Hepatic Epithelioid Hemangioendothelioma Diagnosed through 18F-Labeled Fluoro-2- Deoxyglucose Positron Emission Tomography

Introduction

Hepatic Epithelioid Hemangioendothelioma (HEHE) is a rare malignant type of vascular tumor composed of epithelioid and histiocytoid endothelial cells in a myxohyaline or fibrous stroma. It is often misidentified as a metastatic tumor if it is multifocal in the liver or if the patient has another concurrent primary malignancy. HEHE cells can be classified into three histological types: epithelioid, dendritic, and intermediate cells. Most patients with HEHE are asymptomatic and receive their diagnoses incidentally. Liver core biopsy is the standard method for diagnosing HEHE. the typical imaging features of HEHE include enhancement on arterial-phase CT scans and low signals on venous-phase and delayed-phase CT scans. In addition, 18F-labeled fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET) usually reveals increased 18F-FDG uptake. Hepatectomy and liver transplantation are firstline treatments for HEHE. If a patient cannot receive surgery, then antiangiogenic drugs, radiotherapy, chemotherapy, radiofrequency ablation, or transcatheter arterial chemoembolization may be considered. The prognosis of HEHE is generally more favorable than that of other malignant liver tumors. Herein, we present the case of a patient with buccal cancer and HEHE. The patient underwent segmental hepatectomy and had no recurrence at a 3-month follow-up.

Case Report

A 50-year-old male with chronic hepatitis C reported having engaged in habitual smoking and betel nut chewing for over 20 years. He complained of odynophagia and tenderness over his left buccal area for 2 months. He visited a physician for help. An ulcerative lesion was discovered over his left buccal area. A biopsy of the lesion was performed, and pathology revealed squamous cell carcinoma. PET was therefore arranged for cancer staging. The PET revealed a hypermetabolic lesion of approximately 0.55 cm without definite evidence of nodal or distant metastasis (Figure 1). The patient’s stage was tentatively denoted as T1N0M0. However, some hypermetabolic nodules (of up to 2 cm) in the right hepatic lobe were also observed (Figure 2). Malignant tumors or metastasis was suspected. The patient’s tumor markers, including αFP, CEA, and CA19-9, were within the normal limits. The patient was transferred to the gastrointestinal clinic for further management. The patient’s liver tumors were further investigated through abdominal sonography; some of the lesions were hyperechoic (Figure 3a), and others were hypoechoic (Figure 3b). The patient also underwent CT. Some nodules were observed in the patient’s liver; two were heterogeneous tumors (1.2 and 1.9 cm) with delayed-phase enhancement in the S4b and S5 segments (Figure 4a), and the others were identified as hemangiomas (Figure 4b). Liver biopsy was arranged for the S4b and S5 tumors. The final pathology revealed epithelioid hemangioendothelioma. Segmental hepatectomy was arranged after the patient had recovered from buccal cancer surgery. The surgical specimens were sent to a pathologist, and the diagnosis of epithelioid hemangioendothelioma was finalized. A CT scan was performed 3 months later and revealed no recurrence of the liver tumors (Figure 5).

Figure 1: A small increased FDG uptake (SUV:6.7, 0.55 cm) in left anterior buccal region, and compatible with malignant tumoral uptake. SUV: standard uptake value.

Figure 2: Some hypodense nodules (about 2 cm) in right hepatic lobe, with FDG uptake similar to or slightly higher than normal hepatic parenchyma.

Figure 3: A. A hyperechoic lesion (up to 1.6cm) in the right lobe of liver (white arrow).

B. A hypoechoic lesion about 1.5cm is also found in the right lobe of liver (white arrow).

Figure 4:

A. A heterogeneous tumors with delay enhancement is found in the right lobe.

B. A hyper-vascular lesion is noted in the right lobe, and hemangioma is diagnosed.

Figure 5:

a. In 100x power field, it shows proliferation of epithelioid tumor cells with round hyperchromatic and pleomorphic nuclei, small nucleoli and moderate amount of eosinophilic cytoplasm, in myxohyaline stroma.

b. In 400x power field, some tumor cells contain intracytoplasmic vacuoles, with entrapped red blood cells. Occasional abnormal mitotic figures are seen.

c. In Immunohistochemical staining, it’s positive to CD34.

