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CASE SERIES

Terlipressin: A life saver but Treacherous: A Case SeriesVijant Singh Chandail*, Annil Mahajan*, Vishal Tandon

Terlipressin is a tri-glycyl-lysine analogue(prohormone) of vasopressin with longer duration ofaction and lesser side effects and in comparision havingaffinity for both V1 and V2 receptors. Two receptorsubtypes (V1A and V2) mediate vasopressin's majorphysiological effects. V1A receptors are located onvascular smooth muscles cells and cardiac myocytes,affecting vascular tone and myocardial function. . Argininevasopressin type 1 receptor (AVPR1) activation leadsto selective splanchnic and extrarenal vasoconstrictioncausing reduction in splanchnic blood flow, increase inmean arterial pressure and systemic vascular resistanceand decrease in heart rate, cardiac output and portalpressure (1). V2 receptors are located on cells lining thekidney's collecting ducts. Activation of the V2 receptorsinserts vasopressin-sensitive water channels in the cellmembrane, promoting the reabsorption of water andelaboration of a concentrated urine. Excessive reuptakeof electrolyte free water into the blood circulation maylead to hyponatremia. Terlipressin, a vasopressin analogin which the V1A receptor affinity has been increasedand the V2 receptor affinity has been decreased ascompared to vasopressin. Therefore terlipressin has astronger vasoconstrictive effects than vasopressin andless effects on water reabsorption in the kidney collectingducts. Terlipressin is now widely used in the treatmentof cirrhotic patients with variceal bleeding andhepatorenal syndrome. It is a vasoconstrictor that

acts preferentially on the splanchnic circulation, loweringportal venous pressure. When compared withvasopressin and its other synthetic analogues, adverseeffects are relatively rare. However, vasonstrictoreffects on the systemic circulation may result inischaemic complications.

The contraindications for terlipressin use are age morethan 70 years, history of COPD, peripheral vasculardisease, cerebrovascular or ischaemic heart disease andcardiomyapathies. The commonest adverse effectsinclude diarrhea and abdominal pain (20%), cardiaceffects (6-40%) including myocardial ischemia, left andright ventricular dysfunction, bradycardia and variousarrhythmias (2). This is a retrospective analysis of eightpatients who were admitted as complications of livercirrhosis and we observed these complications, whichwe think are worth mentioning, so that these complicationsare watched for in such patients and terlipressin is timelywithdrawn. . We present retrospective analysis of 4patients who presented with cutaneous complications, 3patients who presented with hyponatremia and 1 patientwith bradycardia.Cutaneous Complications Case 1 :A 47-year-old obese man; a diagnosedcase of cryptogenic cirrhosis of liver decompensated withascites, hepatorenal syndrome, hepatic encephalopathywas admitted with lower limb oedema, jaundice with abilirubin of 5.2 mg/dl and renal impairment with a

Introduction

AbstractTerlipressin is a tri-glycyl-lysine analogue (prohormone) of vasopressin with longer duration of action andlesser side effects and in comparision having affinity for both V1 and V2 receptors. The commonestadverse effects include diarrhea and abdominal pain (20%), cardiac effects (6-40%) including myocardialischemia, left and right ventricular dysfunction, bradycardia and various arrhythmias. This is a retrospectiveanalysis of eight patients who were admitted as complications of liver cirrhosis and were treated withTerlipressin. While on treatment , we observed these complications, which we think are worth mentioning,so that these complications are watched for in such patients and terlipressin is timely withdrawn. Wepresent retrospective analysis of 4 patients who presented with cutaneous complications, 3 patients whopresented with hyponatremia and 1 patient with bradycardia.

