Patient with Fabry disease undergoing cardiac surgery: a word of caution

Abstract

Fabry disease (FD) is a rare genetic disorder that affects various organs and systems in the body. The disease is caused by a deficiency in the lysosomal enzyme α-galactosidase A (AGAL), which leads to the accumulation of globotriaosylceramide (Gb3) within lysosomes. This accumulation can cause damage to cells and organ systems, leading to a wide range of symptoms and complications. FD is a heterogeneous disorder, with a wide range of clinical phenotypes, ranging from the classic form, which is severe and associated with early onset, to milder non-classical forms, which are often limited to one organ and manifest later in life. We describe the case of a 23-year-old FD patient who was admitted as an emergency transfer due to newly discovered severe aortic regurgitation and suspected aortic valve endocarditis with vegetations of high embolic potential. Three years ago, the patient underwent a living donor kidney transplantation—the kidney graft lost its function 1 year after transplantation, and a chronic hemodialysis program was reinstituted.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12055-024-01717-6.

Fabry disease (FD) is a rare X-linked lysosome storage disease [1]. Anderson and Fabry independently described patients with cutaneous manifestations of red and purple maculopapular lesions in 1898 [2], thinking it was a dermatological disease. However, Sweeley and Klionsky later recognized the condition as an X-linked multisystem lipid storage disorder [3].

The absence or inadequate amount of lysosomal enzyme α-galactosidase A (AGAL) [2] activity leads to a progressive accumulation of globotriaosylceramide (Gb3 or GL-3) within lysosomes of various cell types, including capillary endothelial cells, renal podocytes, tubular cells, glomerular endothelial, mesangial, and interstitial cells, as well as cardiac (cardiomyocytes and fibroblasts) and nerve cells [1]. Great importance is placed on establishing the diagnosis of FD, as well as assessing the disease severity and therapeutic monitoring, through the use of the deacylated derivative of Gb3, globotriaosylsphingosine (lyso-Gb3). Lyso-Gb3 is a valuable biomarker that mainly speaks to the burden of FD, as it reflects the severity of the disease and corresponds well with tissue accumulation of Gb3. The defective enzyme AGAL is transcribed from the q21, 22 regions on the long arm of the X chromosome. To date, more than 1080 mutations in the galactosidase alpha (GLA) gene have been detected, many of them of obscure significance [2].

FD has long been considered an adult disease, with most, if not all, affected men developing the “classic” phenotype. Female heterozygotes have been mistakenly described as “carriers of a defective gene” protected from the development of manifestations and symptoms of the disease. However, evolving knowledge regarding the natural course of FD suggests that it is more appropriate to describe it as a disease with a wide range of heterogeneously progressive clinical phenotypes [4, 5]. FD affects people around the world, regardless of ethnicity or nationality. Given the lack of a comprehensive international database on this rare disease, the challenge is to assess its true prevalence [3]. Several studies report a prevalence ranging from 1 in 476,000 to 1 in 117,000 based on estimates during neonatal screening for specific mutations [6].

The disease can be divided into a classic form and generally milder, non-classical phenotypes (so-called late-onset), mostly manifested as heart or kidney disease. In the severe classic form of FD, there is typically no residual enzyme activity. The late-onset FD patients often show more variable severity and disease progression, and it is often limited to one organ with mostly isolated renal or cardiac manifestations [2].

Individuals affected by FD will experience multiorgan dysfunction of the heart, kidney, and cerebrovascular system. Life-threatening cardiovascular or cerebrovascular complications can greatly impact normal life expectancy [1]. Therefore, early diagnosis of FD before irreversible organ damage occurs is of paramount importance. The average time from the onset of symptoms and signs of FD to proper diagnosis is 10.5 years for adults [2].

Patients with FD are at an increased surgical risk due to impaired renal and respiratory function, as well as cerebrovascular and cardiovascular diseases. Intraoperative monitoring of these patients, as well as the administration of anesthesia, can be a challenge [6]. However, very little is known about the implications of anesthetics in the treatment of patients with FD who have undergone surgery [6–9].

Case report

A 23-year-old patient was admitted as an emergency transfer due to newly discovered severe aortic regurgitation and suspected aortic valve endocarditis with vegetations of high embolic potential. The patient was initially hospitalized at the Department of Nephrology as an elective patient to perform a complete clinical check-up after the diagnosis of FD was established. Six years prior to this event, the patient was treated for a prolonged fever of unclear etiology at another hospital. Four years ago, the patient developed end-stage renal disease and was started on intermittent hemodialysis. Three years ago, the patient underwent a living donor kidney transplantation (with the mother as the donor). Due to the patient’s noncompliance, the kidney graft lost its function 1 year after transplantation, and a chronic hemodialysis program was reinstituted with a patent left arm distal arterio-venous fistula serving as a vascular access.

