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Lupine Publishers | The Risk of Hospitalization due to COVID-19 in Patients with Inflammatory Bowel Disease

Abstract

Objectives: The novel coronavirus SARS-CoV2 became a worldwide pandemic in 2020. It is known that patients with inflammatory bowel disease (IBD) are at an increased risk of infection, particularly when on immunosuppressive therapy. The outcomes of COVID-19 in IBD patients remain somewhat unclear.

Methods: This Finnish retrospective observational cohort study enrolled 74 patients with an established IBD diagnosis and a confirmed COVID-19 infection. Patient data (age, sex, body mass index, IBD type, biochemical and clinical activity, comorbidities [Charlson comorbidity index [CCI]) and symptoms of COVID-19 were compared with hospitalization due to the COVID-19 infection.

Results: We found that older age (p < 0.01) and comorbidities (CCI score higher than one [p < 0.01]) were associated with hospitalization due to COVID-19 infection. In contrast, none of the studied pharmacological treatments for IBD, IBD type or disease activity were associated with a higher risk of hospitalization.

Conclusion: Our study shows that comorbidities and older age are associated with hospitalization due to COVID-19. On the other hand, different pharmacological treatments for IBD were not linked to a higher risk of hospitalization.

Keywords:Inflammatory bowel diseases; Crohn’s disease; Ulcerative Colitis; COVID-19; Immunosuppressive Treatment

Introduction

The coronavirus pandemic is a worldwide health crisis brought on by severe acute respiratory syndrome coronavirus 2 (SARS CoV 2), which causes a COVID-19 (coronavirus disease 2019) infection [1]. The disease has continued to spread globally and was classified as a pandemic on 11 March 2020, by the World Health Organization [2]. Clinical symptoms in COVID-19 vary between patients, but most individuals have a mild form of the disease with no or flu-like symptoms, including a dry cough, fever, runny nose and fatigue. Additional symptoms may comprise shivering, throat pain, anosmia, headache, joint pain, nausea and diarrhoea [3,4]. In more severe forms of the disease, marked inflammation and progressive pneumonia occur, leading to difficulties in breathing. A COVID-19 infection has often proved to be more severe in patients over 60 years of age. Furthermore, most patients with COVID-19 requiring hospitalization or intensive care unit (ICU) admission have been shown to have at least one comorbidity, such as chronic lung or heart disease, diabetes or conditions that affect their immune system [5]. In addition, smokers have been suggested to develop more severe symptoms of COVID-19 and are more likely to be admitted to intensive care, to need mechanical ventilation or to die than to non-smokers [6].

The treatment of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), frequently includes immunosuppressant medications [7-10]. The immunomodulators commonly used in IBD are corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, anti-tumour necrosis factor agents or other biologicals. Their modes of action differ from each other, but they all compromise, to some extent, the patient’s immune response [11]. This may increase the patient’s risk of viral and bacterial infections and adverse outcomes of COVID-19 [12,13]. However, published data on possible associations of immunosuppressive therapy with severe COVID-19 remain inconsistent. Data extracted from the international registry Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD; 1,439 cases, 112 with severe COVID-19) suggest an increased risk with thiopurines either combined with biologicals or as a monotherapy [14], whereas data from the French national health system (268,185 IBD patients, 600 hospitalizations) indicate no such association [15]. So far, there is no clear evidence for an increased risk of more severe outcomes in patients with IBD in the context of COVID-19. This study aimed to describe how COVID-19 presents and evolves in patients with IBD and to identify potential risk factors that may predict the severity and outcomes of a COVID-19 infection in IBD patients.

Methods

This was a retrospective, observational cohort study. All eligible patients were adults (18 years and older) with an established diagnosis of CD or UC and a confirmed diagnosis of COVID-19, which was defined as the PCR-confirmed presence of the SARS-CoV-2 genome in a nasopharyngeal swab. The Hospital District of Helsinki and Uusimaa is the largest hospital district in Finland, covering a population of more than 1.7 million. The IBD registry is an integrated platform of the hospital patient data system and comprises 5,194 secondary or tertiary care patients with an IBD diagnosis, treated mostly with immunosuppressants and biologicals. We identified IBD patients with a COVID-19 diagnosis by performing a search combining the hospital district’s COVID-19 registry and the IBD registry. The more detailed patient and disease data were collected retrospectively from the patient electronic charts in April 2021. For all eligible patients, we collected the following data: age, sex, ethnicity, pregnancy, body mass index, IBD type, IBD duration, surgical IBD treatment, pharmacological IBD treatment, other comorbidities (expressed with the Charlson Comorbidity Index [CCI] [16] signs and symptoms of COVID-19 (fever, cough, dyspnoea, dysosmia/dysgeusia, pharyngitis, diarrhoea, arthralgia-myalgia/ asthenia, rhinitis, dysphonia, headache, abdominal pain, nausea/ vomiting, thrombosis), antibiotic and anticoagulant therapies for COVID-19, COVID-19 outcomes (hospitalization on a regular ward and in an ICU as well as death), and smoking status.

Data on faecal calprotectin (FC) as a surrogate marker of inflammation were recorded 0–6 months before the COVID-19 infection, during the COVID-19 infection and after the COVID-19 infection. Values considered to be normal for FC were < 200 μg/g [17,18]. The last registration on clinical activity of IBD was assessed based on patient charts. Clinical disease activity was determined according to the presence or absence of symptoms due to IBD (number of bowel movements, presence or absence of abdominal pain and presence of blood on defecation). The Charlson Comorbidity Index (CCI) is a validated and easily applicable method of estimating the disease severity and the risk of death from a comorbid disease. It has also been shown that a higher mean CCI score is significantly associated with mortality and disease severity in COVID-19 patients [19].

Statistical analysis

Statistical analysis was performed using the R software environment (version R-3.6.2). Differences in the hospitalization status and the studied variables were tested for significance using logistic regression, where the age and BMI of the patients served as confounding factors. Statistical significance was set at p < 0.05. The values are presented as numeric with percentage or as mean with SD.

Ethical considerations

Permission to conduct the study was received from the institutional review board of Helsinki University Hospital. As this was a retrospective, non-interventional patient records review study, no ethics committee approval was required.

Results

Study population

Between 29 January 2020 and 15 April 2021, 74 patients with IBD (CD n = 32 [43%], UC n = 42 [57%]) had been diagnosed with a COVID-19 infection. The patients’ baseline characteristics are shown in (Table 1). Within the six months prior to the COVID-19 infection, 18% (n = 13) of the CD patients and 18% (n = 13) of UC patients had an active IBD. Based on the available data, 22% (n = 7) of the CD and 24% (n = 10) of the UC patients had a biochemically active disease, whereas 28% (n = 9) of the CD and 19% (n = 8) of the UC patients had a clinically active disease. Six percent (n = 2) of the CD patients and 19% (n = 8) of the UC patients were not on any pharmacological treatment for IBD at the time of COVID-19 diagnosis. At the time of COVID-19 diagnosis, three patients (4%) were on systemic corticosteroid and thiopurine combination therapy; of these, only one UC patient was hospitalized on a regular ward and did not require ICU admission. We identified only one patient who was on concomitant medication with systemic corticosteroids, thiopurine and biologicals, and this patient was not hospitalized. Seven CD patients (22%) and eight UC patients (19%) were treated with thiopurine and biologicals, of these, one patient with CD and one with UC were hospitalized on a regular ward. Overall, two patients were pregnant, and neither of them was hospitalized. Nearly threequarters (72%, n = 23) of the CD patients and two-thirds (60%, n = 25) of the UC patients had no significant comorbidities (CCI 0). One comorbidity was present in 22% (n = 7) of the CD patients and in 19% (n = 8) of the UC patients. Hence, only 15% of all patients had two or more comorbidities. Seven patients (9%) had asthma, while none had been diagnosed with chronic obstructive pulmonary disease. For 36 patients, an FC value determined 0–6 months prior to the COVID-19 infection was available: the average value for CD patients was 279 μg/g and for UC patients 421 μg/g (FC range in all patients 5–1,600 μg/g, SD 482 μg/g). During the study period, 13 (18%) patients were hospitalized, four (5%) were admitted to an intensive care unit, and one patient died (Table 2). Except for the patient who eventually died, no-one needed mechanical ventilation. Among all hospitalized patients, the average number of days spent on a regular ward due to COVID-19 was 3.7 for CD, 6.3 for UC and 5.7 for all patients. Most patients (n = 62, 84%) were not on antibiotic therapy at the time of the COVID-19 infection. After the COVID-19 diagnosis had been established, 43% (n = 32) of all patients and 100% of those hospitalized received thrombosis prophylaxis.