Key WordsTerlipressin, Liver Cirrhosis, Esophageal Varices, Hepatorenal Syndrome

From the Department of Pharmacology and Internal Medicine* Govt. Medical College Jammu, J&K IndiaCorrespondence to :. Dr Vijant Singh Chandail, Lecturer, PG Department of Medicine, Govt Medical College, Jammu, J&K, India

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creatinine of 2.7 mg/dl. His platelets were 120000/cu mm,prothrombin time (PT) was 15.1 s (11.5-13.5 s) with anactivated partial thromboplastin time (APTT) of 39.6 s(23-35 s). He was subsequently commenced onterlipressin at a dose 1 mg qds, and albumin for treatmentof hepatorenal syndrome. Two days later he started todevelop bullous haemorrhagic lesions, initially of the legsbut later spreading to involve the feet and thighs (Fig 1& 2) and subsequently lead to digital gangrene of the leftsecond toe (Fig 2). There was no evidence of arterialinsufficiency or underlying infection. The skin biopsyrevealed epidermal necrosis, acute ulceration andhaemorrhage, with fibrin thrombi in superficial dermalvessels. In the absence of other causative agents theselesions were attributed to treatment with terlipressin.Despite cessation of this agent, the patient's lower limbslesions worsened with the development of extensive areasof necrosis and gross fluid exudation. This coincided witha progression in both liver and renal failure. He becameprofoundly acidotic and hypotensive and died 5 days afterstarting the vasopressor therapy

Case 2:A 53-year-old woman, with underlying cirrhosissecondary to non-alcoholic fatty liver disease (NAFLD)and morbidly obese with a body mass index (BMI) of48kg m-2, presented with ascites and hepatorenalsyndrome with a creatinine of 4.2 mg/dl. Her renal functionreturned to normal following treatment with terlipressin,and albumin supplementation. Her ascites was controlledwith large volume paracentesis and diuretic therapy. After5 days of terlipressin she developed extensive bruisingand large exudative blistering of the skin of the abdominalwall and upper thighs . Despite withdrawal of theterlipressin, her skin condition worsened. The patient'sliver function deteriorated with worsening of jaundice andencephalopathy and died 2 days later.

Case 3: A 41-year-old man presented with varicealhaemorrhage secondary to alcoholic liver disease Thebleeding oesophageal varices were controlled withendoscopic banding and the addition of terlipressin, andintravenous antibiotics. During this time his renal functiondeteriorated with a creatinine of 2.1 mg/dl. His plateletswere 135000/cu mm. The PT was prolonged at 22 s (11.5-13.5 s), as was the APTT at 76 s (23-35 s). Terlipressinwas used at a dose of 1 mg qds intravenously. Following3 days of treatment, the patient developed large areas ofecchymosis and blistering on the skin over the posterioraspect of the thighs and legs (Fig 3). Punch biopsy ofthe lesions showed subepidermal bulla formation with noinflammation. Terlipressin was stopped and the lesionsstarted improving after 2 weeks of stoppage of the drugand the patient was discharged.

Case 4: A 63 years old female, diagnosed case ofcryptogenic cirrhosis with portal hypertension presentedwith decreased urine output and pain abdomen.Investigations showed Biluribin 4.2mg/dl and creatinine2.9mg/dl, platelets were 150000/cu mm. The PT was 12

s (11.5-13.5 s), and the APTT at 30 s (23-35 s).Thediagnosis of hepatorenal syndrome was made and shewas managed with terlipressin 1 mg I/V qds and I/Valbumin 20%. Patient started improving but on 5 dayspost terlipressin, she developed extensive echymosis andhemorrhage of the skin of the whole abdomen and upperthighs (Fig 4). This was attributed to ischaemic andvasoconstrictive complications of terlipressin.Immediately the terlipressin was stopped andsubsequently the abdominal wall echymotic andhemorrhagic changes were resolving (Fig 5) anddisappeared after 7 days of stopping the drug.