Discussion

Background

HEHE is a rare malignant type of vascular tumor composed of epithelioid and histiocytoid endothelial cells in a myxohyaline or fibrous stroma. Its incidence is 1 to 2 cases per 1 million people [1]. HEHE can originate in soft tissue, bone, the head or neck, or the liver or other organs. HEHE is slightly more common among patients aged 30 to 40 years than among other age groups and is more common among women than among men [2]. The etiology of HEHE remains unknown; however, some studies have reported that oral contraceptive use, alcohol consumption, liver trauma, sarcoidosis, Crohn disease, vinyl chloride or asbestos exposure, and hepatitis B and C are associated with HEHE [1-4]. Studies have reported that 25% to 40% of patients with HEHE are asymptomatic upon diagnosis. Among patients with symptoms, right upper quadrant pain is the most common symptom. Other symptoms include ascites, weight loss, anorexia, weakness and fatigue, nausea, and vomiting. Alkaline phosphatase, aspartate aminotransferase, and alanine transaminase may be elevated in some patients [3,5-7].

Imaging

HEHE lesions are hypoechoic in ultrasonography. In contrastenhanced ultrasound images, HEHE lesions exhibit enhancement in the arterial phase and low signals in the venous and delayed phases [8]. On CT scans, single or multifocal nodular peripheral lesions with early ring enhancement followed by late appearance of central core enhancement are common features used to diagnose HEHE [2]. Low and high signals appear on T1 and T2 magnetic resonance images, respectively [9]. A common feature of HEHE on T2 images is a target sign with a high-signal core, low-signal ring, and weak secondary high-signal halo. 18F-FDG PET is a powerful tool for detecting metastasis in patients with HEHE [10]. Most HEHE cells exhibit only slightly elevated FDG uptake; this differs from cholangiocarcinoma cells, which exhibit greatly elevated FDG uptake [10].

Histology

HEHE appears as nests and cords of epithelioid endothelial cells spread throughout a myxohyaline stroma. HEHE cells can be classified into three types: epithelioid cells (which are rich in eosinophilic cytoplasm and contain atypical nuclei), dendritic cells (which contain cytoplasmic processes), and intermediate cells (which have characteristics between those of epithelioid cells and dendritic cells). These cells are typically embedded in mucus hyaluronate or hardened matrix. In addition, signet ring–like cytoplasmic vacuoles may appear in epithelioid and dendritic HEHE cells [11]. Immunohistochemical staining of HEHE cells is typically positive for the endothelial markers CD31, CD34, CD12, vimentin, and factor VIII antigen [12]. One study determined that 99%, 94%, and 86% of HEHE cells are positive for factor VIII antigen, CD34, and CD31, respectively [12].

Molecular Characterization

CAMTA1 is a calmodulin-binding transcriptional activator, and WWTR1 is a transcriptional coactivator [13]. Up to 90% of HEHE tumors exhibit WWTR1–CAMTA1 fusion resulting from t(1; 3) (p36; q25) translocations [14]. Therefore, HEHE presents with a rearrangement/deletion of WWTR1–CAMTA1 or YAP1–TFE3 fusion and is characterized by well-formed vasoformative tumors with abundant eosinophilic cytoplasm, atypical cytogenetics, pseudoalveoli, and partly solid-state growth patterns [15]. Only one case of TFE3 rearrangement in HEHE has been reported [16]. Researchers have suggested that testing for TFE3 rearrangement through immunostaining may be useful in the differential diagnosis of HEHE. Other markers such as ERG and AE1/AE3 are expressed in HEHE cells but are also expressed in other tumor cells and are therefore not useful for differential diagnosis [17,18].

Diagnosis

Although specific image findings can be used to diagnose HEHE, liver core biopsies with immunohistochemical staining still play a key role [19]. HEHE is commonly diagnosed on the basis of microscopic features, specifically numerous proliferating dendritic or epithelioid cells with eosinophilic cytoplasm that test positive for CD31, CD34, or factor VIII antigen.

Treatment

HEHE is a rare cancer for which no standard treatment strategy currently exists. Antiangiogenic drugs, radiotherapy, chemotherapy, hepatectomy, liver transplantation, radiofrequency ablation, transcatheter arterial chemoembolization, and observation (watchful waiting) are commonly applied in the treatment of HEHE [20,21]. Surgical resection may be the optimal treatment for single or small HEHE tumors. Because of the vascular origin of HEHE, vascular endothelial growth factor inhibitors such as sorafenib, pazopanib, and bevacizumab are crucial in the treatment of HEHE [22]. For patients with extrahepatic lesions, adjuvant chemotherapy may be an effective alternative approach to disease control [23].