COVID-19 symptoms

The most common COVID-19 symptoms, presented in Table 2, were cough (56%), rhino-pharyngitis (51%), fever (46%), headache (34%), dyspnoea (26%), diarrhoea (24%), arthralgia/myalgia (16%), dysosmia/dysgeusia (15%), flu-like symptoms (13%), abdominal pain (12%) and nausea/vomiting (9%). Five percent did not develop any symptoms due to the COVID-19 infection. No thromboembolic complications were diagnosed.

Factors predicting hospitalization

In all statistical analyses age, body mass index (BMI) and sex were examined simultaneously with the variable, and each variable was also examined alone. Increasing age was associated with a higher risk of hospitalization (p < 0.01), presented in (Figure 1A). With a CCI of two or more, the risk of hospitalization was significantly increased (p < 0.01 vs CCI 0–1), as seen in (Figure 1B). When the points for age were omitted from the CCI score, patients who had points due to an underlying medical condition were still more likely to be hospitalized (p < 0.01 vs no underlying medical condition).

Factors not predicting hospitalization

We could not demonstrate any significant association between BMI and risk of hospitalization, although there was a trend towards such a risk (p = 0.09). Interestingly, there was a significant association between BMI and hospitalization when one patient with a BMI of 54 was removed as an outlier (p = 0.02) (Figure 1C). Neither sex nor IBD type (UC or CD) had a significant impact on COVID-19 outcomes. There was no significant difference in hospitalizations among patients on biological medication, thiopurines or systemic corticosteroids, nor among patients who were taking any of the said medications as a combined therapy.

Discussion

Our study, which aimed at identifying risk factors for COVID-19 in IBD patients confirms previous findings indicating an association between hospitalization and both comorbidities and older age. Importantly, the use of any medication as maintenance therapy for IBD was not associated with an increased risk of a more severe COVID-19 infection or an undesirable outcome. The data of SECURE-IBD are likely to drive treatment recommendations for IBD during the COVID-19 pandemic. Immunosuppressive medications, especially thiopurines, used to treat IBD may result in a degree of immunosuppression, which has been hypothesized to lead to a more severe COVID-19 infection. Most of the patients in the IBD registry were on immunosuppressive treatment and were therefore thought to be at a higher risk of a severe COVID-19 infection. A recently published review article by Al-Ani and colleagues encourages the continuing of usual maintenance medications and highlights the importance of avoiding corticosteroids [20]. The finding of our study are in line with previous studies. In the case of an IBD flare-up, the risks and benefits of the treatments should be carefully discussed with the patient. More severe COVID-19 has been associated with older age and obesity [21-24]. Moreover, earlier studies have shown male sex to be a risk factor for more severe COVID-19 [25,26]. In the present study no significant association between sex and a higher risk of hospitalization was found. In the context of obesity, it is believed that the excess amount of adipose tissue causes inflammation and an impairment in the immune response. However, no significant correlation between BMI and the risk of hospitalization was found in our study. On the other hand, we found a significant association between age and hospitalization. It has been previously reported in studies of the general population that patients with comorbidities have a higher risk of more severe COVID-19 symptoms [27,28]. This was also seen in our population of IBD patients. Brenner and colleagues have found that increased age, comorbidities and, contrary to our study, also systemic corticosteroids are associated with severe COVID-19 in IBD patients [29].

Between 29 January 2020, when the first COVID-19 case in Finland was confirmed, and 15 April 2021, a total of 48,438 cases had been reported in the Hospital District of Helsinki and Uusimaa, which constitutes 2.8% of the population of 1.7 million [30]. In the present study, we identified 74 (1.4%) out of 5,194 patients in the IBD registry with a confirmed COVID-19 diagnosis since the beginning of the pandemic. The proportion of IBD patients with confirmed COVID-19 is less than half of the corresponding proportion of the general population of the same geographical area. Earlier studies have indicated that patients with IBD are at risk of serious opportunistic infections, particularly when they are treated with immunosuppressive medication. However, the findings of our study suggest that patients with IBD are not at a higher risk of contracting the SARS-COV-2 than the general population. This could be partly explained by a more rigorous hygiene routine. The patients in the Uusimaa Region have received detailed hygiene and health instructions from the specialized IBD nurses since the beginning of the pandemic. In the future, more data are needed on the social impact that the pandemic may have had on these immunocompromised patients. This study has some limitations. Firstly, the number of patients was limited as the incidence of COVID-19 in Finland has remained relatively low. Secondly, the lack of data in the patient records made it challenging to find variables associated with an unfavorable outcome and a higher risk of hospitalization. Additionally, during the pandemic, patients have tended not to attend scheduled laboratory follow-up tests, resulting in missing data. Despite these limitations, we believe that this study reflects well the real-life situation in clinical practice and provides important data on the COVID-19 infection in the IBD population.

The present study also has several strengths. Firstly, as the COVID-19 registry of the hospital district covers all reported cases in the region, it is extremely unlikely that a COVID-19-positive patient included in the IBD registry would have been missed in our search. Secondly, this study was performed in a country with a high IBD prevalence of one percent of the population [31] and with, consistent IBD treatment patterns and active patient organization counselling in place. All patients have equal access to treatment, and most hospital districts have specialized nurses who are trained to treat patients with IBD and advise them on travelling, vaccinations and hygiene. The observation period of this study mainly took place before the national vaccinations against COVID-19 started. Although no vaccine data is available for this study population, the number of COVID-19-vaccinated patients can be neglected, as IBD patients on immunosuppressive therapy were among the groups to receive the vaccine, starting from mid-April 2021. Some of the newest COVID-19 strains that have emerged after the data collection for this study have been found to be more infectious and linked to a higher mortality rate. Future studies will show whether the outcome of COVID-19 will differ from today’s studies.

Conclusion

This is the first report on the characteristics and outcomes of COVID-19 in patients with IBD in Finland, a country with a high prevalence of IBD and low prevalence of COVID-19. We found that comorbidities and older age were associated with a negative COVID-19 outcome such as hospitalization. On the other hand, immunosuppressive treatment for IBD was not associated with the risk of hospitalization or death. The lower incidence of COVID-19 infections among IBD patients in comparison to the general population may be explained by the rigorous hygiene measures undertaken particularly by patients on immunosuppressive therapy.

Author Contributions

Statement of authorship: study design (MK, PM, Ca B, PA), statistical analysis (JJ, JA), initial manuscript drafting (MK), critical revision and final approval (all authors).

Funding

The authors received no specific grant for this research. Patient involvement and patient consent for publication. Patients were not involved in the design, conduct reporting or dissemination plans of this research. Patient consent was not required.

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Lupine Publishers | Herbally Treated Electro Spun Nano Fibrous Membranes for Medical Applicatons*

Abstract

Curcumin is a naturally occurring hydrophobic polyphenol compound. It exhibits a wide range of biological activities such as antibacterial, anti-inflammatory, anti-carcinogenic, antifungal, anti-HIV, and antimicrobial activity. In this research work, antimicrobial curcumin nanofibrous membranes are produce by an electrospinning technique using the Eudragit RS 100 (C19H34ClNO6) polymer solution enriched with curcumin. The morphology and chemistry of the membrane are analyzed using scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. Kirby Bauer disk diffusion tests are carried out to examine the antibacterial effectiveness of the membrane. Experimental results show that the nano fibers produced are of uniform thickness morphology and curcumin is successfully incorporated into the nanofibrous mat, while no chemical bonding was observed between curcumin and the polymer. The antimicrobial curcumin nanofibrous membranes can be effectively applied as antimicrobial barrier in a wide variety of medical applications such as wound healing, scaffolds, and tissue engineering.