Terlipressin induced Hyponatremia :Case 1 : A 55 years male known case of Liver

Cirrhosis secondary to Hepatitis B infection presentedwith massive hemetemisis. His BP was 70/50 mm Hg,Pulse was feeble. EGD revealed high grade Esophagealvarices . EVL was done and patient was started onTerlipressin 2mg I/V bolus followed by 1mg 6 hourly.Patient started improving. On 4th day of admission, thepatient was drowsy but oriented to time, place andperson. On examination his BP was 120/70 mm Hg, andrest of the systemic examination was normal.Investigations revealed normal LFT and KFT but SerumNa was 112mmol /l and serum osmolality had decreasedto 240 mOsm/kg . CT Scan brain was done which wasnormal. Na correction was done and also completing 3days of terlipressin ,it was stopped. Patient had respondedto the treatment and serum Na levels improved. Patientwas discharged on 8th day of admission. After 4 weekssame patient came to medical emergency withhematemesis, EGD was done, which revealed again highgrade varices with red color sign and EVL (endoscopicvariceal band ligation) was performed . Patient was againstarted on Terlipressin 2 mg I/V stat followed by 1 mgevery 6 hourly . Patient had shown remarkableimprovement , hematemesis stopped and patient improvedhaemodynamically. On 4th day of admission, patientbecame drowsy . Again all the systemic examination andInvestigation were normal except for low sodium levelof 110 meq/l and serum osmolality was 243 mosm/kg.terlipressin was stopped after 3 days and Sodiumcorrection was done. Patient had responded to thetreatment and sensorium improved. Retrospectively, weanalysed that patient developed hyponatremia due toterlipressin and during his second admission also, hedeveloped hyponatremia after terlipressin rechallenge ashe again presented with variceal bleed and had to beprescribed terlipressin in addition to endoscopic varicealband ligation.

Case 2: A 47 year old male, Alcoholic Liver Diseasepatient, presented with hematemesis and malena. OnExamination his BP was 100/50 mm Hg, Pulse rate was116/min, respiratory Rate 26/min, Pallor present, mildicterus and abdominal examination revealedhepatosplenomegaly. Investigation revealed Hb of 5.7gm/

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l, TLC of 10,000/cumm, Platelets 1.8lakhs/cu. HisLFT,KFT,Electrolytes,PT,PTT ,PTI and BT was normal.EGD showed high grade esophageal varices with redcolor sign. EVL was done and patient was started onTerlipressin a bolus of 2mg I/V stat followed by 1 mg 6hourly. Patient started improving and becamehaemodynamically stable and was started on orals . On3rd day patient had generalized tonic -clonic type ofseizure with post-ictal confusion. Patient was investigated,his Na levels were 110 mmol/l where as calcium andmagnesium levels were normal. CT Scan Brain and EEGwas normal. Serum osmolality was 240 mosm/Kg, Urineosmolality was 350 mosm/Kg. Na correction was donebut hyponatremia did not improve . so a Possibility ofTerlipressin induced Hyponatremia was kept andterlipressin was stopped. With the stopping of drug, thepatient started improving and after 3 days of stoppingterlipressin, the patient 's serum sodium levels were -136mmol/l

Case 3: A 66 years old male presented with varicealhaemorrhage secondary to alcoholic liver disease. Thebleeding esophageal varices were controlled withendoscopic band ligation and terlipressin was started .After about 36 hours after starting of Terlipressin, thepaient started with delirium and altered sensorium . CTScan Brain was normal, and other baseline investigationswere normal except for hyponatremia, with Serum Nalevel of 114 mmol/l, and serum osmolarity of 360 mosm/Kg. The possibility of Terlipressin induced hyponatremiawas kept and subsequently terlipressin was discontinued.The Patient's sensorium started improving and his serumsodium levels also increased from 114 to 134 in next 4days. Thus again a possibility of terlipressin inducedhyponatremia and then altered sensorium was made,which again improved once the offending drug was

