Terlipressin-induced ischaemic skin necrosis

Abstract

Terlipressin is a commonly used drug in hepatology practice for the two most serious complications of cirrhosis, that is, acute oesophageal variceal bleed and hepatorenal syndrome. Acute-on-chronic liver failure (ACLF) is a medical emergency and is frequently associated with acute kidney injury (AKI). Two male patients with alcohol-induced ACLF with high MELD (Model for End-Stage Liver Disease) score presented with AKI. Both were treated with terlipressin infusion. There was no response to terlipressin in these sick patients, and further both patients developed ischaemic skin necrosis and succumbed to multiorgan failure. Continuous infusion of terlipressin is superior to bolus dosing, but we noted that continuous infusion might as well be associated with severe adverse effects in patients with a high MELD score. More extensive prospective studies, including patients with high MELD score, are required to ascertain the safety of terlipressin.

Background

Acute variceal bleed (AVB) and hepatorenal syndrome (HRS) are serious complications of cirrhosis.¹ Terlipressin (also known as triglycyl lysine vasopressin) is a synthetic analogue of the neuropeptide hormone vasopressin and a prodrug for lysine vasopressin. Terlipressin has been approved as a first-line drug for the management of AVB and HRS.¹ However, the safety of terlipressin remains a concern, which is the reason for its non-availability in some countries. Here we report two patients with acute-on-chronic liver failure (ACLF) awaiting liver transplant who developed terlipressin-induced ischaemic skin necrosis, along with a review of published case reports.

Case presentation

The first case is a 54-year-old chronic alcoholic who presented with complaints of jaundice for 1 month and abdominal distension for 15 days. He also complained of decreased urine output for 2 days. He had no significant personal or family history of any illness. Clinically he was icteric, had hepatosplenomegaly, and ascites on abdomen examination.

The second case is a 45-year-old chronic alcoholic man with no significant personal or family history of any illness who presented with complaints of jaundice and ascites for 20 days. On examination, he was deeply icteric, and had tense ascites and hepatomegaly (8 cm below the right costal margin).

Investigations

In case 1, investigations revealed serum creatinine of 3.2 mg/dL with serum total bilirubin of 18.6 mg/dL and International Normalized Ratio (INR) of 2.1. The patient also had hypoalbuminaemia (albumin of 2.7 g/dL). Sepsis (serum procalcitonin, blood and urine cultures) screening was negative.

In case 2, investigations revealed a haemoglobin of 96g/L, bilirubin of 21.4 mg/dL, INR of 1.9 and creatinine of 2.3 mg/dL.

Differential diagnosis

Both patients had organ failure (liver and renal) and satisfied the Asian Pacific Association for the Study of the Liver and the European Association for the Study of the Liver criteria for ACLF.^{2 3}

Treatment

In case 1, the patient was started on albumin infusion. Despite 60 g of albumin (1 g/kg), he had progressive acute kidney injury (AKI) and was hence started on terlipressin 2 mg/day on continuous infusion after 48 hours.

In case 2, the patient was resuscitated with intravenous albumin at 1 g/kg dose. Sepsis was ruled out, and he was started on terlipressin at 2 mg/day infusion at 48 hours as there was no decline in creatinine (2.2 mg/dL at 48 hours).

Outcome and follow-up

In case 1, we noted extensive skin necrosis on the lower limbs with a gangrenous lesion on the right knee on day 5 of terlipressin therapy, and terlipressin was withheld (figure 1A). He had worsening kidney functions despite changing to octreotide and midodrine, and later required renal replacement therapy. He succumbed to multiorgan failure on day 16 of admission.

Figure 1.

(A) Ischaemic necrosis on the lower limbs in case 1. (B) Cyanosis of the upper limb in case 2. (C) Cyanosis of the toes and necrotic purpuric lesions on the lower limbs in case 2.