During admission, the patient was conscious, had a sub-febrile temperature (37.3 °C), was eupnoeic, and remained stable in terms of rhythm and hemodynamics. The patient reported no symptoms. Blood analyses revealed elevated values for renal parameters (urea 20.9 [2.5–7.5] mmol/l, creatinine 750 [50.0–120.0] µmol/l). The initial potassium level was 5.7 mmol/l. An electrocardiogram showed a typical hyperkaliemic pattern.

An echocardiogram was performed and confirmed the presence of a vegetation of unclear etiology on the aortic leaflets (Fig. 1, Video 1 and 2) with high embolic potential and severe aortic regurgitation (grade + 3/4) (Fig. 2, Video 3). The left ventricular myocardium was markedly hypertrophic, with a fine-grained echo structure, increased endocavitary dimensions, slightly reduced systolic function, and diastolic dysfunction grade 2 (pseudo normalization). The right heart was also slightly enlarged, and tricuspid regurgitation was severe (+ 4) with vegetations present on the tricuspid valve (Video 4).

Fig. 1.

Trans-esophageal echocardiography—vegetations on the aortic valve

Fig. 2.

Trans-esophageal echocardiography—massive aortic regurgitation

During the patient’s hospital stay, she had persistently high potassium levels while on regular hemodialysis. A nephrologist was consulted, who recommended emergency hemodialysis to be done 12 h before the operation. The patient’s potassium level was still elevated at 7.8 mmol/L on the morning of the operation and had significantly high levels of urea and creatinine. Despite these issues, the patient was given medication according to the hospital’s protocol and prepped for surgery.

Upon arriving in the operating room for anesthesia preparation, the patient had extremely high blood pressure (205/85 mmHg). Anesthesia was induced using propofol, sufentanil, xylocaine, and atracurium.

During the first blood gas analysis, pronounced hyperkalemia (potassium level 9.3 mmol/L) was observed, and the electrocardiogram (ECG) showed accompanying changes, which prompted immediate treatment with medications.

During the surgery, anesthesia was administered and adjusted using BIS monitoring, with a continuous intravenous infusion of sufentanil and atracurium at recommended doses, along with sevoflurane, with the goal of keeping the minimum alveolar concentration above 0.6. The patient’s ventilation was adjusted with a minute volume of 6–8 ml/kg to maintain an EtCO2 level of 35–45 mmHg, and tranexamic acid was also administered according to the hospital protocol. Hyperkalemia was corrected multiple times during the surgery (the potassium level before the start of extracorporeal circulation (ECC) was 6.3 mmol/l).

The aortic valve was found to be tricuspid, and all the leaflets exhibited signs of fibrotic thickening with multiple perforations in the region of the non-coronary and right coronary cusps (Fig. 3). Complete removal of the leaflets was carried out, and a mechanical two-leaflet Abbott Regent 23 mm valve was successfully implanted. The tricuspid annulus exhibited marginal dilation, accompanied by a discernible septal leaflet cleft. A minute fibrotic thickening was evident on the septal leaflet (Fig. 4). The decision was made to effectuate valve repair through the application of suture ring annuloplasty, coupled with direct suturing of the septal leaflet cleft (Video 5). A swab was collected during the procedure and sent for microbiological examination. Additionally, tissue samples were excised from the tricuspid and aortic valves for further histopathological diagnosis. Hemofiltration was used to remove excess volume during ECC. Potassium was corrected intermittently with medication.

Fig. 3.

Excised aortic valve

Fig. 4.

Intraoperative finding on the tricuspid valve

The specimen underwent staining using the hematoxylin and eosin (HE) method and subsequent examination. It comprised sections predominantly composed of calcified and fibrous tissues within the cusps, infiltrated by a rare presence of lymphocytes. Additionally, a substantial number of individual histiocytes, notably in the form of Anitschkow cells, and individual giant multinucleated cells, resembling Aschoff giant cells, were observed. Fibrin deposits were locally present on the fragment’s surface. These findings primarily indicated the existence of subacute and chronic forms of rheumatic endocarditis.

The patient was transferred to the Intensive Care Unit, hemodynamically and rhythmically stable, with corrected electrolyte levels. Hemodialysis was continued in the immediate postoperative period according to the established routine, and there were no electrolyte imbalances. The patient experienced complications after surgery, including the development of pericardial effusion, which was resolved on the tenth postoperative day through pericardial drainage under general anesthesia. On the 14th day, the patient was transferred back to the nephrology clinic for further evaluation and treatment in good condition. One month after the operation, the patient began enzyme replacement therapy (ERT) with agalsidase alpha, receiving 0.2 mg/kg intravenously every other week.

