First report of successful liver transplantation following supermicrosurgical lymphaticovenous anastomoses for lymphorrhea with intractable infection: A case report

Abstract

BACKGROUND

Liver transplant (LT) candidates face a heightened risk of infection both pre- and post-transplant, owing to immunosuppressive therapy and complications from chronic liver disease. Infections during the pre-transplant period, such as lymphorrhea-induced cellulitis, can cause significant delays in transplantation and increase mortality while on the waiting list. Lymphorrhea, characterized by substantial lymphatic leakage and recurrent skin infections, presents a significant challenge in managing patients who are already immunocompromised. Effective preoperative infection control is critical to enhancing the prospects for a successful liver transplantation.

CASE SUMMARY

We report the case of a 50-year-old female diagnosed with Hepatitis C virus-related cirrhosis (Child-Pugh C) and recurrent cellulitis due to lymphorrhea in her left lower leg. She suffered repeated episodes of cellulitis over five years, which prevented her from undergoing LT. Initial conservative treatments were unsuccessful in managing the lymphatic leakage and accompanying infections. In February 2019, she underwent supermicrosurgical lymphaticovenous anastomoses (LVA) to address her lymphorrhea. This procedure, which created multiple lymphatic-venous connections in the lower limb, led to significant improvements in her condition. After the LVA, she experienced no further episodes of cellulitis. Eighteen months later, she successfully underwent a deceased donor liver transplantation. Postoperative complications, including a wound hematoma, were effectively managed, and she was discharged 3 months post-operation. At her 3-year follow-up, her liver function was stable, with no recurrence of cellulitis.

CONCLUSION

Despite numerous challenges, the patient achieved a successful recovery with satisfactory graft function and was free from lymphorrhea/lymphedema in her left lower limb 3 years post-transplantation. This case underscores the importance of robust infection control during both the pre- and post-transplantation phases and highlights the potential of LVA as a treatment option for managing lymphorrhea and infections in patients with liver cirrhosis.

Key Words: Liver cirrhosis; Liver transplantation; Hepatitis C; Lymphorrhea; Cellulitis; Lymphaticovenous anastomosis; Case report

Core Tip: Lymphorrhea, characterized by significant lymphatic leakage, frequently leads to repeated skin infections that can preclude liver transplantation and increase the risk of dropping out of the waiting list. We present the case of a 50-year-old female patient with Hepatitis C virus-related liver cirrhosis and left lower leg lymphorrhea, which caused repeated episodes of cellulitis. This condition was successfully treated with supermicrosurgical lymphaticovenous anastomoses (LVA), followed by a deceased-donor liver transplantation. This case underscores the importance of stringent infection control both before and after transplantation and highlights LVA as a viable treatment option for managing lymphorrhea and infections in patients with liver cirrhosis.

INTRODUCTION

Infection poses a significant challenge in liver transplant (LT) candidates, particularly in those with decompensated cirrhosis. During the post-transplant period, managing infections becomes complicated owing to immunosuppressant use, which impairs the body’s ability to combat pathogens and are associated with poor outcomes. In the pre-transplant period, uncontrolled infections may lead to a temporary suspension of LT and increased mortality while on the waiting list. Lymphorrhea, characterized by prominent lymphatic leakage and persistent infection, represents the most severe form of lymphedema[1]. Approximately 200 million people globally are affected by various degrees of lymphedema. It remains a significant public health issue even in developed Asian countries. For instance, a 2024 statistical report from Korea indicates an annual incidence rate of about 1.85 per 1000 individuals[2]. The lymphatic system, a branching tubular network that extends around blood vessels and into organs, is essential for the human immune and circulatory systems. Notably, the liver produces approximately 25%-50% of the body’s lymph, which recirculates through the bloodstream via the thoracic duct[3]. As cirrhosis progresses, it overwhelms the lymphatic compensatory mechanisms, leading to the development of ascites and edema, which can cause complications such as recurrent soft tissue infections[4]. The incidence of concurrent lymphedema in cases of liver disease is significant. Clinical guidelines recommend that treatment for lymphedema should aim to reduce limb volume and prevent severe infections[5]. Initial treatment should focus on conservative measures such as manual lymphatic drainage, physical therapy, multilayer bandaging, limb elevation, exercise, and skincare. Surgical treatments, which are supported by a lower level of evidence, are recommended only for selected patients, including those with severe deformity from swelling, unsuccessful conservative treatment, poor response to compression therapy, recurrent cellulitis, or intractable pain. In our case of a high-risk patient with lymphorrhea, non-invasive management proved ineffective, leading to continued bouts of recurrent cellulitis. Owing to the high surgical and anesthetic risks associated with liver cirrhosis complications, more invasive options like extirpative reduction and debulking surgery were deemed unsuitable. After careful evaluation, lymphaticovenous anastomoses (LVA) was considered the most suitable treatment option.