Prognosis

The prognosis of HEHE has a good prognosis compared with that of other malignant liver tumors, and 50% of patients with HEHE survive more than 5 years after diagnosis without treatment. Tumor metastasis has no effect on the 5-year survival rate of HEHE [24]. Hepatectomy and liver transplantation improve patients’ chances of survival; the 1-year and 3-year disease-free survival rates of patients with HEHE who undergo such procedures are 100% and 75%, respectively [25]. The prognosis of HEHE among patients with tumors more than 10 cm in diameter and older adult patients is poor [26]. In one study, researchers developed a HEHE risk stratification strategy based on clinicopathological features; high mitotic activity (>3 mitoses/50 high-power fields) and a tumor size >3 cm were associated with poor prognosis [12]. In addition, 18F-FDG PET is a useful tool for disease follow-up; one study reported that FDG uptake levels provide key information about the progression of HEHE. The prognosis of HEHE among patients with high FDG uptake is usually poor [27].

Conclusion

HEHE is a low-grade to moderate-grade malignant tumor. The 5-year survival rate of patients with HEHE is higher than those of patients with other malignant liver tumors. HEHE can be distinguished from other liver tumors through immunohistochemical staining. Surgical resection remains the first-line treatment for HEHE. If a patient with HEHE is unable or unwilling to undergo surgery, then antiangiogenic drugs, radiotherapy, chemotherapy, radiofrequency ablation, or transcatheter arterial chemoembolization may be considered.

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Aesthetic Rehabilitation with Implant Prosthesis for Maxillofacial Fractures due to High-Energy Trauma: A Case Report

Introduction

Severe maxillofacial fractures due to high-energy trauma often result in damage to the teeth and alveolar bone. Facial deformities and disfigurement, poor aesthetics, and articulation and masticatory disorders may delay the patient’s social rehabilitation and reduce postoperative quality of life (QOL). Therefore, it is important to achieve symmetric facial morphology and reliable occlusion reconstruction. Restoring morphology and function using conventional removable dentures is difficult. Maxillofacial implants are required for predictable occlusal reconstruction in patients with maxillofacial trauma. The periodontal tissue environment around the implant affects its long-term stability; therefore, a treatment plan involving bone augmentation (bone graft and GBR) and periodontal plastic surgery is required. Digital data and setup models can help with the treatment plan. In this case, mandibular mini-plate removal and bone augmentation for maxillary alveolar bone atrophy were performed at the same time according to the treatment plan. We believe that the reduction in surgical opportunities and treatment duration has helped patients to rehabilitate early. Herein we report cases in which patient satisfaction was high after treatment and good outcomes were obtained.

Case Presentation

A 29-year-old woman accidentally fell at a construction site. It took an hour to rescue her from the site, and then she was brought to our emergency department for advanced trauma life support. She was fortunate to have no significant intracranial, spinal, or viscerotropic injuries. There were extensive abrasions and a subcutaneous hemorrhage on the face. The right mid-third of the face had recessed, and there was a deep laceration in the lower jaw. The frontal wall of the maxillary sinus was shattered and depressed, and the maxillary dentition was displaced inward, resulting in loss of continuity. Furthermore, the alveolar bone in the upper right 13–17 region presented with a comminuted fracture. Teeth 13, 15, and 16 were located within the fractured area. There was an insular depressed fracture in the right mandible, and the lower right 42– 46 dentition were displaced inwards, resulting in an open bite due to early occlusal contacts of the molars. There was a the right inferior alveolar nerve paralysis (Figures 1 & 2). We confirmed the preoperative and postoperative dentition and occlusal conditions before surgery via model surgery and formulated a surgical plan. The first surgery was performed under general anesthesia to restore the continuity of the jawbone and the dentition. As the zygomatic arch was intact, the frontal wall of the maxillary sinus and the maxillary dental arch were repositioned to restore the contour of the cheek. The dislocated tooth 13 was fixed within the dentition, whereas teeth 15 and 16 were excised due to the crushed alveolar bone and the maxillary sinus’s anterior wall. Tooth 14 had previously been extracted through an orthodontic procedure.

Figure 1: Facial 3DCT image at the time of initial treatment. The right maxilla has a crushed fracture. The upper right canine is dislocated and invaginated, and the upper right second premolar and first molar are invaded into the crushed bone. The right mandible has a depressed fracture, and the fracture line crosses the mental foramen.

Figure 2: Examination models of the upper and lower dentitions.

A. The right maxillary dentition is displaced medially with loss of continuity. The upper right canine is dislocated, and the second premolar and first molar have deviated from the dentition. The right mandibular dentition is laterally displaced.

B. Model surgery was performed before the first surgery to clarify the posttreatment dentition imaging.

Figure 3: Radiographic images were obtained 6 months after open reduction and fixation.