Keywords:Antimicrobial Nano Fibrous Membrane; Curcumin; Electro Spinning; SEM; FTIR; Kirby Bauer Disk Diffusion Test

Introduction

Nanofibers have emerged as exciting new class of materials, useful for many applications owing to their thickness (100 nm) and large surface-to-volume ratio [1]. Depending on polymer type, attainable fiber assembly, production rate, and cost, several techniques have been developed to produce nanofibers. Among these are electrospinning, melt-blowing, template synthesis, self-assembly, multi-component spinning, flash spinning, and nanolithography [2-8]. It is recognized that electro spinning is the most versatile fabrication process that can produce nano fibers from a wide range of polymeric materials at high production rate and low cost. Electro spinning is a process of applying high voltage between a polymer solution contained in a syringe with a capillary tip and a collector. Electro spun fibers are collected at the collector during the fabrication process in the form of membranes. The properties of nanofibers can be customized by regulating the voltage, concentration and viscosity of the polymer solution, and solvent composition [9]. Till the recent past, electrospinning of more than 100 varieties of natural and synthetic polymers, composites and ceramics into ultra-fine nano fibers have been demonstrated. Nano fibers can also be functionalized by mixing with functional additives or surface modification [10,11]. Electro spun nano fibrous membranes have found a wide range of applications in health care, energy storage, environment engineering and biotechnology due to their relatively light weight, high surface area, and interconnected porous structure.10 Recent developments in the field of nanostructures have opened up exciting opportunities for new materials design, such as nanofibrous membranes with antimicrobial properties for medical applications such as wound dressings [12,13]. Conventional wound dressings provide basic environments for wounds with regards to barrier to evaporation and protection from outside bodies. However, the biologically functional electro spun antimicrobial nanofibrous membranes encourage healing, and also compensate the functions of conventional wound dressing [14]. Antimicrobial agents inhibit the growth of microorganisms by bacteriostatic and bactericidal responses (they can, however, also be harmful in the case of specific allergies) [15]. Compared with synthetic alternatives, natural antimicrobial agents are less harmful, biocompatible, economically viable and readily available. Natural antimicrobial agents are the major chemical constituents of some common plants such as turmeric, aloe vera, basil and neem, etc. Turmeric was used in ancient times to promote wound healing because of one of its major chemical components, curcumin. Figure 1 shows the structure of the curcumin molecule. Curcumin is an anti-oxidant, anti-inflammatory, anti-cancer molecule used to reduce pain and accelerate the process of wound healing [16,17]. Curcumin dissolves in organic solvents such as ethanol, acetone and dimethyl formamide (DMF), and its anticoagulant property makes it suitable for drug-eluting stents [18]. Several researchers have successfully incorporated curcumin into biomaterials and observed its medical efficacy. Nguyen et al. produced curcumin loaded poly-lactic acid (PLA) nano fibers and reported its potential antimicrobial effectiveness. Xie et al. fabricated curcumin-loaded silk fibroin nanofibrous membranes and suggested that the drugloaded nano fibrous membranes can be useful as biomaterials with antimicrobial and antitumor function [19].

A wide range of natural (collagen, gelatin, chitosan, elastin, silk fibroin and alginate) and synthetic (PGA, PLGA, PCL, PLLA-CL, PEO and PVA) polymers are used to produce nanofibrous membranes for biomedical applications [20-22]. Natural polysaccharide polymers are biocompatible and biodegradable compared with synthetic polymers, and they display improved structural properties. In return, they have inferior mechanical properties. Consequently, copolymers of natural and synthetic polymers are sometimes mixed to enhance the functional properties of membrane [23]. Among the synthetic copolymers, Eudragit RS 100 (C19H34ClNO6) is greatly appreciated for biomedical applications because of its exceptional permeability and swelling properties [24]. For the first time, an economical and effective antimicrobial nano fibrous membrane is fabricated by applying an electro spinning technique on the Eudragit RS 100 polymer solution enriched with curcumin (a natural antimicrobial agent). Surface morphology and chemical composition of the nanofibrous membrane are studied using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR), respectively. To evaluate application in the medical field, Kirby Bauer disk diffusion tests are carried out to examine the antibacterial effectiveness of the antimicrobial curcumin- loaded nano fibrous membranes. Based on the performance properties of the fabricated antimicrobial scaffold, its use is recommended in industrial applications such as tissue engineering, medical devices and wound care dressings.

Properties of polymer solution

The viscosity, surface tension and conductivity of the prepared polymer solutions for electrospinning of nanofibrous membranes were measured at 0 wt%, 1 wt%, 5wt% and 9wt% curcumin concentrations. The results from studies show a decreasing trend in viscosity and surface tension of the polymer solution with the increase in curcumin concentration. In order to achieve uniform and beadless nano fibers, the concentration of the electrospinning polymer solution should be above entanglement concentration (Ce), which is the minimum concentration required to develop nanofiber [25]. Lower viscosity of the polymer solution may cause electro spraying instead of electro spinning, while lower surface tension of the polymer solution leads to bead-free nanofibers production in electrospinning [26]. The addition of curcumin to the polymer solution was kept to the level to keep the viscosity above the entanglement concentration (Ce) threshold; therefore, at the attained viscosity, the workable range of polymer solution is expanded. A higher conductivity was observed when the concentration of curcumin was increased in the polymer solution. Wang et al. also reported the increase in conductivity with the addition of curcumin to the polymer solution and observed that the enhanced electrical conductivity favors the electrical drawing effect on the jet fluid and decreases the fiber fineness.

Morphology

The SEM studies images showing the morphology of the electro spun nano fibrous membranes. The results evidence that the nano fibers are apparently produced with uniform thickness, and no accumulation of polymer mass in the form of beads was observed across the fibrous membrane. Researchers in the recent past reported that there are several electro spinning process parameters such as polymer concentration, applied voltage, type of solvent system, solution fed rate, type of collector and rotation speed that can affect the morphology of the nanofibers [27,28]. In this study, for all the specimens prepared, the electro spinning process parameters were first optimized and then kept identical during the series of experiments. As a direct consequence, diameter, layer thickness and distribution were found to be uniform in all nano fiber sheets.

The absence of bead formation and apparently even distribution of nanofibers in the nano fibers cluster shows the uniform dispersion of curcumin in the polymer and in the membrane. A relative discontinuity of nano fibers was noticed. However, uniform and continuous nano fibers were observed when the curcumin content in the polymer solution was increased to 9 wt%. The relative discontinuity noticed in Figure 2, can be ascribed to the lower capacity of these two polymer solutions to carry charges in comparison with the 9 wt% polymer solution. The latter seems to be the best doping concentration to obtain continuous and uniform thickness electro spun nano fibers at the designated optimized electro spinning conditions.

FTIR analysis

FTIR spectra of the polymer (Eudragit RS 100), antimicrobial agent (Curcumin) and the electro spun curcumin-loaded (9 wt %) nanofibrous membrane have been reported. The FTIR spectrum of the polymer reveals the presence of methyl band at 2930 cm-1, ester C-O band at 1724 cm-1 and C–O band at 1160 cm-1. Similar observations are reported in the literature by other researchers [29,30]. The FTIR spectrum of the antibacterial agent used in this study, The presence of hydroxyl, methyl, carbonyl and C-C bands have been evidenced at 3307 cm-1, 2950 cm-1, 1640 cm-1 and 1560 cm-1 bands, respectively. The observations are supported by the findings reported by Rohman et al. and Siregar et al. while working on curcumin-based drugs for medicinal applications [31,32]. Curcumin-loaded electro spun nanofibrous membrane FTIR spectrum, Figure 2, indicates the peaks for the constituents of polymer and curcumin such as at 3310 cm-1 (phenolic OH), at 1740 cm-1 (C=O ketone), at 2970 cm-1 (alkane CH3 stretching), at 1550 cm-1 (C=C) and at 1160 cm-1 (C–O). These results confirm the incorporation of antimicrobial agent (curcumin) into the nano fibrous membrane, while no apparent chemical linkages between the antimicrobial agent and polymer are observed.

