The “dark” side of terlipressin: a case report of ischemic skin necrosis and review of literature
Egyptian Liver Journal volume 13, Article number: 39 (2023)
Terlipressin is a commonly used drug in cirrhotic patients with acute variceal bleed (AVB) due to its vasoconstrictor effects. Ischemic complications are uncommon adverse events associated with worse outcomes.
We present a case of alcohol-related cirrhosis, who was started on terlipressin for AVB. However, he developed bilateral lower limb gangrene with ischemic skin necrosis and ultimately succumbed to death.
Although ischemic adverse events are uncommon with terlipressin, it is important to be aware of these complications as they may be severe and potentially life threatening.
Terlipressin is widely used in the treatment of bleeding esophageal varices in patients with cirrhosis. It is found to decrease the mortality by reducing splanchnic blood flow and portal pressures and the need for emergency procedures required to stop rebleeding . Ischemic adverse events are uncommonly observed with terlipressin of which cutaneous complications are among the rarest . It is important to be aware of such uncommon events to facilitate early recognition and prompt withdrawal of terlipressin. Herein, we report a case of bilateral lower limb gangrene with ischemic skin necrosis in a patient of acute on chronic liver failure who was started on terlipressin for acute variceal hemorrhage.
A 45-year-old gentleman previously diagnosed with liver cirrhosis presented to the emergency with hematemesis, melena, and altered sensorium for 1 day. He had a history of significant alcohol consumption (60–80 g/day for last 20 years) but no tobacco or other substance abuse. There was no history of ischemic heart disease, peripheral vascular disease, or metabolic comorbidities including diabetes mellitus, hypertension, or obesity in the patient or his family members. On examination, he was disoriented, pale, and icteric with free fluid per abdomen as evidenced by shifting dullness. Patient was shifted to the intensive care unit and was intubated in view of poor sensorium. Intravenous ceftriaxone (1 g intravenously twice a day), terlipressin (intravenous boluses of 2-mg stat followed by 1 mg every 4 h), and other supportive management were started. Investigations revealed anemia (hemoglobin: 4.8 g/dL) with thrombocytopenia (92 × 103/µL) and leukocytosis (2 × 103/µL) with deranged liver (bilirubin: 3.8 mg/dL, AST: 384 IU/L, ALT: 141 IU/L), coagulation (INR: 1.7), and renal function parameters (blood urea nitrogen: 59.7 mg/dL, creatinine: 1.5 mg/dL). After stabilization, upper gastrointestinal endoscopy was performed which revealed large, high-risk esophageal varices with white nipple sign, and endoscopic variceal ligation was done. During the first 36 h of admission, he was also transfused with 3 units of packed red blood cells, and the hemoglobin was built up to 8.1 g/dL. On the 3rd day of admission, he developed cyanosis of bilateral lower limbs with absent peripheral pulses which progressed rapidly to bluish-black discoloration up to the knees and skin necrosis over left medial ankle (Fig. 1). Arterial Doppler corroborated the absence of flow in popliteal artery and its branches. Vasculitis work-up including ANA, ANCA, and complement levels was non-contributory. Terlipressin was stopped immediately. However, the patient continued to deteriorate with worsening sepsis, rise in total leukocyte counts, and development of new-onset shock. Despite upgradation of antibiotics and optimization of management, he had a rapidly downhill course and expired on day 5.
Acute variceal bleed (AVB) is a potentially life-threatening complication of cirrhosis. Mortality has decreased substantially over the last three decades due to advancements in medical and endoscopic therapies. Current guidelines advocate combined endoscopic and pharmacological therapy in patients with AVB due to improved outcomes as compared to either modality alone . Pharmacotherapy in AVB includes vasoconstrictors like terlipressin, somatostatin, and octreotide. Where available, terlipressin is usually the preferred vasoconstrictor as it has been shown to have a survival benefit . It acts on V1 receptors in vascular smooth muscle cells leading to splanchnic vasoconstriction and reduction of portal venous pressures. Apart from AVB, terlipressin is also used in the management of hepatorenal syndrome (HRS) in cirrhosis and has been recently approved by the US FDA based on the phase 3 CONFIRM trial .
