EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Liver transplant is a definite treatment of decompensated liver disease. Because of the shortage of livers from deceased donors, living-donor liver transplant is becoming more common. Here, we analyzed our clinical experience in the follow-up care of these patients.

Materials and Methods: Liver transplant recipients seen at the Sindh Institute of Urology and Transplantation (Karachi, Pakistan) were included in this analysis. Baseline characteristics and follow-up events were recorded.

Results: Our study population included 76 liver transplant patients registered at our clinic. Median age was 42 years, with 62 patients (81.6%) being males. The most common indication of transplant was hepatitis C virus-related cirrhosis (42 patients; 55%), followed by hepatitis B-hepatitis D virus coinfection (8 patients; 10.5%). Anastomotic biliary stricture developed in 16 patients (21.1%),which required biliary stenting. Biliary leak developed in 5 patients (6.6%), and renal cell carcinoma developed in 1 patient. Two recipients died due to hepatitis C virus-related fibrosing cholestasis hepatitis and pulmonary complications. Posttransplant diabetes mellitus developed in 36 (47.1%), hypertension in 17 (38.6%), and dyslipidemia in 19 patients (25%). Of 42 patients with hepatitis C virus infection, 26 were treated with pegylated interferon and ribavirin, of which 65.3% achieved sustained virologic response at 24 weeks. The other 16 patients received sofosbuvir combined with ribavirin for 24 weeks. A sustained virologic response at 12 weeks was achieved in 5 patients, with not yet determined results in the remaining patients. Seven patients were lost to follow-up.

Conclusions: Hepatitis C-related cirrhosis was the most common indication for liver transplant, and infection recurrence was observed in our patients. Biliary anastomotic stricture formation was the most prevalent complication after transplant. As liver transplants are becoming more widely available for Pakistani patients at home and abroad, gastroenterologists and trainees in our country should be sensitized, educated, and skilled in the posttransplant care of these patients.

Key words : Anti-viral agents, Diabetes mellitus, Dyslipidemia, HCV, Hypertension

Liver transplant is the definitive treatment for end-stage liver disease.¹ With advancements in technology and experience, transplant activities have enormously increased during the past decade in our region. New transplant centers are being established with increasing workloads. Because of shortages in organs through deceased donations, transplant activities have shifted focus to living-donor transplant.

After transplant, recipients are followed-up in our outpatient department. Here, day-to-day problems and complications are addressed. A number of patients who have received transplants in neighboring countries are also followed in our clinic. This study was undertaken to analyze our clinical experience in the follow-up care of liver transplant patients.

Materials and Methods

All registered liver transplant patients from June 2013 until present were enrolled in our study.

At our institute, living-related liver transplant recipients are seen weekly for 1 month after discharge. After this, they are seen every 2 weeks for the next 3 months, followed by monthly for the next 6 months, and then every 3 months thereafter. Patients who undergo liver transplants outside our institute are registered 3 months after surgery and then followed-up at 3-month intervals.

We collected the following from patients’ records: age, sex, cause of transplant, posttransplant complications, and care and use of immunosuppressive agents. This study was approved by our Ethical Review Committee, and all protocols conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from all study participants.

Hepatitis C virus (HCV) recurrence was diagnosed on the basis of HCVRNA and genotype. No protocol liver biopsies were performed as per institutional policy. Patients were diagnosed as hypertensive if blood pressure of more than 140/90 mmHg was documented at 2 consecutive visits.² Diabetes mellitus was diagnosed based on a fasting plasma glucose of more than 126 mg/dL at 2 consecutive visits.³ Dyslipidemia was diagnosed as cholesterol of more than 220 mg/dL and triglyceride of more than 200 mg/dL at 2 consecutive visits.⁴

Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 20.0, IBM Corporation, Armonk, NY, USA). Results are presented as means ± standard deviation for quantitative data or as numbers with percentages for qualitative data.

From June 2013 to 2016, a total of 75 living-related liver transplant patients were registered at our clinic. Most patients were males (81.6%), with mean age of 36.8 ± 17.7 years (range, 2-60 y). Pediatric liver transplant was performed in 17 patients (22.3%). As per institutional policy, no recipients with commercial donors were enrolled.

Indications for liver transplant are shown in Table 1. Most patients underwent liver transplant secondary to HCV-related cirrhosis (42 patients; 55%). Except for 2 patients, all were treatment naïve. One patient was a nonresponder to interferon-based therapy, and the other patient was a nonresponder to direct antiviral agent (DAA) therapy. During the time when DAAs were not available in Pakistan, pegylated interferon and ribavirin were offered to 26 patients, among which in 17 patients (65.3%) sustained virologic response (SVR) at 24 weeks was achieved. Three patients (11.5%) did not respond to treatment. Six patients were lost to follow-up. Because sofosbuvir had been the only DAA agent in Pakistan at time of prescription, 16 patients received sofosbuvir and ribavirin for 24 weeks. Sustained virologic response at 12 weeks was achieved in 5 patients, 1 patients was lost to follow-up, and the results are still to be determined in 10 patients.

Four patients underwent liver transplant secondary to hepatocellular carcinoma. All were within the Milan criteria.⁵ At 3-year follow-up after transplant, no hepatocellular carcinoma recurrence was documented. Of 14 patients, hepatitis B virus recurrence was noted in 1 patient due to noncompliance with entecavir.