Kirby Bauer disk diffusion test results

Inhibition zones were measured around the nano fibrous membrane without curcumin and 9wt% curcumin- loaded nanofibrous membrane disks in the agar plate. For the ease of comparison, the black arrows, visible in the pictures, identify the specimens loaded with antimicrobial agents. Studies have made it evident that the curcumin spreads into the agar and stops the growth of bacteria in the indicated zones compared with the zones having disks of nano fibrous membrane without curcumin. It is thus possible to conclude that the bacteria were totally killed after the incubation process and antibacterial activity of the nano fibrous membranes lasts even after 7 days. In order to avoid the spread of bacteria, different antimicrobial liquids were used on hand gloves during the material handling in the antimicrobial experiments. The lids look differently because the writing was erased during the experiment, and it was replaced. The inhibition of bacterial growth is confirmed by several researchers. Xie et al. exhibited the drug release properties of SF/PEG nano fibrous membranes loaded with curcumin. Nguyen et al. reported higher closure rates of wounds treated with curcumin-loaded PLA nanofibers. Wang et al. proposed that PVP nano fibers loaded with curcumin display enhanced bioavailability and effective anti-cancer effect. Hussain et al. proposed that alginate containing natural polyphenol based antimicrobial agents can be a potential candidate for wound care [33]. The current results show promising properties for the development of curcumin-based antimicrobial membranes for medical applications.

Conclusion

An economical and readily available natural antimicrobial agent, curcumin, extracted from a turmeric plant is successfully incorporated into a nano fibrous membrane using the electro spinning technique for medical applications. The nano fibrous membranes were characterized for morphology, chemistry and antimicrobial effectiveness. The SEM results show the formation of smooth, uniform and beadles nano fibers, clustered in a fibrous mat/ membrane when the concentration of curcumin was 9 wt%. The FTIR analysis confirmed the incorporation of antimicrobial agent curcumin into the nanofibrous membrane without chemical linkages between the antimicrobial agent and the polymer. The Kirby Bauer disk diffusion test results verified the antimicrobial effectiveness of the fabricated curcumin-loaded nano fibrous membranes. Future work in progress is in the direction of incorporating several other naturally occurring antimicrobial agents such as aloe vera, neem and basil, and their blends, into the nano fibrous membranes for high-end medical applications at lower cost.

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Lupine Publishers | May Gastrointestinal and Sensory Manifestations be related to Worse COVID-19 Phenotypes

Abstract

Extra pulmonary symptoms may contribute to poor outcome in COVID-19. We compared the frequency of gastrointestinal and sensory manifestations (GSM) between mild and severely ill patients with COVID-19, alone or combined with classic respiratory manifestations (CRM). Hospitalized patients with COVID-19 (n = 357) were classified according to their disease severity by using a neutrophile/lymphocyte ratio value ≥18 for severe illness. Presence of CRM and baseline clinical data were recorded. Presence of >3 liquid evacuations per day (diarrhea), decreased usual bowel movements (constipation), nausea/vomiting, lack of appetite (anorexia), abdominal pain, loss of taste (dysgeusia) and/or loss of smell (anosmia) were personally recorded by the investigators at the study admission. Severely ill patients (47.3%) presented worse clinical markers than mildly ill patients, including higher risk of malnutrition and higher need for non-invasive respiratory support (p<0.001). Most of severely ill patients presented at least one GSS (78.1%) and a higher frequency of general and specific GSM (anorexia, constipation, nausea, dysgeusia, and anosmia) than mildly ill patients (p<0.001). The prevalence of CRM without GSM combination was higher in mild illness than in severely ill patients (p<0.001), while the prevalence of GSM without CRM combination was similar between them (p>0.005). Our findings highlight a higher GSM prevalence in severe than in mildly ill patients with COVID-19 presenting CRM, suggesting that GSM may contribute to a worse COVID-19 phenotype when combined to CRM.

Keywords:Anorexia, Diarrhoea; Constipation; Nausea/Vomiting; Abdominal Pain; Dysgeusia; Anosmia; COVID-19

Introduction

Beyond classic respiratory manifestations (CRM), gastrointestinal and sensory (dysgeusia and anosmia) alterations are often described in patients suffering from the coronavirus disease 2019 (COVID-19) [1]. The clinical presentation of COVID‐19 may range from a mild, self‐limiting disease to a multi-organ failure and death [2]. It is unclear whether Gastrointestinal and Sensory Manifestations (GSM) are associated with a more severe disease phenotype either alone or associated to CRM. The neutrophile/ lymphocyte ratio (NLR) have been suggested as a suitable parameter for early-stage prediction of critical illness. Indeed, in COVID-19 patients the NLR proved to be an objective basis for early identification and management of severe pneumonia [3-6]. By using NLR as a disease severity marker, here we characterized the clinical profile of mild and severe illness of COVID-19 hospitalized patients and compared the frequency of GSM between them.

Material and Methods

Study Design and Ethical Issues

This study is part of a larger prospective, multicenter, longitudinal clinical study that enrolled patients from two hospitals in São Paulo (Brazil), Hospital de Caridade São Vicente de Paulo (public) and Hospital Sírio-Libanês (private), and which protocol was approved by the local ethics committee (CAPPesq, nº 4.171.967), registered at the Brazilian Clinical Trials (https://ensaiosclinicos.gov.br/rg/RBR-3h5fr2s) and applied after patients or their legal representatives (when the patient was unable) provided written informed consent.

Patient Selection

A convenience sample of 357 patients was recruited from the wards attended by the Multidisciplinary Nutritional Support Teams at both hospitals. Adult patients (18–90 years old), both genders, any ethnicity, with COVID-19 suspected (lung imaging by computed tomography) or diagnosed (positive polymerase chain reaction) were included. Exclusion criteria were pregnancy, critically ill patients at the Intensive Care Unit (ICU), patients receiving palliative care, and absence of COVID-19 diagnosis confirmed by a positive polymerase chain reaction until the end of their hospital follow-up.

Patient’s stratification according to the disease severity

Patients were stratified according to a disease severity grading, based on the absolute number of neutrophils divided by the absolute number of lymphocytes (NLR). Patients with NLR<18 were considered moderately ill, and those with NLR ≥ 18 were considered severely ill [7].

Descriptive and Clinical Data

Age, sex, ethnicity, body mass index (BMI–usual weight/ height 2), underlying diseases, need for non-invasive respiratory support, presence of CRM (cough and dyspnea), sore throat, clinical complications associated with COVID-19, and administered medications were recorded at the study admission. Up to 36 hours from admission, the nutritional risk screening 2002 tool (NRS-2002) was also applied, where patients with scores ≥ 3 were considered at nutritional risk [8,9]. Hospital discharge was recorded at the study end, where patients non-achieving hospital discharge included those who were admitted to ICU, considered for palliative care, or died.

Prevalence of GSM

Presence of > 3 liquid evacuations per day (diarrhea), decreased usual bowel movements (constipation), nausea/vomiting, lack of appetite (anorexia), abdominal pain, loss of taste (dysgeusia) and/or loss of smell (anosmia) were personally recorded by the investigators at the study admission. Prevalence of GSM was further characterized according to the following categories: absent, at least one, more than one, and combined with respiratory symptoms and/or sore throat.