Discussion

FD is a debilitating, inherited metabolic disorder that progresses slowly. The buildup of globotriaosilceramide (Gb3) leads to damage in multiple systems [2]. Lyso-Gb3 is a valuable biomarker that primarily indicates the severity of the disease, as it reflects the burden of FD and corresponds well with the accumulation of Gb3 in tissues [1]. The frequency of cardiovascular manifestations ranges from 40 to 60% in FD patients, most often presenting as myocardial fibrosis and left ventricular hypertrophy [10]. Different cell types have been found to be affected due to chronic intracellular accumulation of Gb3, including endothelial cells, vascular smooth muscle cells, cardiomyocytes, conduction system cells, and valvular fibroblasts [1, 10]. Excessive Gb3 deposits within cardiomyocytes can also cause sarcomeric myofilament dysfunction and myofibrillosis [3, 10]. The accumulated data suggests that the pathological process in FD typically begins with Gb3 deposition as an initial step, followed by altered pathological signalling, subsequent inflammation, hypertrophy, and interstitial fibrotic processes [1, 2]. Furthermore, coronary microvascular ischemia due to endothelial dysfunction, impaired endocytosis/autophagy processes, and mitochondrial dysfunction may also contribute to the progressive disease in the myocardium [1]. Various cardiac arrhythmias have been identified, including bradyarrhythmia, conduction blocks, ventricular tachycardia, malignant forms of ventricular tachyarrhythmias, or sudden cardiac death [1, 10].

Renal complications are one of the most common manifestations of FD and can affect podocytes and glomerular, vascular smooth muscle, and tubular cells in the early stages of the disease [2]. Large amounts of Gb3 deposits have been found in different types of renal cells, and this can start very early in childhood, both in males and females with the classic form of FD. This highlights the importance of making an accurate diagnosis as early as possible. In specialized labs, findings of podocytes in urine can serve as an early sign of nephropathy before albuminuria or a decrease in the estimated glomerular filtration rate [1]. Podocyturia due to continuous loss of podocytes may precede proteinuria in FD, while proteinuria probably indicates a more advanced stage with glomerular involvement [1, 11]. Data from the US Dialysis Registry showed that FD may represent 0.01% of patients with end-stage renal disease, likely due to continuous and irreversible cellular loss of glomeruli and podocytes without early ERT [1].

In addition to cardiovascular and renal symptoms, other organs are also affected by FD. The disease can manifest with various symptoms depending on the organ involved—central nervous system: transient ischemic attacks and strokes, depression, anxiety; respiratory system: dyspnoea, obstructive pulmonary disease; gastrointestinal tract: gastrointestinal pain, diarrhea, nausea, and vomiting. FD is also presented by hypo-, or anhidrosis, small fiber neuropathy, tinnitus, hearing loss, angiokeratomas, lymphedema, osteopenia, osteoporosis, and facial dysmorphism [2, 3]. Patients with Fabry disease present a multifaceted challenge for cardiac surgery due to the complex nature of this genetic disorder. Metabolically, these individuals often exhibit derangements, with signs of hyperkalemia being particularly noteworthy. Hyperkalaemia, characterized by elevated potassium levels, introduces a heightened risk for severe rhythmic disturbances that can potentially lead to cardiac arrest, necessitating meticulous monitoring and management during surgery.

Cardiac surgeons must possess a comprehensive understanding of the ramifications of Fabry’s disease in the context of surgical decision-making. Special attention is required for considerations related to myocardial protection and the application of cardioplegia, especially in light of the potential presence of deposits within the coronary arteries as well as hyperkaliemic status.

Beyond metabolic concerns, Fabry disease is intricately linked to severe forms of cardiomyopathy and myocardial fibrosis. The cardiac manifestations of the disease involve structural alterations in the heart muscle and fibrous tissue, posing increased risks during surgical interventions. The potential presence of myocardial fibrosis can complicate surgical procedures, impacting both the immediate and long-term outcomes.

Additionally, the overall course of cardiac surgery is further complicated by the unpredictable status of Fabry disease in individual patients. The variability in disease progression and manifestation necessitates a personalized approach to surgical planning and execution. Furthermore, FD is not limited to the cardiovascular system; it affects multiple organ systems in the body, making it challenging to predict and address potential interactions during surgery.

The intricate relations between FD and various systems, such as the renal, nervous, and vascular systems, introduce additional layers of complexity. Understanding and managing these interactions are crucial for ensuring a successful surgical outcome. Therefore, comprehensive preoperative assessments and tailored perioperative care are essential for navigating the challenges posed by Fabry disease during cardiac surgery. Collaborative efforts between cardiac surgeons, geneticists, and other specialists are instrumental in optimizing the surgical approach and improving overall patient outcomes.

In a study conducted by Kampmann and colleagues involving 50 patients with FD, the prevalence of heart valve diseases was reported as follows.

• Aortic valve thickening (25.5%)

• Mitral thickening with mild insufficiency (25.5%)

• Mitral valve prolapse (10.9%) [12].

