Mouth Ulcers in Liver Transplant Recipients as an Adverse Reaction to Tacrolimus Used in Immunosuppressive Therapy: A Report of 2 Cases

Introduction

Oral lesions are very common in solid organ recipients and in hematopoietic stem cell transplant patients and can be related to the use of immunosuppression to prevent transplant rejection. Improvements in surgical techniques and the use of modern immunosuppressants have increased the long-term survival of transplant recipients, but they are still at high risk of oral lesions [1].

Immunosuppression is inhibition of production of antibodies and immune cells by various agents called immunosuppressors, usually pharmacologically-induced by immunosuppressants. Immunosuppressive therapy (IST) leads to a lowering of the body’s immune system function [2]. Immunosuppression can be achieved in a variety of ways, including surgical removal of specific organs of the immune system, physical methods (eg, X-ray radiation), or chemical methods (eg, pharmacological preparations) [2]. In addition to its desirable effects, IST can also cause general suppression of the body’s immune system, which increases susceptibility to viral, bacterial, and fungal infections and increases the risk of various malignancies.

Long-term use of immunosuppressants such as cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil is a prerequisite for maintaining the transplanted organ [3]. Adverse reactions to the drugs used can include systemic infections, neoplastic lesions, post-transplant lymphoproliferative disorder (PTLD), and agranulocytosis, while the oral cavity can present with aphthous ulcers, leucoplakia, glossitis, erosions and ulcers, exophytic lesions in the oral mucosa, gingival hypertrophy, and mucosal hyperplasia.

The most commonly used immunosuppressant in liver transplant recipients is tacrolimus. According to some authors, tacrolimus causes fewer oral complications than cyclosporine.

In the literature, erosions and ulcers are also described as possible adverse reactions to mycophenolate mofetil, but there are only single reports of erosive and ulcerative oral lesions as adverse effects of tacrolimus [1,4–6].

Oral lesions described as an adverse reaction to tacrolimus include mucosal hyperplasia, exophytic lesions, and PTLD. Clinically, oral lesions appear to be closely related to tacrolimus intake as a toxic effect or a complication of immunosuppression.

We describe 2 cases of liver transplant recipients who developed ulcers in the oral mucosa during therapy with Prograf (Astellas).

Case Reports

FIRST CASE REPORT:

A 14-year-old boy underwent liver transplantation with simultaneous splenectomy in February 2019 due to cirrhosis secondary to extrahepatic biliary atresia. Since the day of transplantation, he has been treated with IST with tacrolimus (2×3 mg) and mycophenolate mofetil (2×300 mg). Tacrolimus levels after LTx ranged from 4.6 ng/ml (Table 1) to a maximum of 10.2 ng/ml (Table 1). In May 2019, he was diagnosed as having oral mucosal lesions at the Children’s Dental Clinic of the Children’s Memorial Health Institute.

In early May 2019, during a visit at the Liver Disease and Liver Transplant Clinic of the Children’s Memorial Health Institute, he was consulted by an ENT specialist and a dentist due to the presence of whitish lesions in the oral mucosa, persisting for about a month. The TAC level at that time was 5.6 ng/ml (Table 1). Dental examination revealed mixed dentition consistent with age, small carious cavities in teeth 54 and 74, and mucosal lesions in the palatoglossal arch, palatopharyngeal arch, and in right palatine tonsil, partially covered by fibrin with rolled edges (Figure 1A, 1B). Topical disinfectants and anesthetics were recommended as well as a follow-up visit at the Dental Clinic after 14 days and, in the absence of improvement, a biopsy of the lesions.