Statistical Analysis

Continuous variables were expressed using descriptive analysis to measure central tendency (mean or median) or measures of dispersion (standard deviation or minimum-maximum). Categorical variables were expressed as means of percentage values in absolute and relative frequencies. The T-test was performed to compare two continuous variables with a normal distribution (Anderson–Darling test), while the non-parametric Mann–Whitney and Brunner–Munzel tests were used for homogeneous and heterogeneous variables (Bartlett test), respectively. Fisher’s exact test was used for comparisons using categorical variables. Twotailed hypotheses were evaluated, and the confidence intervals were 95%. All statistical analyses were performed using Software R (version 4.0.2) and considering a significance level of 5%.

Results

Patient’s description

From the 357 patients studied, the majority was male (57.1%), white (54.6%), with a median age of 60 [18–99] years old and a median BMI of 28.3 [15.0–58.4] kg/m2. Almost half of them were severely ill (47.3%), presenting several worse clinical markers than mild illness patients, including higher risk of malnutrition, higher need for non-invasive respiratory support, higher frequency of at least one respiratory manifestation, dyspnea and sore throat, higher frequency of general and specific underlying diseases (previous comorbidities), higher frequency of acute kidney disease as COVID-19 complication, higher requirement for antiviral, antiemetic, antiacid and analgesic medications, and higher frequency of non-hospital discharge (Table 1).

Prevalence of GSM

Most patients with severely ill phenotypes presented at least one GSS (78.1%) and a higher GSS frequency than mild illness patients, whether isolated (>1 GSS) or combined to respiratory manifestations or/and sore throat. They also experienced a higher frequency of specific GSS (anorexia, constipation, nausea, dysgeusia, and Anosmia) than mild-illness patients (Table 2). The prevalence of GSM without CRM combination was similar between mild and severe illness patients. On the other hand, the absence of GSM (49.5% vs. 21.9%) and prevalence of CRM without GSM combination (33.5% vs. 15.4%) were higher in mild illness than in severe illness patients (p<0.001).

Discussion

Extra pulmonary symptoms in COVID-19 may also contribute to poor outcome. By stratifying COVID-19 patients according to the disease severity we found 78.1% of our severe illness patients with at least one GSM, exhibiting a higher frequency of GSM combined to respiratory signal/symptoms than mild illness patients. On the other hand, the absence of GSM or respiratory manifestations alone was significantly more frequent in mild than in severe illness patients, while the frequency of GSM alone was similar between them. Our findings suggest that GSM may contribute to worsen COVID-19 phenotypes.

Accordingly, Han et al. observed that COVID-19 patients with mild disease presenting digestive symptoms are more likely to test positive for viral RNA in stool, have a longer delay before viral clearance, and experience delayed diagnosis than those presenting only respiratory symptoms [10]. In a meta-analysis, COVID-19 patients with gastrointestinal involvement tended to have a poorer disease course (e.g., acute respiratory distress syndrome) [11]. Another meta-analysis highlighted a higher frequency of gastrointestinal symptoms in severe disease [12].

Our data support that GSM may be related to worse COVID-19 phenotypes, but they also suggest that severe disease may primarily occur when GSM are associated with CRM. Nevertheless, most COVID-19 patients with initial gastrointestinal complaints seems to develop CRM within few days [13]. For instance, in a sample of 206 afflicted patients, the frequency of digestive symptoms alone and combined with CRM was 23,3% and 33.5%, respectively [10]. In our sample of 357 afflicted patients, only 7.3% of them presented GSS not combined with CRM.

In our study, anorexia was the most prevalent GSM (44%) and also was more frequent among severe illness (61.5%) than in mild illness (28.2%) patients. Lack of appetite can impair food intake and further contribute to body weight loss and malnutrition. Severely ill patients with COVID-19 may suffer additional nutritional burdens, due to catabolism and increased energy requirements to fight severe infection [14]. It is possible that GSM may contribute to more severe phenotypes of COVID-19 by impairing energy-protein intake.

In our study, stratification of COVID-19 patients was done using NLR as a disease severity marker. The cut-off value for NLR here applied was based on a COVID-19 patients’ study that categorized NLR values into quartiles (4.61, 11.3, 19.3, and ≥19.3), where the highest NLR quartile was significantly associated with older age and mortality [7]. This NLR classification distinguished the severely ill patients with worse clinical patterns and lower hospital discharge from those with mild illness. We, by using NLR ratio, could identify worse COVID-19 phenotypes, and suggest the adopted cutoff as an efficient parameter for this purpose.

Conclusion

In summary, our findings highlight a higher GSM prevalence in severe than in mild illness patients with COVID-19, suggesting that these extra pulmonary manifestations may contribute to worse COVID-19 phenotypes when combined to CRM. Anorexia was prevalent suggesting that nutritional supplementation may be a relevant intervention to prevent poor clinical outcomes in COVID-19 patients manifesting GSM. Finally, NLR with a cutoff value of ≥ 18 showed a good performance to identify worse clinical phenotypes and could be considered to identify more vulnerable COVID-19 patients.

Acknowledgements

We thank Bianca Zanchetta Buani Miguel, Thaís Nunes Freire, Marli Alves Ramelho da Silva, Fabiana Ruotolo, Daniela Hummel de Almeida, Janayna Nayara Buzato, and Henrique Oliveira e Silva for the kindly support in collecting the study data.

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Lupine Publishers | Pathological Aspect following Neoadjuvant Radiotherapy in Locally Advanced Rectal Cancer

Abstract

In locally advanced rectal cancer (LARC), neoadjuvant radiotherapy (RT) is usually performed. RT can avoid an aggressive operation and colostomy creation and can preserve the function of the anus. And various clinical trials for additional treatment, such as immunotherapy, which has recently attracted attention, after RT are being made. In rectal cancer, it is known that it is associated with mutational burden and MSI status rather than PD-L1 expression. Therefore, it is necessary to pay close attention to the pathological changes after RT to predict the efficacy of additional treatment after RT or to find a method for immune modulation for immunotherapy to work effectively.

Assessment of Post-Radiation Tumor Reduction and Sampling

First, the entire tumor volume is obviously reduced. Extravasated mucin, thickened and hyalinized vasculature was often observed. Compared to chemotherapy, which transforms into significant eosinophilic cytoplasm or bizarre morphology, the morphologic change of the tumor cell due to RT is slight. Because the operation is performed several weeks after RT, the tumor portion is replaced by dense fibrotic tissue and often regenerating surface epithelium rather than young fibroblasts. Because of only a tiny number of scattered tumor nests exist, it is difficult to confirm the remaining tumor tissue after RT for research grossly, even an experienced pathologist. So, it is so challenging to collect fresh tissue from an appropriate site. To proceed with research using the remaining tumor tissue after RT, it is appropriate to use formalin-fixed paraffin-embedded tissue as a laser dissection method through microscopic review. Alternatively, it is not easy to distinguish it from normal tissue, even using specific markers if fresh tissue is used. It is necessary to make a slide with the tissue on the mirror side and check whether there is a tumor or not. The evaluation of treatment responsiveness after radiotherapy is made by pathologic examination. The widely accepted tumor regression grade (TRG) is the American joint committee on cancer system, Mandard, and Dworak [1].

Tumor Budding after RT

Tumor budding is a unique tumor pattern known as one aspect of the epithelial mesenchymal transition of colorectal cancer. After RT, it is difficult to evaluate tumor budding because of the sparsely present tumor cells in a small number. However, there is a report that tumor budding of residual rectal cancer in post-RT samples is also related to prognosis such as overall survival. Loss of cohesiveness, that is, tumor budding, is related to nodal metastasis, the evaluation of tumor budding after RT was also related to disease specific recurrence in the pattern that appeared or remained after RT [2]. In the sample that received RT, it was evaluated into clusters of 4 or less tumor cells and 3-tiers - low, intermediate, and high, in the same way as the method for measuring tumor budding in general [3, 4].