In case 2, the patient developed cyanosis of the upper hands and diffuse ischaemic purpuric lesions on the lower limbs 2 days after terlipressin infusion (figure 1B, C), with creatinine reaching 2.5 mg/dL. Hence terlipressin was changed to octreotide and midodrine. However, he developed pneumonia and succumbed to multiorgan failure on day 21.

Discussion

Terlipressin is an approved drug for AVB and HRS. However, there are case reports of terlipressin causing skin necrosis and gangrene (table 1).^4–22 Nineteen articles reporting a total of 25 patients were analysed. Of these patients, 80% were male and the mean age was 58.88±12.36 years. MELD (Model for End-StageLiver Disease) score was reported in 11 patients, and the mean MELD score was 21.18±8.08. The most common aetiology of liver cirrhosis was ethanol in 52%, followed by viral in 16% and non-alcoholic steatohepatitis in 12%. Twenty per cent of the total had vascular comorbidity (hypertension or cardiovascular disease) and 16% had diabetes mellitus. Indication for using terlipressin was HRS in 64% and variceal bleed in 36%. Terlipressin dosing was reported in 24 patients. Eighty-four per cent (21 patients) had received bolus dosing compared with only three who received continuous infusion. The mean dose in the continuous arm was much higher than in the bolus arm (continuous: 8.34±2.33 mg/day; bolus: 5.05±0.58 mg/day; p=0.07). However, the time to the development of side effects was similar in both groups (continuous: 2.95±0.48; bolus: 2.67±0.88; p=0.82). The most common site was the lower limbs (figure 2). A total of 72% of patients who developed ischaemic side effects succumbed to the disease.

Table 1.

