vitamin K 2,3-epoxide to the

activated form required for the carboxylation of glutamic acid residues in blood-clotting proteins.

Polymorphisms of the VKORC1 gene have been associated with warfarin resistance (41). In

particular, VKORC1 activity is affected by -1639G>A (VKORC1*3) polymorphism, suggesting


that patients with the A allele have a VKORC1 protein with lower enzymatic activity than those

with the G allele. This accounts for the fact that lower warfarin doses are needed to inhibit

VKORC1 and to produce an anticoagulant effect. In fact, carriers of the VKORC1 A allele

require, on average, a 28% reduction in their warfarin dose per allele compared to those who

carry the wild-type alleles (42). CYP2C9*3*3 polymorphism can be found in about 32% of the

general population, while VKORC1 A/A polymorphism is found in about 0.5% of individuals.

The concurrent presence of CYP2C9*3*3 and VKORC1 A/A polymorphisms is extremely rare,

since it affects only about 0.1% of patients receiving warfarin therapy and strongly increases

warfarin sensitivity (43).

The current patient

In our patient, after the initial evidence of a high INR value and after restoration of a

normal INR, a low-dose warfarin therapy (2.5 mg/day) was reinstituted.

Although the predicted warfarin dose, according to a Clinical Algorithm previously described

(8), would have been about 3 mg/day, the INR value increased again up to 6.5 after two days.

After genetic analysis, the individualized warfarin dose was calculated using a

pharmacogenetic algorithm, previously described (8), and the algorithms reported in

http://warfarindosing.org/Source/Home.aspx. The presence of the CYP2C9*3*3 and VKORC1

A/A polymorphisms reduces the predicted warfarin starting dose to 0.3 mg/day or 1 mg/day,

respectively, making it very difficult to manage warfarin therapy and thereby increasing the risk

of overtreatment. In addition, concomitant thyrotoxicosis and glucocorticoid therapy - not

considered in the previous models - further increase warfarin’s effect (44, 45).

CONCLUSION

In conclusion, in patients with AIT, warfarin therapy should be gradually introduced, starting


with a very low dose because of the effect of amiodarone, per se, and of the thyroid hormones

excess on the warfarin sensitivity.

The evaluation of genetic factors is currently not routinely recommended for all patients

treated with warfarin (8) and we have not found sufficient evidence supporting the expedience of

a genetic analysis of the CYP2C9 and VKORC1 polymorphisms in this subset of patients.

However, this search may be relevant in AIT patients who show a strong and unexpected rise of

the INR value after starting warfarin therapy.

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Table 1. Clinical and biochemical features of the patient at the admission to Department of

the Endocrinology.

Variable PATIENT NORMAL RANGE

Weight (Kg) 69

Height (cm) 168

BMI 24.6

FT4 (pg/ml) 52.5 7-17

FT3 (pg/ml) 6.06 2.7-4.5

TSH (mU/liter) <0.005 0.4-3.4

TGAb (U/ml) <1 <10

TPOAb (U/ml) <1 <30

TRAb <1 <2

UIE (mcg/liter) 18690 <300

3rd h RAIU (%) 1.4 10-20

24th h RAIU (%) 0.6 30-45

TV (ml) 21 <17

ECD Pattern 0

Presence of nodules NO


To convert serum FT4 and FT3 values from pg/ml to pmol/liter multiply by 1.29 and

1.54, respectively. BMI: Body mass index. TSH: thyroid-stimulating hormone. TgAb:

thyroglobulin antibodies. TPOAb: thyroperoxidase antibodies. TRAb: thyroid hormone receptor

antibodies. UIE: urinary iodine excretion. Median UIE in our area is 110 �cg/liter. 3rd h and 24th

h RAIU: 3rd and 24th hour thyroidal radioiodine uptake measured after the administration of a

tracer dose (50 �Ci) of 131-I. The normal 3-and 24-h RAIU values in our area are 10-20% and

30–45%, respectively. TV: thyroid volume estimated with ultrasonography; thyroid volume was

measured by ultrasonography and calculated by the ellipsoid model (width x length x thickness x

0.52 for each lobe), as previously described (46). ECD pattern: echo-color-Doppler pattern. ECD

was performed as previously reported (46-48).


Table 2 Foods and Drugs interacting with Warfarin metabolism

Mechanism of action Effect

FOOD

VITAMIN-K RICH

FOOD

Decrease effect of

warfarin

• Broccoli

• Brussel sprouts

• Spinach

Increase effect of

warfarin

• Garlic

• Ginkgo biloba

• Ginseng

• Cranberry

DRUGS

CYP2C9 INHIBITOR Increase effect of

warfarin

• Antimicrobials (fluconazole,

isoniazid, metronidazole,


sulfamethoxazole, voriconazole)

• Antidepressant (fluoxetine,

paroxetine, sertraline)

• Amiodarone

• Statins (atorvastatin, fluvastatin,

lovastatin, simvastatin)

• Antibiotics (levofloxacin,

ciprofloxacin)

• Fenofibrate

• Valproic acid

• Gastric (Cimetidine, Rabeprazole)

CYP3A4 INHIBITOR Increase effect of

warfarin

• Cardiovascular (diltiazem,

amlodipine, nicardipine,

felodipine, verapamil)

• Erythromicin

• Cyclosporine

• Ketoconazole

CYP2C9 INDUCER Reduce effect of warfarin

• Anticonvulsivant (carbamazepine,

phenobarbital, secobarbital,


phenytoin)

• Rifampin


LEGEND TO FIGURE

Figure 1. INR values during Warfarin therapy.

Figure 2. Warfarin Metabolism and interaction with Vitamin K-cycle. Modified from Shindley L,

Dale JC, Masoner DE, Moyer TP, Jaffe AS, O’Kane DJ. Warfarin: genotyping and improving

dosing. Communique. 2008. Aug; 33(8) available at

http://www.mayomedicallaboratories.com/articles/communique/2008/08.html. Used with

permission of Mayo Foundation for Medical Education and Research all right reserved.

S-‐WARFARIN INACTIVATION

WARFARIN

CYP2C9

VITAMIN K REDUCTASE (VKORC1)

Reduced VITAMIN K Oxidized VITAMIN K

γ GLUTAMYL CARBOXILASE

VIitamin K-‐dependent coagulaEon factors (Factors II,VII, IX, X) AcEvated factors

R S

VKORC1

CYP2C9

effects of amiodarone, thyroid hormones and cyp2c9 and vkorc1 polymorphisms on warfarin metabolism:...

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