Post-RT Immune Cell Infiltration and Components

Rectal cancer is a tumor with an active immune response than any other cancer. In post-RT surgical specimens, it is usually observed that immune cells are reduced, but in the early stage of RT, many inflammatory cells are thought to infiltrate as an inflammatory response. Immunoscore has also been evaluated a lot, and since TIL is known as a prognostic factor [5], it is necessary to evaluate the immune cell population after RT in the future.

Tumor Stroma in the post RT Specimen

In many studies, as an extracellular matrix, tumor stroma has been shown to affect tumor invasion and metastasis [6]. Generally, stroma-rich tumors are resistant to immunotherapy. In addition, it has been reported that stromal maturity can be used as a significant prognostic marker in a large number of cohorts in rectal cancer [7]. However, evaluation studies on the changes in stroma around the tumor after RT are not yet available.

Conclusion

Analysis of changes in the tumor surrounding microenvironment after RT will be a key to predicting the efficacy of RT and its combination therapy for chemotherapy and immunotherapy.

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Lupine Publishers | Food Sources and Bioavailability of Calcium

Abstract

The identification of the calcium ration by self-questionnaires validated in the region of Blida and the Wilayas of approximately is one of the rare studies in Algeria. She was interested in a part of the Algerian population with characteristics that do not seem very different from the general population; however, this dietary survey must be supplemented by a study on a representative sample of the general population. The study showed insufficient calcium intake mainly secondary to low consumption of milk and dairy products. This low calcium intake was objectified by the two questioning methods (Fardellone and CERIN), however, it will be desirable to establish Algerian self-questionnaires validated and verified by our learned society. The results obtained are worrying, which obliges us to immediately introduce a prevention and control strategy against the multiple pathologies linked to this low calcium intake, the main one being osteoporosis with its serious fracture complications.

Keywords:Calcium; Milk ; Oxalic Acid; Self-Questionnaire ; Bioavailability

Introduction

The role of calcium in nutritional balance and its importance in the proper functioning of the

body are widely accepted [1]. Calcium is very common in the diet, however it is milk and its derivatives that exhibit optimal bioavailability [2]. The interest of studying the factors influencing this bioavailability is capital for better management of dietary advice to cover calcium needs; calcium absorption depending on the source of calcium and the nature of the diet [3,4]. Our study aims to define the dietary sources of calcium, the factors influencing the absorbability and its bioavailability in order to adapt the diets to calcium needs.

Patients and Methods

100 volunteers of both sexes aged between 20 and 60 years, from the regions of central Algeria (Médéa, Chlef and Ain Defla) participated in the cross-sectional study for 3 months in 2021.

Inclusion Criteria

a) Healthy subjects, without specific and active medical or surgical history.

Non-Inclusion Criteria

a) subjects with, in particular, a digestive pathology with repercussions on the absorption of calcium

b) subjects with an endocrine (goiter) or metabolic disorder (diabetes, obesity)

c) pregnant or breastfeeding women

d) subjects under calcium supplementation

The survey carried out is based on a validated frequency self-questionnaire (Fardellone) as a model for questioning the main dietary sources of calcium, the level of daily calcium intake and factors reducing its bioavailability. This frequency self-questionnaire comprises 20 items whose calcium content is assessed using Fardellone equivalence tables; each item is associated with a multiplying coefficient making it possible to obtain a result in mg / day.

Foods are divided into 6 groups

a) Dairy products group

b) Group of cereals, starches and pulses

c) Group of meats, fish and eggs

d) Confectionery group and particularly chocolate factories

e) Group of drinks (water, fruit juice, coffee and tea)

The descriptive analysis of the population is based on the calculation of means and standard deviations for quantitative variables and percentages for those which are qualitative. Data entry and statistical analysis are performed using SPSS4 statistical software.

Results

The study workforce was 60% women and 40% men. Subjects over 60 years of age represented 60% of the total population. The work revealed an insufficient calcium intake (calcium intake of 659, 12 mg / d in men and 736.62 mg / d) essentially linked to a low consumption of milk and dairy products and a high consumption of foods containing oxalic acid: beetroot, spinach, coffee and tea in 96% of the study population.

Discussion

The population who participated in the study is predominantly female (60%) and relatively young (71% of the subjects surveyed had an average age of 28.71 years). We have adopted the WHO references for daily consumption levels, i.e.: low intake level for consumption <500 mg / d, mediocre intake level for calcium inputs of 500-999 mg / d and a suitable level for an intake> 1000 mg / d [4]. Based on the Fardellone frequency self-questionnaire, easily performed, reliable and adapted to our eating habits, the low absorbability of calcium has been associated with the current consumption of products rich in oxalic acid (contained in beets, spinach, tea and coffee) which affects the digestive relay of calcium bioavailability [5]. Overall, our results are similar to those obtained in Morocco [6] where the average calcium intake is 699 mg / d in a population aged between 16 and 59 years, and, also to those found in Tunisia [7] in the survey which concerned premenopausal Tunisian women whose calcium intake was greater than 800 mg / day in only 4% of those concerned.

Conclusion

The results will be alarming, which encourages the immediate implementation of a prevention program for poor calcium status linked to the low calcium content of the food intake or its poor bioavailability in order to deal with the resulting pathological consequences such as osteoporosis exposing to major fracture risks. This survey must be reinforced by a study on a representative sample of the Algerian population.

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Lupine Publishers | Different Toxicity of Aristolochic Acids in Kidney and Liver

Introduction

Aristolochic acid (AAs) is a group of nitrophenanthrene compounds comprised of AAI, AAII, AAIII and AAIV, which are widely found in Aristolochia plants and used in herbal therapy and traditional Chinese medicine [1]. Consistent use of aristolochic acids- containing drugs could lead to aristolochic acid nephropathy and subsequent urinary tract tumors [2-4]. Active metabolites of AAs form adducts with DNA, inducing characteristic A-T transversion (A:T to T:A mutation) known as AA mutational signature [5]. In 2017, a study has analyzed AA mutational signature of several datasets and concluded that AAs and their derivatives were widely implicated in liver cancers in Taiwan and throughout Asia [6]. Ever since the paper published, there has been an intensive debate on whether the prevalence of AA signature mutation is high in HCC patients and if this mutation spectra is really correlate with traditional Chinese medicine consumption in Asia. Since no case report has linked AAI to liver cancer by far, many researchers held doubts regarding AA-induced liver cancer. Herein, we summarized previous reports of animal experiments indicating the organ specified toxicity in kidney other than liver and shared our opinion about the possible reasons.

For long, several reports have linked AAs to the development of urothelial cancer, kidney and forestomach tumors in rodents [7-11]. Although AA could be bioactivated in both kidney and liver, in most studies, it only induces tumors in kidney [12]. Therefore, kidney was usually considered as the prior target organ of AAs. AA-DNA adduct is a well-known biomarker for AA exposure. Studies conducted on rat kidney and liver found that kidney had at least two-fold higher levels of DNA adducts and mutant frequency than livers inducted by AAI [13, 14]. The same dose didn’t cause liver tumor in rat, but DNA adducts were detectable at lower levels than kidney [13]. The experiment on Muta mice showed the same tendency [15]. A most recent study also indicated that although forestomach carcinoma was the main cause of death in long-term small dose (0.3-3.0 mg/ kg) AAI-treated mice, kidney was still the organ with most AA-DNA adducts accumulation compared with forestomach and liver [16].