discontinued.Terlipressin Induced Bradycardia

A 76 years female known case of cirrhosis of liver,secondary to Hepatitis B virus infection presented to uswith moderate ascitis with decreased urine output.Investigations showed S.urea 78mg/dl, S.creatinine4.1mg/dl, S.Bil 3.4mg/dl, SGOT 110 U/L, SGPT 98 U/Lelectrolytes were normal. The diagnosis of HepatorenalSyndrome was made , patient was managed with I/Valbumin and Terlipressin 2mg I/V stat followed by 1mg6hrly. After administration of 5th dose of terlipressin,patient complained of dizziness. On examination pulserate was 50 beats/min, BP 110/80mmHg, Cardiovascularand Neurological examination was normal. ECG showedSinus bradycardia (Fig 6), but the cardiac enzymes werenormal, and so was the Echocardiography, as we wantedto rule out any cardiac event. All the electrolytes like Na,K, Ca, Mg were normal . Possibility of terlipresssininduced bradycardia was kept and the drug wasdiscontinued. Patient responded to that and his heart rateimproved .Discussion

The arginine vasopressin analogue, terlipressin is thetreatment of choice for variceal bleed and hepatorenalsyndrome in patients with portal hypertension and livercirrhosis (5) The vasoconstrictive effects of terlipressinon splanchnic vessels moved blood volume from thesplanchnic vessels into the central blood circulation andthus increases blood flow to the kidneys. Terlipressin'svasoconstrictive effect on post glomerular blood vesselscauses increased glomerular filtration pressure andincreased diuresis. Although terlipressin is selective forthe splanchnic circulation, it can exert vasoconstrictoreffects on the systemic circulation. Undesirable effects

Fig 6. ECG with Sinus Bradycardia

Fig1&2. Bullous Lesions Over Right Foot & DigitalGangrene of Second Toe of Left Foot

Fig 4 &5. Diffuse Echymotic & Hemorrhagic Patches OverWhole of The Abdomen & Healing of The Same Patches AsIn Image 4 After Withdrawl of Terlipressin

Fig.3 Bullous Lesions With Blueish Discoloration Over thePosterior Aspect of Both Calves

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1 Moreau R, Lebree D. The use of vasoconstrictors in patientswith cirrhosis: type 1 HRS and beyond. Hepatology 2006:43: 385-94

2 Gludd LL, Kjaer MS, Christensen E. Terlipressin forhepatorenal syndrome. Cochrane Database Syst Rev2006;4:CD005162

3. Donnellan F, Cullen G, Hegarty JE, et al. Ischaemiccomplications of glypressin in liver disease: a case series.Br J Clin Pharmacol 2007; 64: 550-52.

4. Lee JS, Lee HS, Jung SW, et al. A case of peripherals ischemiccomplication alter terlipressin therapy. Korean JGastroenterol 2006; 47: 454-57

5. Gines P, Torre A, Terra C, Guevara M. Pharmacologicaltreatment of hepatorenal syndrome. Aliment PharmacolTher 2004; 20 (Suppl. 3): 57-62

6. Willems MG, Schoenemann J, Rey C, et al. Ischaemia ofthe cecum caused by glycylpressin. Leber Magen Darm1985; 15: 165-68.

7. Schatt W, Wagner-Thiessen E, Lux G. Ischaemic colitis in apatient treated with Glypressin for bleeding oesophagealvarices. Hepatogastroenterology 1987; 34: 134-36.

8. Lee MY, Chu CS, Lee KT, et al. Terlipressin-related acutemyocardial infarction. Kaohsiung J Med Sci 2004; 20: 604-08.

9 Feu F, Ruiz del Arbol L, Banares R, et al. Double blindcontrolled randomized controlled trial comparing terlipressinand somatostatin for acute variceal hemorrhage. Varicealbleeding study group. Gastroenterology 1996;111:1291-9

10 Rai A, Whaley- Connell A, McFarlane S, et al.Hyponatremia, arginine vasopressindysregulation, andvasopressin receptor receptor antagonism. Am J Nephrol2006;26:579-89.