Herein, we present a case involving a female patient with Child-Pugh C hepatitis C virus (HCV)-related cirrhosis and lower left leg lymphorrhea accompanied by repeated episodes of cellulitis. This patient was successfully treated with supermicrosurgical LVA and later underwent deceased donor liver transplantation (DDLT). The interplay of severe liver cirrhosis and refractory infections due to lymphorrhea posed significant challenges. This case report not only underscores the importance of stringent infection control but also offers a potential solution for similar clinical scenarios. Additionally, it exemplifies the critical role of interdisciplinary consultation and collaboration in providing timely and effective treatment for patients with complex conditions.

CASE PRESENTATION

Chief complaints

A 50-year-old Asian female patient who presented with anorexia, reduced urine output, and tea-colored urine was referred to our department in July 2014.

History of present illness

The patient had recurrent episodes of biliary tract infection and lower limb cellulitis.

History of past illness

She had a history of hepatitis C infection, hypertension, esophageal varices, and coagulopathy.

Personal and family history

No family history of liver disease.

Physical examination

The patient’s vital signs were stable, although she exhibited jaundice, bilateral leg edema, and gradual lymphatic leakage from the skin of her lower left leg. Additional findings included hyperkeratosis and a positive Stemmer sign (Figure 1).

Figure 1 Clinical images and magnetic resonance volumetry comparison before and after supermicrosurgical lymphaticovenous anastomosis. A: Appearance of the lower left limb prior to the lymphaticovenous anastomoses (LVA) procedure; B: The lower left limb 1 year after the LVA procedure; C: Pre-LVA volumetric measurements of the right and lower left extremities, recorded at 6871.9 and 8743.8 mL, respectively; D: Post-LVA volumetric measurements of the right and lower left extremities 1 year later, recorded at 6054.7 and 5934.3 mL, respectively. LVA: Lymphaticovenous anastomoses.

Laboratory examinations

Initial laboratory results revealed the following: Glutamic-oxaloacetic transaminase (GOT): 234 U/L, glutamic-pyruvic transaminase (GPT): 71 U/L, international normalized ratio (INR): 2.06, creatinine: 0.51 mg/dL, sodium: 136 mEq/L, albumin: 2.2 g/dL, total bilirubin: 9.9 mg/dL, and prothrombin time: 22.1 s. The Model for End-Stage Liver Disease (MELD) score was 23.

Imaging examinations

Abdominal and liver computed tomography scans showed liver cirrhosis with refractory ascites, esophageal varices, and partial portal vein thrombosis. Lymphoscintigraphy and indocyanine green lymphography revealed partial obstruction of lymphatic drainage and diffuse dermal backflow over the lower left leg.

FINAL DIAGNOSIS

The patient was diagnosed with Child-Pugh C HCV-related cirrhosis and stage 3 lymphedema accompanied by severe lymphorrhea.

TREATMENT

The patient was diagnosed with Child-Pugh C HCV-related cirrhosis, characterized by refractory ascites, repeated esophageal varices bleeding, and partial portal vein thrombosis. Owing to her end-stage liver disease and the absence of a compatible living donor, she was placed on the waiting list for a LT. Concurrently, she experienced bilateral leg edema, gradual lymphatic leakage from the skin of her lower left leg, hyperkeratosis, and a positive Stemmer sign (Figure 1), which raised significant concerns regarding her suitability for LT under these conditions[6]. She received conservative treatment for recurrent cellulitis in her lower left leg until February 2019, when she was referred to the Plastic Surgery Department for comprehensive evaluation. Lymphoscintigraphy and indocyanine green lymphography confirmed stage 3 lymphedema with severe lymphorrhea upon results showing partial obstruction of lymphatic drainage and diffuse dermal backflow in her lower left leg[7]. A supermicrosurgical LVA was then performed to alleviate the lymphedema. The procedure involved creating five anastomoses in the dorsal foot, below the knee, and middle thigh areas to facilitate the drainage of stagnant lymph into the recipient’s vein. The lymphatic ducts measured between 1.0-1.5 mm, matching the venule sizes. Nylon 11-0 sutures were used for the LVA anastomoses. Indocyanine green was employed intraoperatively to identify the lymphatic ducts and to evaluate flow and ectasis following the anastomoses. The success of the procedure was evidenced by a significant reduction in limb volume, as verified by post-LVA magnetic resonance volumetry (Figure 1).

Following the LVA, there was a marked improvement in the condition of the patient’s lower left leg, including the cessation of lymphorrhea and resolution of recurrent cellulitis. After successfully managing the severe lymphedema, the patient was readmitted for an LT evaluation. Laboratory results confirmed Child-Pugh C cirrhosis with a MELD score of 21, characterized by an INR of 1.85, creatinine 0.51 mg/dL, sodium 144 mEq/L, albumin 2.04 g/dL, and total bilirubin 7.4 mg/dL. Computed tomography angiography revealed complete portal vein thrombosis with wall calcification (Yerdel’s grade 4). Eighteen months after the LVA, the patient underwent a DDLT using a right liver graft without the middle hepatic vein. The surgery included a portal vein thrombectomy and stent insertion. The total blood loss was 2800 mL, managed without vasopressors. On postoperative day 1, a complication arose in the form of a surgical wound hematoma, requiring exploratory laparotomy, classified as grade 3B in the Clavien–Dindo classification. The patient was administered mycophenolate mofetil and tacrolimus for post-transplant immunosuppression. Her liver function subsequently normalized, and she was discharged 3 months post-transplantation.