Adverse events with terlipressin are infrequent. The most concerning adverse effects are related to respiratory failure, myocardial ischemia, arrhythmias, bradycardia, and fluid overload. Other commonly reported adverse events include abdominal pain, nausea, and dyspnea . Ischemic complications with terlipressin are uncommon and were seen in 4.5% of patients in the phase 3 CONFIRM trial. These complications may range from intestinal ischemia and myocardial ischemia to peripheral gangrene. Cutaneous complications are rare and may include bulla, cyanosis, necrosis, and purpura. The exact incidence of ischemic skin necrosis and gangrene following terlipressin is difficult to estimate because of the rarity of the event. In a recently published prospective cohort study on the safety and efficacy of terlipressin, ischemic skin necrosis was documented in only one patient (0.9%) . As such, fewer than 40 cases have been reported in the literature (Table 1), and it commonly involves legs followed by abdomen, scrotum, upper extremities, and hands. It is more common in patients with high MELD scores and those with underlying comorbidities like diabetes, hypertension, obesity, or cardiovascular disease [2, 6]. Our patient had a MELD score of 35 but did not have other comorbidities or risk factors for peripheral vascular disease.
It should be noted that our patient received bolus doses of terlipressin (2-mg stat followed by 1 mg 4 hourly) as is the usual practice in AVB . In HRS, use of terlipressin as a continuous infusion instead of boluses has been shown to be equally effective with significantly less adverse effects and a lower cumulative dose . However, data on the use of terlipressin as infusion for management of patients with AVB is virtually non-existent. Furthermore, ischemic complications including skin necrosis have also been reported with the use of continuous infusion of terlipressin in HRS [2, 6].
Development of ischemic complications with terlipressin is associated with increased morbidity and mortality, and there is no specific treatment to revert it. Terlipressin should be stopped immediately, and some cases may resolve with supportive care. Sildenafil has also been tried anecdotally with mixed results . Therefore, patients receiving terlipressin should be closely watched out for terlipressin-induced ischemic events.
Terlipressin is the most enthusiastically used drug in clinical practice in patients with AVB or HRS. However, it is uncommonly associated with ischemic complications that can prove detrimental. Hence, it is necessary to be in knowledge of such adverse events to facilitate early recognition and prompt withdrawal of terlipressin.
Availability of data and materials
Anti-neutrophilic cytoplasmic antibody
Acute variceal bleed
- US FDA:
United States Food and Drug Administration
Model for end-stage liver disease
Zhou X, Tripathi D, Song T et al (2018) Terlipressin for the treatment of acute variceal bleeding: a systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 97(48):e13437
Zhou Y, Zeng J, Song L et al (2022) Clinical characteristics and treatment of terlipressin-induced ischemic skin necrosis: a synthesis of 35 literature reported cases. J Clin Pharm Ther 47(8):1270–1275. https://doi.org/10.1111/jcpt.13671
Garcia-Tsao G, Abraldes JG, Berzigotti A et al (2017) Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 65(1):310–335. https://doi.org/10.1002/hep.28906
Wong F, Pappas SC, Curry MP et al (2021) Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med 384(9):818–828. https://doi.org/10.1056/NEJMoa2008290
Kulkarni AV, Ravikumar ST, Tevethia H, Premkumar M, Kumar K, Sharma M, Gupta R, Rao PN, Reddy DN (2022) Safety and efficacy of terlipressin in acute-on-chronic liver failure with hepatorenal syndrome-acute kidney injury (HRS-AKI): a prospective cohort study. Sci Rep 12(1):5503
Kulkarni AV, Kumar P, Rao NP et al (2020) Terlipressin-induced ischaemic skin necrosis. BMJ Case Rep. 13(1):e233089
Iglesias Julián E, Badía Aranda E, Bernad Cabredo B et al (2017) Cutaneous necrosis secondary to terlipressin therapy. A rare but serious side effect. Case report and literature review. Rev Esp Enferm Dig 109:380–3
Sarma P, Muktesh G, Dhaka N et al (2017) Terlipressin-induced peripheral ischemic gangrene in a diabetic patient. J Pharmacol Pharmacother 8:148
Ozel Coskun BD, Karaman A, Gorkem H et al (2014) Terlipressin-induced ischemic skin necrosis: a rare association. Am J Case Rep 15:476