There are several possible reasons for the tissue specificity of AA, one of which could be the ability of proximal tubules to transport and concentrate AA and their metabolites, resulting in renal toxicity. OAT family, mainly expressed on renal proximal tubules, is considered to be one of the pivotal determinants mediating the accumulation of AAI into the proximal tubules [17]. In addition, the level of enzymes catalyzing the reductive activation of AAI are varied in different cells. The activation pathway for AAI is nitroreduction catalyzed by both cytosolic and microsomal enzymes. One of the main human and rat enzymes activating AA-I toxicity was NAD(P) H:quinone oxidoreductase (NQO1), present in hepatic and renal cytosolic subcellular fractions. Other involving enzymes include NADPH: CYP reductase (POR) in kidney microsomes and protaglandin H synthase (cyclooxygenase, COX) in urothelial tissues [18]. In addition to gene expression level of the AAI activation related enzymes in liver and kidney, in vivo oxygen concentration in specific tissues might also affect the balance between AAI nitroreduction and demethylation, which in turn would influence tissue-specific toxicity or carcinogenicity [19]. A recent study also indicated that hepatocyte-specific metabolism of AA-I substantially increases its cytotoxicity toward kidney proximal tubular epithelial cells, including formation of aristolactam adducts and release of kidney injury biomarkers [20].Moreover, AA exposure could cause significantly altered gene expression profiles between kidney and liver, involving defense response, apoptosis and immune response, cell cycle etc, which might also be possible reasons for the tissue-specific toxicity and carcinogenicity of AA [12, 21].

Although the toxicity and carcinogenesis of AAs in kidney is well-defined, their role in liver damage and tumor development may be different. Besides, AA exposure as the main cause of liver cancer was not consistent with the actual scenario in Asia since hepatitis B virus infection remains as the highest risk. Therefore, we believe the toxicity of AAs in liver and kidney should be considered separately.

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Lupine Publishers | Safety and Efficacy Assessment of PCNL in the Pediatric Population: A Single Centre Experience

Abstract

Introduction and Objective: Renal stone disease in children is on the rise with increased incidence and better modalities to diagnose the disease. Hence there is a necessity to strategize the evaluation and treatment of children with kidney stones. Our study was conducted to assess stone distribution, stone burden, and efficacy of PCNL in pediatric age group.

Methods: All paediatric patients with renal stone disease who subsequently underwent PCNL at our department from January 2017 to December 2020 were analysed.

Results: 84 patients ranging 1-18 years were analysed. Pain abdomen was the most common presenting symptom (61.9%) followed by fever (19.04%). The mean stone size was 2.16cm with equal side distribution. Most stones were located in the lower calyx (38%). The mean operative time was 65 minutes. Exposure to radiation from C arm ranged from 1.6-8.3 minutes. Complete stone clearance was achieved in 90.47% with a mean post- drop in Hb value to 0.72 gm/dl. Mean duration of nephrostomy tube in situ was 2.4 days and with a mean hospital stay of 3.8 days. Calcium oxalate was the most common type of stone (48%).

Conclusion: PCNL is safe and effective treatment for pediatric renal calculi with minimal morbidity and increased stone free rates irrespective of stone size. Proper patient selection, surgical skill and postoperative care contribute towards the success of the procedure.

Keywords:COVID-19; post-covid manifestations; long covid; gastrointestinal disorders; dysbiosis; dyspepsia; microbiome; probiotics

Introduction

The prevalence of renal stone disease in children ranges from 5 to 15%. Stone disease has a higher risk of recurrence in the pediatric age group making it crucial to identify the most effective method for complete stone removal to prevent recurrence from residual fragments. The optimal management of for pediatric stone disease is still evolving [1, 2]. Currently, ESWL is the procedure of choice for treating most upper urinary tract calculi in the pediatric population. However, a higher incidence of metabolic and anatomical abnormalities in pediatric patients has led to increased recurrence. Moreover, ESWL has relatively less efficacy for stones >1.5cm. Surgical intervention should be preferred in such cases so as to minimize the need for retreatment [3-5]. Percutaneous nephrolithotomy (PCNL) is less invasive than open surgery which can be a good candidate for complex and large burden stones [6]. Several studies over time with different power and limitations have reported safety and efficacy of PCNL leading to its consideration as the treatment of choice for children with stone larger than 15mm [7-9]. The advent of newer, finer instruments and increase in experience of endourological techniques such as tubeless PCNL, mini-perc, ultra-mini perc and micro-perc has resulted in reducing the morbidity rate among patients without affecting the outcomes in terms of clearance [10-14].

Therefore our study was conducted to assess the safety and efficacy of PCNL in the pediatric age group in terms of

a) Renal stone distribution & stone burden

b) The outcomes of PCNL including stone clearance, operative time, hospital stay, haemoglobin changes and

c) The associated complications of PCNL.

Materials and Methods

A prospective study was conducted at our hospital from January 2017 to December 2020 after obtaining institutional ethical committee clearance. All paediatric patients posted for PCNL at M.S. Ramaiah Medical College were considered in the study. The patients compatible for the study were interviewed and after obtaining informed and written consent they were enrolled in the study.

Inclusion Criteria:

All the patients below the age of 18 years undergoing PCNL.

Exclusion Criteria:

Anatomic abnormalities of the kidney (horseshoe kidney/malrotated kidney); Bleeding disorders; deranged renal function.

Patients were initially evaluated with a detailed medical history and a thorough clinical examination followed by a battery of investigations including CBC, RFT, Serum electrolytes, serum levels of calcium, phosphorus, alkaline phosphatase, uric acid, total protein, carbonate, albumin, parathyroid hormone (if there is hypercalcaemia), blood group & Rh typing , HbsAg, HIV, HCV, Urine: Routine & Microscopy, Urine: Culture & Sensitivity. For imaging –ultrasonography was used as a first study followed by spiral CT KUB if no stone was found. Intravenous pyelography was performed when a need arose to delineate the calyceal anatomy prior to percutaneous or open surgery. A sterile urine culture was confirmed before surgery. In patients with evidence of infection, antibiotics were given preoperatively to clear the infection prior to surgery. All patients received broad-spectrum antibiotics beginning 12h prior to the procedure and these were continued until 5 days postoperatively. All PCNL are performed under general anaesthesia. The patient initially placed in lithotomy position and a ureteric access catheter was placed under fluoroscopic guidance. The patient was then turned prone. After initial puncture, the tract was dilated using metallic or Teflon dilators. Paediatric PCNL was performed using adult instruments and clearance assessed intraoperatively by fluoroscopy. Ureteric stents and nephrostomy tubes were placed in most patients at the end of the procedure. Baseline patient characteristics, intraoperative and post-operative data were collected and analysed. Perioperative complications were classified using the modified Clavien Dindo system. In case of a supra-costal puncture, a chest X-ray was obtained subsequently in the post op period. An x ray of kidney ureter bladder was taken at 48 hours after PCNL. If needed a re-look procedure was done. The patient was followed up with an ultrasound & serum creatinine at 3 months, DMSA scan after 6 months to know the functional status of kidney & amount of renal scarring. Statistical analysis was performed using SPSS 22. Categorical variables were presented as number and percentage (%), whereas continuous variables were presented as mean ± standard deviation and median.

Results

84 patients ranging between 1-18 years of age were analysed with the mean age of study population of 11.04 years. Pain abdomen was the most common presenting symptom (61.9%) followed by fever (19.04%) with 4/84 having had prior surgical intervention for stone disease. The mean stone size was 2.16cm with equal side distribution. Most stones were located in the lower calyx (38%) followed by renal pelvis – 33%, middle calyx 17% and upper calyx 12% . The total operative time ranged from 30 minutes to 120 minutes with a mean of 65 minutes. Exposure to radiation from C arm ranged from 1.6-8.3 minutes. Intraoperative location of stone, puncture and after clearance are shown in figures 1a,1b,1c. Complete stone clearance was achieved in 90.47% with a mean post- drop in Hb value to 0.72 gm/dl. Mean duration of nephrostomy tube in situ was 2.4 days and with a mean hospital stay of 3.8 days. Intra-operative and post-operative complications in the study population are depicted. Calcium oxalate was the most common type of stone (48%).