OUTCOME AND FOLLOW-UP

At the 3-year follow-up, the patient’s liver function remained stable, with an INR of 1.31, creatinine: 0.84 mg/dL, albumin: 4.34 g/dL, total bilirubin: 0.7 mg/dL, GOT: 19 U/L, and GPT: 12 U/L. There has been no recurrence of cellulitis (Figure 2).

Figure 2 Long-term comparison of preoperative and postoperative conditions. A: Clinical image from the preoperative phase; B: Condition of the bilateral lower legs 3.5 years after lymphaticovenous anastomosis and 2 years following liver transplantation. LVA: Lymphaticovenous anastomoses.

DISCUSSION

In this case, recurrent infections delayed the patient’s eligibility for an LT for > 5 years. Following a successful LVA, she underwent a DDLT and experienced a favorable outcome over a 3-year follow-up. Previous reviews indicate that active infections and uncontrolled sepsis are contraindications for LT[8]. Eradicating the source of infection is essential before proceeding with transplantation. Additionally, several studies highlight that peritransplant infections and sepsis can significantly increase 90-day mortality[9]. Another retrospective study involving 24122 LT recipients found that those with preoperative infections were more likely to experience postoperative complications such as effusions, infections, abdominal bleeding, biliary complications, and lower overall survival rates[10]. Conversely, a study including 466 LT cases demonstrated that although pre-transplant infections increased the incidence of postoperative infections and septic shock, they did not significantly impact overall survival rates, suggesting that transplantation should not be delayed if the infection is adequately managed[11]. However, these reviews mostly address infections related to single events. In our case, the infections were recurrent and predictable, with prolonged antibiotic use potentially leading to resistance and increasing post-transplantation risks. Therefore, controlling recurrent cellulitis in this case was mandatory. Although studies on preoperative cellulitis are limited, the necessity for LVA surgery intervention has become increasingly clear.

Lymphedema can be classified into primary and secondary forms, with primary lymphedema typically being congenital and secondary lymphedema often resulting from cancer, surgery, trauma, or infection. As no known causes of lymphedema/lymphorrhea could be identified, lymphedema tarda, a primary lymphedema that occurs after the age of 35, is the most likely diagnosis[12]. For our patient’s treatment, nonsurgical management, known as complex decongestive therapy[7], which includes manual lymph drainage, compression garments, and skin care, was unsuitable owing to her infectious condition. Surgical options such as vascularized lymph node transfer and liposuction were also impractical because of the high risk of recipient site infection, which could lead to complications such as flap pedicle thrombosis, flap failure, and extensive subcutaneous infection following liposuction. Accordingly, for patients with high perioperative risk due to cirrhosis and recurrent cellulitis, supermicrosurgical LVA presents a viable alternative. LVA, a type of supermicrosurgery, involves connecting small lymphatic ducts (0.3-0.8 mm) to veins to facilitate the drainage of obstructed lymph into the venous system, thereby improving lymphedema. LVA has proven effective in treating severe lymphedema, reducing oxidative stress, and restoring dysregulated gene expression in patients with lymphedema[1]. It also significantly lowers the frequency of cellulitis, reduces limb volume, and enhances quality of life[13]. Concerning infection control, a study involving 150 cases showed that the average number of cellulitis episodes within 1 year post-surgery was only 0.31 times that of pre-surgery, a significant reduction from the preoperative frequency[14]. These findings indicate that LVA can be an effective method for managing infections prior to LT.

Although the relationship between cirrhosis and lymphedema remains unclear owing to a lack of extensive studies, an observational study by Arya et al[15], that included 155 cases of cirrhosis with ascites, found that 33.5% of the cases exhibited varying degrees of lymphedema, and 44.5% had lymphatic dysfunction. The liver, as the primary organ for protein synthesis and a crucial component of the portal venous system, significantly influences the distribution of body fluids. As liver function deteriorates and portal pressure increases, more fluid accumulates in the interstitial space, placing a greater burden on the lymphatic system and eventually leading to its damage[16]. This case highlights a feasible strategy for managing the interconnected issues of infection, lymphedema, and cirrhosis.

CONCLUSION

Despite facing numerous challenges, the patient achieved a successful recovery with satisfactory graft function and was free from lymphedema/lymphorrhea in her lower left limb 3 years after transplantation. This case emphasizes the importance of rigorous infection control during both the pre- and post-transplantation phases and highlights the potential of LVA as a treatment option for lymphorrhea and infection in patients with liver cirrhosis.