A. Orthopantomograph showing the reduction of the upper right canine and its retention within the dentition.

B. 3DCT photograph demonstrating the healing of the fracture line after reduction and fixation with two titanium plates.

The mandibular fracture underwent open reduction and fixation using a titanium plate (Figures 3a & 3b). For the simulation and planning of the second surgery, we used CT digital data, its 3D plastic model, and a set up dentition model with the occlusal reconstruction. A close examination of the CT data revealed that the fractured tooth root remained in the bone and interfered with implant treatment. As the length of the dentition defect was atypical, the prosthesis decided was two premolars larger than the premolars on the healthy side. The amount of periodontal tissue deficiency was visualized by superimposing the set up dentition model with the 3D modeling model (Figures 4 & 5). Six months after the first operation, the second operation was performed for bone augmentation for the maxillary alveolar atrophy and mandibular mini-plate removal. Simultaneously, with the removal of the remaining tooth root at right maxillary, a 40 x 20mm cortical osteotomy was performed on the chin cortical bone from which the mandibular mini-plate had been removed. Half of the chin bone (20 × 20mm) was veneer grafted, and the other was crushed and filled in the gaps using titanium mesh (Figures 6a & 6b). There was no paresthesia in the anterior teeth of the mandible after bone collection. The patient underwent a third operation six months later. Due to trauma and the previous surgery, the scar on the tooth defect’s alveolar mucosa was visible, and the oral vestibule was narrowed. Non-mobile keratinized mucosa were required in the alveolar ridge mucosa of the dentition. Thus, vestibulopathy using atelocollagen was performed when the titanium mesh was removed. Two dental implants (Xive dental implants from DENTSPLY, Mannheim GERMANY) were placed on the alveolar ridge after the healing of the mucosa (4 months after vestibulopathy). The second-stage surgery was performed three months later, wherein the attached gingiva at the alveolar crest was extended to the oral vestibular side to obtain keratinized gingiva around the dental implant (Figure 7). The provisional restoration was used to harmonize the crown form and gingival morphology, and the final superstructure was attached about three years after the injury. The patient was fully satisfied with the aesthetic and functional properties. She responded to a maintenance system every 4-6 months and has maintained her oral hygiene with no signs of peri-implantitis (Figure 8).

Figure 4: CT views of the jaws.

A. The coronal view shows that the fractured root of the upper right first molar within the bone is retained. The amount of alveolar bone required for dental implant placement is insufficient in terms of both height and width.

B. In the axial view, the length of the alveolar at the tooth loss was atypical. It was revealed that the premolars on the opposite side had 2.5 to 3 teeth.

Figure 5: The 3D model.

A. The maxillary 3D model’s occlusal view shows that the alveolar ridge of the upper right premolar is narrow, and implants cannot be placed.

B. Simulation of periodontal tissue in harmony with the prosthesis. The insufficient height and width of the periodontal tissue in the premolar region are clear. The size of the prosthesis was decided to be equal to that of two large premolars.

Figure 6: Surgerical view at the time of bone graft

A. Surgical field from which the titanium plate that was used to fix the mandibular fracture was removed. The cortical bone of the chin was osteotomized at 40 × 20mm.

B. One cortical bone (20 × 20mm) was veneer grafted to provide bone width and height. The other graft was crushed and filled within the veneer graft gaps and shaped with a titanium mesh.

Figure 7: Periodontal plastic surgery was performed twice to obtain the attached keratinized mucosa.

A. Vestibuloplasty using atelocollagen was performed at the same time when the titanium mesh was removed.

B. The keratinized alveolar mucosa was moved apically when the second procedure was performed.

Figure 8: Results of the treatment.

A. Image showing the intraoral frontal view.

B. Image showing the intraoral occlusal view. The final prosthesis was fitted according to the treatment plan. The fixed implant prosthesis was supported by the keratinized mucosa and maintained in a favorable environment. Two years have passed since the last prosthesis was attached, and no peri-implantitis was observed.

C. Orthopantomograph 2 years after the superstructure was attached. No bone resorption was observed around the implant body.

Discussion and Conclusion

High-energy trauma often involves maxillofacial and dental trauma. Traumatic injuries results in loss of jaw continuity, anatomical defects in alveolar hard and soft tissues, and tooth loss [1]. Maxillofacial dental implant treatment enables aesthetic and functional recovery of occlusal and masticatory dysfunction associated with tooth and alveolar bone defects [2,3]. This reconstruction process requires multiple surgeries to treat jaw fractures and implants. There are several benefits to having a maxillofacial surgeon perform oral reconstruction under a series of treatment plans. An important outcome of maxillofacial fractures is the restoration of midface symmetry and mandibular continuity. It is important to follow evidence-based treatment strategies for good results in maxillofacial fracture treatment [4].　Occlusal reconstruction is one of the greatest themes of treatment of the stomatognathic region. For implant-based occlusal reconstruction to be most effective over a long-term period, the implant structure must be placed in the proper position and the keratinized oral mucosa should have adequate thickness around the implant [5]. Recent 3D digital image treatment plans for preoperative diagnosis are interesting. If the maxillofacial surgeon plans bone and tissue augmentation that assumes the proper placement of the implant structure, the patient may be able to reintegrate into society with fewer surgeries and treatment periods. The minimum bone width and height of the alveolar ridge for dental implantation must be >5mm and >10mm, respectively [6]. Reports on the use of distraction osteogenesis, autologous bone grafting [7], titanium mesh tray, and iliac particulate cancellous bone and marrow transplantation (Ti- MESH method) [8,9] for bone defects have been published in the literature. The advantage of distraction osteogenesis is that the soft tissue can concurrently be expanded; however, the dynamic treatment period of several months is a major drawback.