In the second half of May 2019, he was urgently admitted to the Organ Transplantation Unit of the Children’s Memorial Health Institute for suspected PTLD. Clinical examination revealed ulcer-like lesions in the left buccal mucosa, right palatal arch, palatine uvula, and lower lip. He reported severe pain when speaking and eating. The TAC level at admission was 7.4 ng/ml (Table 1). Due to the deteriorating health status of the oral mucosa, mycophenolate mofetil was discontinued in IST, as MMF is typically associated with the development of ulcerative stomatitis. Prednisonum 5 mg/day was initiated, and we added antimicrobial therapy (amoxicillin 1×500 mg and sulfamethoxazole + trimethoprim 1×480 mg every other day) and antifungal therapy (nystatin 1×1 tablet 500 000 IU, fluconazole). There was no improvement in the local condition (Figure 2A, 2B), the lesions enlarged, new ulcers appeared, and necrotic lesions were found within the gingival papillae. Metronidazole was added to the treatment, which was then changed to clindamycin due to neutropenia. There was no clinical improvement, with a further decrease in neutrophil levels to 0.000/μl. Serological tests excluded viral components, including Epstein-Barr virus (EBV). Sections of the lesions were taken twice for histopathological examination, and they were described as fragments of non-specific granulation tissue, tissue with lymphoid cell infiltration and granulocyte infiltration, with visible necroinflammatory fragments, with no infiltrates typical for PTLD.

After consultation with the attending physician, biostimulation laser therapy of the lesions was applied, but there was no improvement in the local condition. Immunosuppressants were changed again – tacrolimus was discontinued and cyclosporine was started, initially at a dose of 2×60 mg, which was increased to 2×70 mg due to its low levels in the patient’s blood (72 ng/ml). After 1 week, blood Cs levels were measured again (65 ng/ml) and the dose was increased to 2×100 mg/day. After tacrolimus was discontinued, gradual resolution of the oral lesions was achieved (Figure 3A, 3B) until they were completely healed after 10 days, with rapid improvement in the patient’s well-being and resolution of pain within just 3 days. In mid-June 2019, he was discharged home from the hospital in good general health.

SECOND CASE REPORT:

A 5-year-old girl underwent liver transplantation in July 2019 due to cirrhosis of undetermined etiology. The girl had similar lesions in the oral mucosa. She was treated with tacrolimus (2×1.25 mg) and mycophenolate mofetil (2×75 mg) starting on the day of transplantation. Tacrolimus levels after LTx ranged from 4.4 ng/ml (Table 2) to a maximum of 15.9 ng/ml (Table 2). She was diagnosed with cirrhosis at the Children’s Dental Clinic of the Children’s Memorial Health Institute in November 2019 due to lesions in the oral mucosa.

In mid-November 2019, during hospitalization in the Organ Transplantation Unit of the Children’s Memorial Health Institute due to suspected biliary tract infection (an increase in inflammatory and hepatic parameters, CRP 1.79 mg/dl, GGTP 314 U/l, and TAC levels 13.2 ng/ml) (Table 2), she was referred for a dental consultation due to oral mucosal lesions. The clinical examination revealed incomplete deciduous dentition consistent with age, without active foci of caries, and generalized gingivitis with a necrotic component in the region of the maxillary and mandibular incisors (Figure 4A, 4B). Topical anesthetics and disinfectants were recommended and metronidazole was included in the treatment due to suspicion of infection with anaerobic bacteria. Oral swabs were taken for cultures. During subsequent dental check-ups, the local condition worsened, the lesions did not improve, and new ones appeared in the form of blisters on the left side of the tongue tip. Tacrolimus levels gradually fell due to dosage decrease and were maintained at below 6 ng/ml (Table 2). Amoxicillin and clavulanic acid extended-release (2×3.5 ml) were included in the treatment and metronidazole was discontinued. Ozone therapy did not result in improvement. The girl’s general health status deteriorated, inflammatory markers remained elevated (CRP increased to 5.74 mg/dl, GGTP to 334 U/l), and the neutropenia progressed. Extraoral examination revealed that the left submandibular lymph node was enlarged to 1.5 cm. Based on these symptoms, we began to suspect PTLD. A biopsy of the lymph node and oral mucosal lesions was scheduled.

In the following days, her general health status still did not improve, she had a fever, there was a continuous increase in CRP levels (up to 7.74 mg/dl) despite extensive antibiotic therapy (amoxicillin and clavulanic acid, ceftazidime, amikacin), and neutrophil levels were low and remained at 0.6000/μl. EBV DNA was detected in her blood (278 copies in plasma), and viral etiologies of HSV, HCV, and HIV were excluded. The lymph node histopathology report revealed tissue composed of a heterogeneous cell population with few immunoblasts and single lymphatic follicles.