Recent investigations have indicated that structural changes, including increased valve thickness and prolapse, are more prominent in the mitral valve compared to the aorta. Linhart et al., in a study encompassing 30 patients with FD, reported a 57% prevalence of mitral abnormalities and a 47% prevalence of aortic valve abnormalities [13].

During cardiac surgery in individuals with FD, it is imperative to bear in mind the possibility of deposits on heart valves, whether they are mitral or aortic. While ERT may contribute to slowing the progression of these deposits, a thorough examination of the valves is essential. This evaluation becomes particularly crucial when deciding whether to repair or replace the affected valves.

In the case of FD patients undergoing cardiac surgery, it is noteworthy that the condition does not preclude the possibility of mitral or tricuspid valve repair, provided it is technically feasible and the patient is actively receiving ERT. However, it is important to acknowledge the current lack of long-term data regarding the durability of such repairs in the specific context of Fabry’s disease.

Due to the small number of surgeries performed under general anesthesia in patients with FD, there is no general recommendation or protocol for ideal preoperative preparation [9]. Preoperative assessment must be personalized and identify all patient-specific concerns. It is necessary to focus on identifying organ dysfunction, with special attention to the heart, kidneys, lungs, and brain [7].

Short interval between the beginning of the P wave and the beginning of the QRS complex of an electrocardiogram (PR interval), sinus bradycardia, and atrioventricular conduction disorders are not unusual findings in FD [2]. The presence of posterolateral fibrosis can cause ST segment depression and T-wave inversion in inferolateral electrodes in some patients [1]. ECG changes that can be observed are also shortened PR interval, reported most often in the earlier phase of the disease, probably due to altered cellular conduction properties from intracardiac Gb3 deposition [1, 10]. In contrast, prolongation of PR and subsequent atrioventricular (AV) block are not uncommon in the later phase of the disease, making these new findings useful in the identification of FD [10].

Patients with renal insufficiency require a thorough examination of their renal function before surgery [5]. The main challenges in anesthesia for these patients are related to the underlying disease, the effects of chronic renal failure on drug metabolism, and the effect of anesthesia on renal function. In advanced stages of renal failure, certain drugs that are eliminated by the kidneys may have prolonged elimination times [9]. It is crucial to closely monitor these patients’ hemodynamics and develop a protective strategy in advance for those who have had a kidney transplant [7]. In the case described here, a nephrologist was consulted, and emergency hemodialysis was performed 12 h before the operation to correct persistent hyperkalemia. The patient was on a chronic hemodialysis program after a previously failed kidney transplant.

Patients with FD may have an accumulation of globotriaosilceramide substrate in the respiratory system and may have obstructive airway disease; therefore, preoperative hydrocortisone treatment should be considered. Bronchodilators may be used, but it is best to avoid treatments or medications that cause histamine release [7]. Sorbello and colleagues reported one patient who had unexpected difficulty with intubation [7].

Anesthesia should be administered considering the patient’s specific risk factors and attention should be paid to their cardiopulmonary function. The dosage of the drugs should be adjusted to their renal function [6]. The use of fentanyl, lidocaine, propofol, rocuronium, and cisatracurium for induction of general anesthesia has been reported as safe [7, 9].

Because patients may suffer from symptoms of autonomic dysfunction, such as decreased sweating, gastrointestinal pain, and changes in gastrointestinal motility and heart rate, anaesthesiologists should be careful when using neostigmine, glycopyrrolate, and atropine to reverse relaxants [8]. Additionally, to eliminate rocuronium, sugammadex should be used with caution in patients on renal hemodialysis, as it is not recommended for use in patients with renal impairment. Our patient was transferred to the intensive care unit without waking up, so there was no need to prescribe decurarization.

Conclusion

FD is a rare, multisystem disorder that can cause severe and life-threatening complications. It is important for healthcare professionals to be aware of the disease and its manifestations in order to make an accurate diagnosis as early as possible. Surgery in patients with FD can be challenging and requires a multidisciplinary approach. Cardiac surgeons must possess a comprehensive understanding of the ramifications of Fabry’s disease in the context of surgical decision-making. With the availability of enzyme replacement therapy, early diagnosis and treatment can prevent or delay the progression of organ damage and improve the patient’s quality of life.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contribution

All authors contributed equally to the design and writing of the paper and provided final approval.

Funding

Autonomous Province of Vojvodina—Projects of importance for the development of scientific research activities. Award Number: 142–451-2568/2021–01 | Recipient: Lazar Velicki, MD, PhD.

Declarations

Ethical approval

Not applicable.

Consent to participate

Informed consent was obtained from the participant included in this case report, and stringent measures were implemented to ensure confidentiality and anonymity.

Conflict of interest

No competing interests exist.