In the Ti-MESH method, the biggest concern is the surgical invasion of the donor site. Expected results may not be obtained due to the titanium mesh’s adverse events (tray exposure and increased risk of infection) and remodeling resorption, leading to loss of the graft [10,11]. Autologous bone grafting, which has excellent bone formation ability, is the gold standard for bone regeneration. Bone grafting is considered optimal for complex and extensive bone loss due to trauma. The outcome of bone grafting is said to be influenced by the donor’s structure, developmental pattern, and anatomical site [12]. Bone graft planning requires consideration of 10%–20% of bone resorption [13]. It has been reported that the amount of the grafted bone absorbed is less generated through intramembranous ossification in the mandible than generated through endochondral ossification as observed in the iliac crest [14,15]. The highly calcified chin bone helps to make an early transition and is useful for providing the primary stability for the dental implants [15,16]. Typical donor sites in the oral cavity are chin, mandibular ramus, and maxillary tuberosity. The advantages of intraoral bone collection are that the surgical approach is easy, no separate surgical intervention is required for bone collection, and the close proximity of the donor to the recipe site can reduce surgical time. On the other hand, it is impossible to collect a large amount of bone. Common postoperative symptoms of chin bone graft include hypoesthesia and paresthesia of the anterior teeth of the mandible [17,18]. In this case, cortical chin bone was selected because it could be collected from the same surgical field at the same time. Alveolar bone grafting for an atrophic alveolar segment is ideal in iliac crest bone graft due to its abundant supply, but chin bone grafting is an option for localized alveolar bone defects in 2-3 teeth.

The keratinized mucosa in the alveolar ridge is often lost along with the alveolar bone following a jaw fracture. Alternatively, a scarred mucosa remains after several surgical procedures. The mobile non-keratinized mucosa around the dental implant is more likely to cause peri-implantitis [19]. Also, the development of a mucosal scar with poor blood flow is disadvantageous for bone formation. The presence of keratinized mucosa around the dental implants affects the long-term prognosis of the implant treatment [20]. Therefore, vestibuloplasty and free gingival grafts to acquire a keratinized mucosa [21] are required. The palatal mucosa or atelocollagen is effective as a recipient of mucosal grafts [22,23]. It is important to ensure that a keratinized mucosa (of 2mm) is present around the dental implant. At present, it is unclear when the periodontal mucosa should be treated [24]. The apically positioned flap technique is often performed at the same time as the secondary operation. However, oral mucosal defects after maxilla-orofacial trauma may require mucosal management before implant placement. For patients with severe facial fractures, strict adherence to a well-established and structured treatment protocol based on surgical experience provides an efficient, appropriate, and successful treatment. Furthermore, superior results for severe traumatic maxilla-orofacial injuries will be achieved if the treatment is combined with efficient occlusal reconstruction.

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Dyslipidemia and Associated Cardiovascular Risk Factors Among Non-Diabetic Taxi-Motorbike Drivers Working in Cotonou, Benin

Introduction

Cardiovascular diseases (CVDs) remain the greatest cause of mortality worldwide [1]. According to the latest statistics from the World Health Organization, CVDs account for 32.0% of all deaths and 17.9 million deaths in 2019 [2]. A significant proportion of the world’s death from CVDs occurred among younger adults in lowand middle-income countries [3]. The pathogenesis of CVDs is multifactorial, involving several Cardiovascular Risk Factors (CVRF) such as dyslipidemia, which is a prominent contributor to CVDs globally and even in Africa [4]. Dyslipidemia is characterized by increased blood levels of Total Cholesterol (TC), Triglycerides (TG), Low-Density Lipoprotein Cholesterol (LDL-C), and by decreased high-density lipoprotein cholesterol (HDL-C) concentrations, occurring singly or in combinations [4]. Dyslipidemia alone or in combination with other known drivers such as hypertension, diabetes, and insulin resistance (IR), contribute to the development of CVDs, leading to increased morbidity and mortality [5,6]. Dyslipidemia can also cause severe diseases in other organ systems, including Non-Alcoholic Fatty Liver Disease (NAFLD) and acute pancreatitis [7]. Moreover, dyslipidemia can induce inflammation, increased production of cytokines, and C-Reactive Protein (CRP) [8]. The liver is the major organ in lipid metabolism, leading the synthesis of new fatty acids, their export and subsequent redistribution to other tissues [9].