Sundriyal D, Kumar N, Patnaik I, et al (2013) Terlipressin induced ischaemia of skin. Case Rep 2013:bcr2013010050
Yefet E, Gershovich M, Farber E et al (2011) Extensive epidermal necrosis due to terlipressin. Isr Med Assoc J 13:180–1
Bañuelos Ramírez DD, Sánchez Alonso S, Ramírez Palma MM (2011) Sildenafil in severe peripheral ischemia induced by terlipressin. A case report. Reumatol Clín 7:59–60
Elzouki A-N, El-Menyar A, Ahmed E, et al (2010) Terlipressin-induced severe left and right ventricular dysfunction in patient presented with upper gastrointestinal bleeding: case report and literature review. Am J Emerg Med 28:540.e1–540.e6
Professor of Medicine and Head, Pulmonary Medicine, Maulana Azad Medical College, New Delhi, India, Kumar N (2020) Terlipressin induced skin ischemia: a case report. JoARM 06(04):10–2
Chandail VS, Jamwal V (2011) Cutaneous complications of terlipressin. JK Sci 13:205
Donnellan F, Cullen G, Hegarty JE et al (2007) Ischaemic complications of Glypressin in liver disease: a case series. Br J Clin Pharmacol 64:550–2
Macedo SS, Cabral C, Novais A, Teixeira M, Knock A (2019) Terlipressin-related ischaemic necrosis of the skin: a rare complication. European J Case Rep Intern Med 6(11):1
Cleva RD, Santarém OLDA, Herman P (2016) Terlipressin-induced irreversible severe skin necrosis: a dreadful complication. Ann Clin Case Rep 1:1040
Chiang C-W, Lin Y-J, Huang Y-B (2019) Terlipressin-Induced peripheral cyanosis in a patient with liver cirrhosis and hepatorenal syndrome. Am J Case Rep 20:5–9
Herrera I, Leiva-Salinas M, Palazón JM, Pascual JC, Niveiro M (2015) Necrosis cutánea extensa por terlipresina [Extensive cutaneous necrosis due to terlipressin use]. Gastroenterol Hepatol 38(1):12–3. Spanish. https://doi.org/10.1016/j.gastrohep.2014.03.014
Lee HJ, Oh MJ (2013) A case of peripheral gangrene and osteomyelitis secondary to terlipressin therapy in advanced liver disease. Clin Mol Hepatol 19:179
Taşliyurt T, Kutlutürk F, Erdemır F et al (2012) Ischemic skin necrosis following terlipressin therapy: report of two cases and review of the literature. Turk J Gastroenterol 23:787–91
Sahu S, Panda K, Patnaik SB et al (2010) Telipressin induced peripheral ischaemic gangrene and skin necrosis. Trop Gastroenterol 31:229–30
Posada C, Feal C, García-Cruz A, Alvarez V, Alvarez M, Cruces MJ (2009) Cutaneous necrosis secondary to terlipressin therapy. Acta Derm Venereol 89(4):434–5. https://doi.org/10.2340/00015555-0651
Mégarbané H, Barete S, Khosrotehrani K et al (2009) Two observations raising questions about risk factors of cutaneous necrosis induced by terlipressin (Glypressin). Dermatology 218:334–7
Di Micoli A, Bracci E, Cappa FM et al (2008) Terlipressin infusion induces ischemia of breast skin in a cirrothic patient with hepatorenal syndrome. Dig Liver Dis 40:304–5
Lee JS, Lee HS, Jung SW et al (2006) A case of peripheral ischemic complication after terlipressin therapy. Korean J Gastroenterol 47:454–7
Vaccaro F, Giorgi A, Riggio O, De Santis A, Laviano A, Rossi-Fanelli F (2003) Is spontaneous bacterial peritonitis an inducer of vasopressin analogue side-effects? A case report. Dig Liver Dis 35(7):503–6. https://doi.org/10.1016/s1590-8658(03)00225-1
Karakuş V. , Soysal D. E (2019) Secondary scrotal necrosis to terlipressin treatment in a patient with hepatorenal syndrome. Muğla Sıtkı Koçman Üniversitesi Tıp Dergisi 6(3):163–165
Ahmed R, Haseeb A (2019) Ischemic skin necrosis in hepatorenal syndrome patient secondary to terlipressin. J Coll Physicians Surg Pak. 29(6):S26–S28
Jain G, Chandran P, Patnaik I, Patel NB (2021) Terlipressin-induced skin necrosis. BMJ Case Rep 14(11):e246678. https://doi.org/10.1136/bcr-2021-246678
Cavallin M, Piano S, Romano A, Fasolato S, Frigo AC, Benetti G, et al (2016) Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study. Hepatology 63(3):983–92. https://doi.org/10.1002/hep.28396
None to declare.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Ethics approval and consent to participate
Consent for publication
Verbal and written informed consent were given by the patient’s wife for the publication of this case. A copy of written consent is available for the journal.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Shastri, A., Rose, S., Vojjala, N. et al. The “dark” side of terlipressin: a case report of ischemic skin necrosis and review of literature. Egypt Liver Journal 13, 39 (2023). https://doi.org/10.1186/s43066-023-00273-9