Published case reports to date on terlipressin-induced ischaemic side effects

Reference	Authors	Aetiology	Age/sex	Indication	Comorbidities	Dose	MELD score	Time to side effects (days)	Site	Others	Mortality
4	Chiang et al 4	Alcohol	65/M	HRS	Hypertension	2 mg every 6 hours for 48 hours, and then 1 mg every 6 hours.	28	3	Fingers, toes, area around the umbilical hernia and scrotum.	–	No
5	Iglesias Julián et al 5	HCV	84/F	AVB	Hypertension, chronic renal failure and auricular fibrillation	1.5 mg 4 hourly.		1	Hypogastrium, flanks and periareolar regions.		No
6	Sarma et al 6	Alcohol	65/M	AVB	DM	1 mg 6 hourly.	NA	2	Bilateral upper and lower limbs.		Yes
7	Herrera et al 7	Alcohol	55/M	HRS	Ischaemic haemorrhage/subarachnoid haemorrhage	1 mg 4 hourly.	29	NA	Lower extremities, buttocks, back and abdomen.		Yes
8	Ozel Coskun et al 8	NASH	65/M	AVB	Obesity, IHD, hypertension	1 mg 4 hourly.	10	2	Skin of the right forearm and hand.	–	No
9	Sundriyal et al 9	Alcohol	47/M	AVB	–	1 mg 6 hourly.		3	Skin of bilateral lower limbs.	–	NA
10	Lee and Oh10	Alcohol + HCV	71/M	HRS	Prior pulmonary tuberculosis	1 mg intravenously 4 hourly.	25	11	Legs and toes.	Osteomyelitis	No
11	Taşliyurt et al 11	(A) Alcohol	79/M	HRS	1 mg intravenously 4 hourly.	NA (bilirubin NA)	2	Scrotum.	–	Yes
		(B) HBV	65/M	HRS	1 mg intravenously 4 hourly.	NA (bilirubin NA)	2	Scrotum.	–	Yes
12	Yefet et al 12	Alcohol	66/M	AVB	Obesity, IHD, DM, CKD	2 mg intravenously 4 hourly, 48 hours. 1 mg intravenously 4 hourly, 24 hours.	NA	3	Skin of thigh, calf and abdomen epidermolysis.	–	Yes
13	Chandail and Jamwal13	(A) Cryptogenic	47/M	HRS	Obesity	0.5 mg 6 hourly.	NA	2	Skin of bilateral lower limbs and toe gangrene.	–	Yes
		(B) NASH	53/F	HRS	Obesity	–		5	Abdominal wall and thighs.	–	Yes
		(C) Alcohol	41/M	AVB	–	1 mg 6 hourly.		3	Posterior of the thighs and legs.		No
14	Bañuelos Ramírez et al 14	Alcohol	51/F	AVB	CKD	4 mg/day.	NA	3	Legs and toes.		No
15	Elzouki et al 15	Cryptogenic	52/M	AVB	DM, hypothyroidism	4 mg stat f/b 2 mg intravenously 6 hourly.	12	2	Bilateral upper and lower limb fingers and toes.	NSTEMI, SVT	No
16	Sahu et al 16	Alcohol	50/M	HRS	DM	1 mg 8 hourly.	NA	2	Digital gangrene and skin of bilateral lower limbs.	–	Yes
17	Posada et al 17	Alcohol	39/M	HRS	–	0.5 mg 4 hourly.	NA	3	Skin of bilateral lower limbs.	–	Yes
18	Mégarbané et al 18	(A) Alcohol/HCC	68/M	HRS	–	1 mg 6 hourly.		3	Skin of trunk, legs, tongue and scrotum.		Yes
		(B) Metastatic adenocarcinoma	74/M	Pseudo-HRS	DM, IHD, dyslipidaemia	0.5 mg/hour infusion.		4	Scalp.	–	Yes
19	Di Micoli et al 19	HCV, HCC	65/F	HRS	Hypothyroidism	3 mg/day × 3 days f/b 9 mg/day intravenous infusion.	15	4	Skin of bilateral breasts.	–	No
20	Donnellan et al 20	(A) AIH, post liver transplant	47/M	HRS	Chronic venous insufficiency	0.5 mg 6 hourly + octreotide.	24	2	Skin of bilateral lower limb epidermolysis.	–	Yes
		(B) NASH	53/F	HRS	0.5 mg 6 hourly + octreotide	23	5	Skin of the abdomen and thigh epidermolysis.	–	Yes
		(C) Alcohol	56/M	AVB	1 mg 6 hourly + octreotide.	9	3	Skin of the right groin and flank epidermolysis.	–	Yes
21	Lee et al 21	HBV	41/M	HRS	1 mg 4 hourly.	30	–	Toes and injection site.	–	NA
22	Vaccaro et al 22	Alcohol	73/M	HRS	0.5 mg 6 hourly.	28	2	Abdomen, thighs, scrotum and penis.		Yes

AIH, autoimmune hepatitis; AVB, acute oesophageal variceal bleed; CKD, chronic kidney disease; DM, diabetes mellitus; F, female; f/b, followed by; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HRS, hepatorenal syndrome; IHD, ischaemic heart disease; M, male; MELD, Model for End-Stage Liver Disease; NASH, non-alcoholic steatohepatitis; NSTEMI, non-ST-elevation myocardial infarction; SVT, supraventricular tachycardia.

Figure 2.

Site of ischaemia reported in studies.

Terlipressin should be used with caution in patients with high MELD score, and is safe when used in continuous infusion rather than bolus dosing. However, in the current report, the patients developed ischaemic necrosis even when continuous infusion was used.²³ Terlipressin is superior to norepinephrine in patients with ACLF with AKI but is poorly tolerated.²⁴ The drawback of the current study was that we did not perform skin biopsy, which would have added more information on the pathogenesis. We also lacked a comparison with patients with low MELD score. Whether sicker patients develop skin necrosis or patients who develop skin necrosis become sick is difficult to conclude, but a large prospective study, including a homogeneous group of patients with ACLF, would help in ascertaining the same.

Learning points.

• Terlipressin is associated with certain undesirable side effects.

• Terlipressin should be used with caution in patients with high MELD (Model for End-Stage Liver Disease) score.

• Most complications develop by the third to fifth day of infusion.

• Terlipressin use requires strict vigilance for adverse events.

• Healthcare providers should report unusual adverse drug reactions associated with clinical applications of terlipressin.