In clinical practice, measurement of concentrations of liver enzymes such as Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP) and γ-glutamyltransferase (GGT) are commonly used biomarkers of liver dysfunction [10]. Epidemiologic studies have revealed that increased liver enzymes are major risk factors for hypertension and CVDs [11], CVDs-related mortality [12], and liver disease mortality [13]. Within Benin, an important rise in the prevalence of Non-Communicable Diseases (NCDs) and associated risk factors has been documented over the last decade [14-22]. For example, in Cotonou the prevalence of low HDL-C has increased from 10.0 % in 2007 to 21.1% in 2011 [16,17]. These data suggest that without adequate interventions measures dyslipidemia will continue to rise, thereby aggravating the burden of CVDs. Therefore, identification of CVRFs associated with dyslipidemia are of critical importance for prevention and management of CVDs. However, there are currently few data on epidemiologic features and influencing factors of dyslipidemia within Benin. In particular, the associations of dyslipidemia with liver enzymes have never been explored in high-risk populations such as the Taxi-Motorbike Drivers (TMDs) exposed to high-level of ultrafine particles [22,23]. We sought to determine the prevalence and patterns of dyslipidemia, and its relationships with CVRFs such as CRP, ALP, ALT, and AST in TMDs. We anticipated that dyslipidemia associates with liver dysfunction and tested this hypothesis in a cross-sectional study.

Materials and Methods

Study Design and Study Participants

We conducted several surveys (between 2004–2018) to investigate the health impacts of air pollution on exposed populations, including TMDs. TMDs were offered several health checkups, which included assessment of cardiometabolic markers. This was a retrospective cross-sectional study that analyzed data obtained in our 2009 survey. The study population has been described previously [22,23]. Briefly, demographic and clinical information such as age, alcohol intake, height and weight, systolic (SBP) and diastolic (DBP) blood pressure were obtained from each participant through face-to-face interviews by trained doctors.

Participants Fulfilling the Following Criteria were Included in the Study

male non-smokers without diabetes or CVDs, age ≥ 20 years, and having measurements of fasting glucose (< 7.0 mmol/L), insulin, lipids, ALP, ALT, AST. Patients missing any of these biochemical markers were excluded. A total of 147 TMDs were assessed for eligibility but 134 met predetermined criteria and were included in the analyses reported in this paper. The study was evaluated and approved by the Benin Environmental Agency. Written informed consent was obtained from each participant prior to enrolment in the study.

Blood Collection and Laboratory Testing

Venous blood (5 ml, EDTA-containing tubes) from fasten participants was collected and processed within two hours in our laboratory, in Cotonou. Aliquots of plasma (1 ml) were transported on dry ice to Nancy, where they were stored at – 20ºC until analyzed. Fasting glucose, ALP, ALT, AST, high sensitivity C-reactive protein (hs-CRP), and blood lipids (TC, TG, LDL-C, HDL-C) were measured on a clinical chemistry analyzer (Siemens, Germany). Insulin was determined by radioimmunoassay (Biorad, France). All biological analyses were performed by standardized methods within the research Unit NGERE, Faculté de Médecine, Nancy, France.

Definitions of Variables

Hypertension was defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg [24] Alcohol intake was defined as the average consumption of 1 or more alcoholic drinks per day. The homeostatic model assessment-insulin resistance (HOMA-IR) was calculated using the formula described by Matthews, et al. [25]. IR was defined as the 75th percentile of HOMA-IR value [25]. Elevated liver enzymes were defined as follows: ALP level >129 UI/L [26], ALT level > 45 UI/L, and AST level >35 UI/L [27]. Dyslipidemia was defined according to the American Heart Association classification, corresponding to any or combinations of the following: TC > 5.2 mmol/L, LDL-C > 3.4 mmol/L, TG > 1.7 mmol/L, and HDL-C < 0.9 mmol/L [28]. The prevalence of dyslipidemia was defined as the proportion of study participants meeting the criteria of dyslipidemia. Mixed dyslipidemia was defined as the presence of ≥2 lipid abnormalities.

Statistical Analysis

Data are expressed as percentage for categorical variables and as median values (interquartile ranges, IQRs 25th–75th) or as mean (± standard deviation) for continuous variables. The student’s t test and chi-square test were used to compare differences between subject groups. Factors associated with dyslipidemia were identified by logistic regression analysis. Results were expressed as adjusted Odds Ratios (ORs) with the corresponding 95% confidence intervals (CIs). P–values < 0.05 were considered to indicate a statistical significance. Data analysis was performed using IBM SPSS Statistics 20.0 software.