One patient developed hepatic artery thrombosis followed by a "redo" arterial anastomosis. Biliary leak developed in 5 patients (6.6%), which required biliary stenting. None of the patients underwent hepaticojejunostomy. Regarding long-term complications, 16 patients (21.1%) developed biliary anastomotic stricture requiring multiple sessions of endoscopic stent placement. Eleven patients (14.5%) had diabetes mellitus before transplant. However, after transplant, diabetes mellitus developed in 25 patients (32.8%), hypertension in 17 patients (38.6%), and dyslipidemia in 19 patients (25%). Renal cell carcinoma was diagnosed in 1 patient who underwent radical nephrectomy.

One of our patients underwent a second liver transplant due to recurrent primary sclerosing cholangitis. Three liver transplant recipients died during the study period: 1 from primary graft dysfunction, 1 from HCV-related fibrosing cholestasis hepatitis, and 1 from acute respiratory distress syndrome secondary to coronavirus.

In the 76 liver transplant recipients seen at our outpatient clinic, 22.3% were pediatric patients, 3 patients died during follow-up (with 1 having primary graft dysfunction), and 7 patients were lost to follow-up.

Liver transplant is a well-established and effective treatment modality for a variety of irreversible end-stage liver diseases.¹ With advancements in surgical techniques, the initial hindrance of graft survival has been overcome.⁶ Contrary to that shown in the Western world, alcoholic liver cirrhosis is not a common indication for liver transplant in our patients due to religious views.⁷

The prevalence of HCV infection in Pakistan is 4.9%.⁸ Hepatitis C virus-related chronic liver disease is the most common indication for liver transplant worldwide.⁹ In our series, 55% of the study population underwent liver transplant due to HCV infection. In the era of interferon-based antiviral treatment, there had been limited options for care of decompensated HCV-related liver disease, which is a major denominator of HCV recurrence in nearly all patients after liver transplant.¹⁰ Most contemporary studies have demonstrated rapid progression to cirrhosis in such patients within 5 years of transplant.^11-13 Fibrosing cholestatic hepatitis is the more dreaded complication from viral hepatitis (hepatitis B virus and HCV), with high mortality.¹⁴ One of our liver transplant recipients died because of this complication, which occurred before the era of DAAs in our country.

Eradication of HCV before transplant not only improves liver function and prevents viral recurrence but also assists with an easier care after transplant.¹⁵ With the advent of novel DAAs, it has become standard practice to seroconvert HCV-positive patients before liver transplant.

Interferon-based therapy after liver transplant is associated with low efficacy and increased adverse effects. Moreover, treatment discontinuation is noted in up to one-third of patients.¹⁰ Although no lethal adverse effects were documented in our patients, 65.3% of recipients achieved SVR 24. Studies have demonstrated effective HCV eradication, in pretransplant and posttransplant patients, who were treated with DAAs.^16,17 At the time of study, sofosbuvir was the only agent available in Pakistan; 16 patients (38%) in our study received sofosbuvir and ribavirin for 24 weeks. Charlton and associates, in a multicenter study, demonstrated 70% SVR in 40 liver transplant recipients. Most importantly, the group did not note graft loss or interactions with calcineurin inhibitors.¹⁶ Data at the time of our study were available for only 5 of 16 patients, and an SVR 12 was achieved in all 5 patients. Although 1 patient has been lost to follow-up, results are in progress in the remaining 10 patients.

With better patient and graft survival after liver transplant, the major concerns are the long-term complications.⁶ These complications, including diabetes mellitus, hypertension, obesity, and malignancy, are mainly attributed to immunosuppression.¹⁸ The prevalence of hypertension is reported to be 60% to 70%, and the effect of a calcineurin inhibitor on renal vasculature is considered a causative factor in liver transplant recipients.^6,18 In our study population, 38.6% of recipients developed hypertension after transplant.

It has been found that transplant recipients who receive tacrolimus-based immunosuppression develop hypertension less frequently, but tacrolimus is associated with increased prevalence of diabetes mellitus.^6,18 Tacrolimus was used as an immunosuppressant in most of our liver transplant recipients, which may be the attributing factor to the lower incidence of hypertension. In our study, 32.8% of patients developed diabetes mellitus after liver transplant. The prevalence of diabetes mellitus in transplant recipients is 30% to 40%, which is consistent with our results.¹⁸ Moreover, attributing factors, such as male sex, HCV infection, and calcineurin inhibitors, were also present in our recipients.

Dyslipidemia is an important risk factor to cardiovascular morbidity and mortality in post-transplant patients. Steroids and calcineurin inhibitors are among the important risk factors contributing to development of dyslipidemia in transplant recipients. In transplant recipients, the known incidence of dyslipidemia is 17% to 66%.¹⁸ We reported a dyslipidemia rate of 25% in our study population.

Our follow-up report of 76 living-related liver transplant recipients shows excellent outcomes. The main factor for living donations is the unavailability of donations from deceased donors. There is a major need for an efficient and sustainable deceased-donor program. A secondary need is public education and sensitization of our medical community and government.

Volume: 15 Issue: 1 February 2017 - Supplement - 1

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