Examination of a fragment taken from the oral cavity revealed small gingival fragments with the presence of abundant infiltrates of lymphoid cells (both B and T cells), granulocytes and histiocytes, and stratified squamous epithelium infiltrated by inflammatory cells. Moreover, there were visible necroinflammatory masses with bacterial colonies. An oral swab culture grew methicillin-resistant Staphylococcus aureus (MRSA); therefore, cloxacillin was included in the treatment. Blood swab cultures for aerobic and anaerobic bacteria showed the presence of physiological bacterial flora, and no fungi were present. New erosive and vesicular lesions began to appear in the buccal mucosa (Figure 5A, 5B).

At the end of November, the IST was modified – cyclosporine (40 mg+50 mg) and prednisonum (1×5 mg) were included, while mycophenolate mofetil and tacrolimus were discontinued. There was improvement in her general health status, she no longer had fever, her CRP levels started to decrease (0.66 mg/dl), and neutrophil levels started to increase up to 3.6000/μl. Initially, there were no local improvements in the oral cavity. The lesion on the tongue enlarged, and only a slight improvement was found in the buccal mucosa and in the gingivae.

In the following 2 days, the oral mucosal lesions began to resolve (Figure 6A, 6B) until they were completely healed. Neutrophil levels were normal and we decided to reinitiate mycophenolate mofetil as part of IST. Due to abnormal liver parameters, she stayed in the hospital for another month. During this time, there was no recurrence of the oral mucosal lesions.

Discussion

Oral mucosal ulcers can be an adverse reaction to immunosuppressants used in organ transplant recipients [4–7]. The presence of ulcers in these patients should initially suggest a viral infection (especially HSV and CMV infections), as mouth ulcers of viral origin are common in immunocompromised patients [1], such as HIV-infected patients, but are also frequently observed in transplant recipients [8–10].

As with other drugs, the pharmacokinetics of tacrolimus shows significant person-to-person variation. Pediatric patients need higher doses of tacrolimus than adults to achieve similar blood levels [11]. For these reasons, frequent monitoring of the drug blood levels allows the dose to be adjusted to the individual patient’s requirements and the desired level of immunosuppression [1]. In the 2 patients reported here, blood levels of Prograf gradually increased from the time of transplantation to the appearance of oral mucosal lesions [1]. The disappearance of symptoms after tacrolimus dosage reduction and following decrease of TAC whole blood concentration suggest a close relationship between the drug and the presence of oral lesions [1].

The lesions should also be differentiated from mucosal injuries, blistering skin diseases, autoimmune and proliferative diseases, and hematological abnormalities [12,13]. Other possible etiological agents of the lesions, including viruses and fungi, were excluded in the cases described in the literature and reported in our patients. Antiviral therapy was unsuccessful.

Patients commonly deny having oral mucosal ulcers prior to organ transplantation [5]. There are single reports of ulcerative and erosive lesions in the oral mucosa as an adverse effect of tacrolimus [1,4–6], and there have been more reports of adverse reactions to mycophenolate mofetil [4,12–16]. Lesions usually appear within a few months after starting therapy with tacrolimus [4,5], as in our 2 patients. In the cases described in the literature, the lesions began to resolve shortly after discontinuation of therapy with tacrolimus [4–6], similar to our patients, with lesions healing within days of modifying IST.

The mechanism of the development of ulcer-like lesions in the oral mucosa during therapy with tacrolimus is not known. Additional case reports and further studies are required to better understand the relationship between drug doses, immunosuppression level, and the presence of mouth ulcers.

Conclusions

Necrotic and ulcerative oral lesions can result from an adverse reaction to tacrolimus used in IST. Lesions of this nature occurred in both of our patients. After tacrolimus was discontinued, there was complete healing of the lesions in 3–4 weeks. Tacrolimus-induced necrotic oral ulcers are a rare adverse reaction and should be considered in the differential diagnosis for organ transplant patients with mucositis who are on tacrolimus therapy.