Results

Clinicodemographic Characteristics, Prevalence and Patterns of Dyslipidemia

Table 1 presents demographic characteristics, CVRFs, and the prevalence of CVRFs. The median age was 39.0 years. Alcohol intake and hypertension were prevalent in 38.1% and 47.0% of participants. The prevalence of elevated ALT and AST were 0.7% and 24.6%, respectively. Overall, the prevalence of dyslipidemia was 29.1% (95% CI: 21.4–36.8%). Among individual lipid abnormalities, the highest prevalence was for elevated TC (17.2%), followed by increased LDL-C (14.2%), low HDL-C (9.0%), and elevated TG (3.7%). Mixed dyslipidemia was present in 19/134 (14.2%), of which 17/134 (12.7%) had TC plus LDL-C (Table 1). As depicted on Figures 1A & 1B, estimates of individual lipid abnormalities were higher in hypertensive (3.2–20.6%) and in IR (5.0–21.2%) than in normotensive (1.4–14.1%) and non-IR and (0.0–15.8%).

Figure 1: Prevalence of individual lipid abnormalities according to hypertension and insulin resistance statuses.

A. Prevalence of individual lipid abnormalities according to blood pressure statuses

B. Prevalence of individual lipid abnormalities according to insulin resistance statuses.

Note: IR: Insulin Resistance; HTN: Hypertension, HDL-C: High-Density Lipoprotein Cholesterol; LDL-C: Low-Density Lipoprotein Cholesterol; TC: Total Cholesterol; TG: Triglycerides.

Table 1: Demographic and biological characteristics and prevalence of cardiovascular risk factors in the study population.

Note: Data are presented as median (interquartile range, IQR) or n (%).

ALP: Alkaline Phosphatase; ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; BMI: Body Index Mass; hs-CRP: high sensitivity C-Reactive Protein; DBP: Diastolic Blood Pressure; HDL-C: High-Density Lipoprotein Cholesterol; HOMA-IR: Homeostatic Model Assessment-Insulin Resistance; LDL-C: Low-Density Lipoprotein Cholesterol; SBP: Systolic Blood Pressure; TC: Total Cholesterol; TG: Triglycerides.

*Mixed dyslipidemia was defined as the presence of ≥2 lipid abnormalities.

Factors Associated with Dyslipidemia

As indicated in Table 2, binary logistic regression showed that hypertension (OR= 1.05, 95% CI: 1.01–1.10, P= 0.015), ALT (OR= 1.10, 95%CI: 1.01-1.20, P= 0.016), and hs-CRP (OR= 1.12, 95% CI: 1.01-1.23, P= 0.027) were independently associated with an increased risk of dyslipidemia, whereas alcohol consumption decreased dyslipidemia risk (OR= 0.37, 95% CI: 0.14-0.97, P= 0.047). Age, BMI, ALP, and AST had no significant influence on dyslipidemia.

Table 2: Cardiovascular risk factors associated with dyslipidemia.

Note: ALP: Alkaline Phosphatase; ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; BMI: Body Index Mass; hs- CRP: high sensitivity C-Reactive Protein; DBP: Diastolic Blood Pressure; HDL-C: High-Density Lipoprotein Cholesterol; HOMA-IR: Homeostatic Model Assessment-Insulin Resistance; SBP: Systolic Blood Pressure; CI: Confidence Interval; OR: Odd Ratio

*Dyslipidemia was considered as dependent variable and other clinicodemographic parameters were set as independent variables.

Discussion

This is the first study to examine the prevalence and associated CVRFs of dyslipidemia in TMDs. Our results showed that the overall prevalence of dyslipidemia was 29.1% and that individual lipid abnormalities ranged between 3.7–17.2%, similarly, to reported estimates in other countries [29,30]. For example, Xi et al. reported an overall prevalence of 31.2% in China [31]. Estimates of lipid abnormalities ranged between 7.6%–29.5% in Nigerian [30]. Moreover, in Africa, the pooled prevalence in the general population from population-based studies was 23.6% [4]. However, the prevalence of dyslipidemia in TMDs was lower than estimates reported in Togo, 60.3% [32], India, 50.7% [33], and Iran, 51.8% [34]. This discrepancy could be ascribed to differences in studied populations, sample size, socio-economic status, lifestyles [34], and the cutoff used for dyslipidemia [4]. Within Benin, the majority of previous studies assessed the prevalence of individual lipid abnormalities, but not the overall prevalence of dyslipidemia. In an earlier study by Sodjinou, et al. [16], estimates of elevated TG and low HDL-C were 3.0% and 10.0%, respectively. However, a study evaluating the evolution of CVRFs over four years in apparently healthy patients from Cotonou found elevated TG and low HDL-C at 2.2% and 26.2%, respectively [35]. Further, in Parakou, estimates of individual lipid abnormalities ranged between 11.2%–39.4% and 25.3%–53.0% in hospital-based and population-based studies, respectively [36,37]. Collectively, these data indicate a significant increase in the prevalence of dyslipidemia, which varied widely across populations and regions.