11 Sola` E, Lens S, Guevara M, et al. Hyponatremia in patientstreated with terlipressin for severe gastrointestinal bleedingdue to portal hypertension. Hepatology 2010;52:1783e90

12) Bruha R, Marecek Z, Prochazka V, et al. Double-blindrandomized multicenter study comparing the efficacy andsafety of 10-day to 5-day terlipressin treatment of bleedingesophageal varices. Hepatogastroenterology 2009;56:390e4.

13) Kang YJ, Bae EJ, Hwang K, et al. Initial serum sodiumconcentration determines the decrease in sodium levels afterterlipressin administration in patients with liver cirrhosis.Springer Plus 2013; 2: 519

14) Yim SY, Seo YS, Jung CH, et al. (2015) Risk factors fordeveloping hyponatremia during terlipressin treatment: aretrospective analysis in variceal bleeding. J ClinGastroenterol 2015; 49(7): 607-12

References

are usually mild and include headache, paleness,abdominal pain and bradycardia. More seriouscomplications are uncommon, but cases of skin necrosis(3,4) , ischaemic colitis (6, 7), myocardial infarction (8)have been reported. We believe that the skin lesion seenin our four patients occurred as a result of terlipressintherapy. There is evidence for a causal relationshipbetween terlipressin and the observed skin necrosis. Themajority of cases related to skin necrosis affecting theextremities, but there are also a small number of casesof foreskin and scrotal necrosis in males. Skin necrosisin atypical areas in obese or severely oedematousindividuals has not been reported to date. Unfortunately,two out of the four patients described in this case seriesdied as a result of multiorgan failure shortly (<72 h) afterdiscontinuing terlipressin. This may explainwhy noimprovement in the skin necrosis was observed ondiscontinuation of the drug. The affected areas in ourfour patients were atypical. Ischaemic complications asa result of vasoconstrictor medication usually affectperipheral areas such as the digits of the hands and feet.It is possible that the venous insufficiency and obesity intwo of our patients, and marked anemia due to varicealbleed leading to decreased tissue perfusion, in one of ourpatients put them at increased risk. We propose that bothobesity, oedema, and marked anemia due to variceal bleed,led to stretching of the skin of the abdomen and lowerlimbs, increasing the surface area for the microvascularblood supply, thereby lowering tissue oxygen levels. Wepostulate that the presence of low tissue oxygen levels incombination with the use of a vasoconstrictor agent ledto development of ischaemic complications .These casessuggest that extra vigil is warranted in administeringterlipressin to patients with cirrhosis of liver and cliniciansshould be aware of these potential complications, so thatterlipressin is stopped right at the onset of such skin lesionsto prevent further complications, as eyes donot see whatthe mind does not know.Terlipressin can also act onarginine vasopressin type 2 receptors (AVPR2) toenhance water permeability of renal tubules by 8-10 foldsto cause antidiuresis , leading to water retention anddilutional hyponatremia. Hyponatremia is a knownadverse effect with estimated incidence of 0.1-1% ofteated patients, but some studies reported a higherincidence. A double blind controlled trial by Feu et al,(9) reported an incidence of hyponatremia in 6% ofpatients treated with terlipressin and another multicentriccontrolled trial, reported 4 cases of hyponatremia out of106 cirrhotics on terlipressin (10). Most of the studieshave reported rapid recovery from hyponatremia afterterlipressin withdrawl (11,12). In our study cases therewas nothing else to suggest the cause of hyponatremiathan terlipressin. Kang et al (13) and Yim et al (14)identified that higher initial sodium plasma levels, lowerpatients age, and preserved hepatic functions representindependent risk factors for development of hyponatremia.

Therefore a careful fluid balance monitoring is requiredfor cirrhotic patients who are treated with terlipressinand if hyponatremia develops, we should consider gradualdiscontinuation of terlipressin.Conclusion

Even though terlipressin is the drug of choice and alsodecreases mortality in patients with variceal bleeding, theabove described adverse effects in the form of cutaneouscomplications, hyponatremia, tachy and bradycardiasshould be taken into account when using this life savingdrug and may sometimes need to be withdrawn to savethe patients life.