Moreover, these reports suggest that a large proportion of individuals within Benin may be eligible for lipid-lowering therapy, which has shown favorable impact on CVDs mortality [38]. Pathophysiologically, elevated TC is known to play important roles in both initiation and progression of CVDs [39]. High LDL-C level is a critical risk factor for CVDs [6] and lowering LDL-C concentrations is the primary target for treatment and prevention of CVDs [40]. Dyslipidemia and hypertension commonly coexist as components of the metabolic syndrome in CVDs [41]. Here, hypertension was positively associated with risk of dyslipidemia, similarly to what was reported in findings of previous studies [30,42,43]. We also found that dyslipidemia was more prevalent in IR patients than in non-IR patients. Dyslipidemia mediated IR was classically associated with elevated TG and low HDL-C, which can be detected years before the clinical diagnosis of diabetes in IR patients [44]. This study also established a positive association between elevated ALT and risk of dyslipidemia, suggesting that patients with dyslipidemia may have a higher chance of developing liver disease than non-dyslipidemia. This finding was in complete agreement with reports by Park et al. who demonstrated significant increases in the levels of several lipid profiles (e.g., TG, TC/HDL-C) with increasing ALT levels [45]. Similarly, positive associations of elevated TG, TC, and LDL-C with ALT as well as AST and GGT were reported in Bangladesh [46]. Further, persistent elevations of ALT and GGT increased cardiovascular risk in white and black adults followed over 12 years [47]. Consistent with this, Zhang et al. revealed that increased ALT was associated, in a dose-response manner, with multimorbidity (e.g., hypertension, diabetes, dyslipidemia, and stroke) [48].

Interestingly, a prospective study from China associated elevations of ALT and AST with increased incident type 2 diabetes risk [49]. Overall, these data indicate that monitoring of ALT may have significant impacts on risk of developing NCDs in patients with dyslipidemia. Alcohol decreased lipolysis of circulating chylomicrons and VLDL by a reduced activity of lipoprotein lipase. Excessive alcohol intake was associated with increased TG and CVDs [50]. However, our results indicated that alcohol reduced risk of dyslipidemia, similarly to findings of study conducted in China [31]. Evidence suggested that the favorable impact of alcohol on blood lipids could be related to the type of alcoholic beverage as well as genetic polymorphisms [50-52]. In this study, CRP, which is a highly sensitive systemic marker of inflammation and tissue damage, showed a linear relationship with risk of dyslipidemia. This was consistent with reports in homozygous familial hypercholesterolemia patients [53]. Further, Koenig suggested that hs-CRP could better predict future cardiovascular outcomes than traditional CVRFs [54]. Consistently, elevated hs-CRP and risk of CVDs was demonstrated in several reports [55,56]. We anticipated that continuous monitoring of hs-CRP in dyslipidemic patients could have favorable impacts on CVDs. We acknowledge that there are important limitations to this study. The sample size is relatively small. The study included only TMDs and did not evaluate influence of sex or lifestyle factors, limiting generalizability of our findings. A further limitation of this study was its cross-sectional nature, which limits our understanding of causal links between dyslipidemia and associated factors. Thus, obtained result represent associations, not causation. In spite of these limitations, this study has several strengths. This is the first study that reports an association of dyslipidemia with risk factors such as hs-CRP and ALT in TMDs. Therefore, this study adds additional flows to existing medical literature on dyslipidemia within Benin. As such, our study provides evidence-based foundation for future broader studies that may help policy makers when planning and implementing interventions to control risk factors of CVDs.

Conclusion

Our findings revealed that three in 10 TMDs had dyslipidemia, which co-occurs with hypertension, increased ALT, and hs-CRP. These are worrying findings given that TMDs without diabetes or CVDs already have coexistence of dyslipidemia with multiple CVRFs. Therefore, dyslipidemia should be considered as a serious public health problem, and strategies for prevention, early detection, and treatment using lipid-lowering therapy are required to reduce the burden of CVDs in high-risk populations. This study provides useful information for future broader studies with different designs to better quantify the relationship of dyslipidemia with CVRFs.

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