Discussion

Although short wave lithotripsy (SWL) is considered the treatment of choice for symptomatic upper urinary tract calculi in children, but not a preferred option in patients with large stone burden, owing to higher rates of failure and residual stones. In such cases, PCNL with proven advantages can be safely advocated as a suitable treatment option in order to avoid numerous SWL sessions under anesthesia. Despite pediatric PCNL being described as early as 1985 by Woodside et al, [6] pediatric surgeons had their reservation in performing PCNL in children. This apprehension was due to the fear of parenchymal damage, early exposure to radiation and risk of major complications associated with the surgery. However, Dawaba et al, [9] proved the fear to be baseless by demonstrating that PCNL in paediatric population improved overall renal function without causing renal scarring. Similarly, Mor et al reported no significant scarring or loss of renal function in radionuclide renal scans [15-19]. He concluded that adult type tract dilation to 24Fr to 26Fr was not associated with significant renal function loss [19]. The size, number and site of tracts are not well defined in pediatric PCNL. While Gunes et al reported a higher complication rate in children <7 years operated with adult sized instruments [17]. Desai et al observed that intraoperative bleeding during PCNL in children is related to the size and number of tracts and suggested the need for technical modifications in children [20]. Although this calls for reduction in tract size, it may have an effect on the clearance rates.

In our study, 54(64.28%) underwent standard PCNL vs 30(35.71%) underwent Miniperc. We used amplatz sheath sizes in the range of 16F-28F. Size of tract dilatation was based on dilatation of pelvicalyceal system, the stone burden and no of punctures. Our clearance rates & transfusion rates were found to be similar in miniperc & standard PCNL. Our results are in concurrence with Bilen et al who reported that smaller tracts did not significantly affect stone-free rates but achieved lower transfusion rates [21]. They concluded that a 20Fr tract was as effective as working with adult sized devices and did not significantly increase the operative time [18]. Provided the quality of the puncture and subsequent tract is high, there is no greater morbidity than that reported from miniperc. Large tracts and instruments can facilitate more rapid and complete stone clearance.

Most of the stone burden was located in lower calyx (38%) in most of our cases with staghorn calculus noted in 4 patients. Single tract access was done in 72 patients with lower calyceal puncture being used mostly (43%) (Figure 2b). Multiple punctures were required in 12 cases (14.2%). We did not find any significant increase in complications following an upper calyceal puncture or with multiple punctures in our study which is comparable to Sedat Oner et al who concluded that an upper pole approach did not prolong operative time or add to the complications, making it a good alternative. A surgeon who has reached competence at performing PCNL should therefore not hesitate to use a superior caliceal approach in pediatric patients if deemed appropriate for stone removal [22-25].

Our length of hospital stay duration of nephrostomy tube in situ is comparable to previously published data. 42.85% of our cases were tubeless, which is safe when performing uncomplicated PCNL [26-34]. Prior renal surgery on the same side didn’t have any impact on outcome of PCNL [35]. Aldaqadossi et al have suggested that a previous open pyelolithotomy or nephrolithotomy does not affect the efficacy and morbidity of subsequent PCNL in pediatric patients [35]. We achieved a complete clearance rate of 90.47% which is similar to the published literature. Residual calculi noted in 8 cases were managed by ESWL. The complication rate during and after PCNL in paediatric patients varies widely in the literature. The difference in complication rates may be explained by the difference in stone burden location and experience of the surgical team. Our complication rate was 9.52% with fever being the most common. The lower incidence in complications could be attributed to the surgeon expertise at our centre.

Limitations

Our study population was from single referral center, which may not be generalizable considering small sample size. Another limitation is the lack of comparative groups such as ESWL/RIRS while evaluating the efficacy of PCNL.

Conclusion

PCNL is safe and effective treatment for pediatric renal calculi with minimal morbidity and increased stone free rates irrespective of stone size. Proper patient selection, surgical skill and postoperative care contribute towards the success of the procedure and reduces the complications.

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Lupine Publishers | The Use of Sodium-Glucose Cotransporter 2 Inhibitors in Non-Alcoholic Fatty Liver Disease

:

Opinion

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of progressive liver abnormalities from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH) to advanced fibrosis, cirrhosis, and/or hepatocellular carcinoma [1]. Parallel to the rising burden of obesity and metabolic syndrome, NAFLD has emerged as the leading cause of chronic liver disease at an estimated global prevalence of 24% [2]. Besides its known clinical burden for liver-related morbidity and mortality, NAFLD is potentially linked with other extra-hepatic chronic diseases and may be considered a multisystem condition. Particularly, NAFLD increases the risk of type 2 diabetes, cardiovascular diseases, chronic kidney disease, and all-cause mortality [1]. Potential pathophysiologic mechanisms underlying the detrimental effects of NAFLD include hyperglycemia, systemic inflammation, and increased oxidative stress [3]. Sodiumglucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents that inhibit the reabsorption of sodium and glucose in the proximal tubules of the kidney [4]. Commonly used SGLT2 inhibitors include canagliflozin, dapagliflozin, and empagliflozin. Large-scale randomized placebo-controlled trials have demonstrated the benefits of SGLT2 inhibitors in reducing adverse cardiovascular/renal events in patients with cardiometabolic conditions, including diabetes, obesity, and chronic kidney disease [5]. In regard to liver function, numerous studies have revealed that SGLT2 inhibition reduced the levels of partate aminotransferase (AST) as well as alanine aminotransferase (ALT) in patients with type 2 diabetes and established cardiovascular disease [6], highlighting the potential role of SGLT2 inhibitors in patients with NAFLD.

The use of SGLT2 inhibitors is associated with reductions in liver fat content in NAFLD. In a meta-analysis of patients with type 2 diabetes and NAFLD, SGLT2 inhibitors improved hepatic steatosis and reduced levels of ALT [7]. In the E-LIFT trial which included 52 patients with type 2 diabetes and NAFLD, empagliflozin treatment reduced liver fat, as measured by MRI-derived proton density fat fraction [8]. While these results seem to support the role of SLGT2 inhibitors in NAFLD, it is important to note that prior investigations are carried out in patients with diabetes. Although the reductions in ALT and AST were independent of levels of glycated hemoglobin in the EMPA-REG OUTCOME trial [6], the effects of SGLT2 inhibitors on NAFLD and hard cardiovascular endpoints in the absence of diabetes remain unknown. Further to this is the uncertain mechanisms underlying the improvement of NAFLD with SGLT2 inhibitors. While the glucose-lowering effects of SGLT2 inhibitors have been postulated as a major mechanism through which SGLT2 inhibitors alleviate hepatic dysfunction, the absence of protection against hepatic dysfunction with other potent hypoglycemic agents, including DPP4 inhibitors and metformin, speak against this hypothesis and highlight that there might be other potential mechanisms responsible for the observed benefits of SGLT2 inhibitors. As our understanding of SGLT2 inhibitors progresses, their pleiotropic effects are becoming increasingly apparent. Recent studies have shown that treatment with SGLT2 inhibitors significantly reduced the levels of pro-inflammatory cytokines that are associated with NAFLD, including interleukin-6 (IL-6) and C-reactive protein (CRP) [9,10]. SGLT2 inhibitors also exhibit antioxidant properties, protecting tissue damage/fibrosis due to oxidative stress, and might also ameliorate atherosclerotic changes which are well-known to be associated with NAFLD [11]. Taken together, SGLT2 inhibitors are a promising therapeutic strategy for NAFLD. Further clinical trials are warranted to establish the benefits of SGLT2 inhibitors in patients with NAFLD regardless of the presence of diabetes to halt the rapidly growing pandemic of NAFLD and its assorted comorbidities/complications.

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Lupine Publishers | Post-COVID-19 GI Manifestations: Are We in for the “Long Haul”?

Abstract

Post-COVID-19 gastrointestinal (GI) disease management remains a clinical challenge as the medical literature continues to evolve and expand. Reports of excess GI disease burden across the population, as well as prescribed use of pharmaceuticals for symptom relief, have proven “long-haul” GI disease is prevalent across the population. This article will help to summarize the current medical literature as it pertains to post-COVID-19 GI clinical presentations, dysbiosis, functional disorders and evidence of lasting liver and biliary injury implications. Increased awareness of the GI implications for this paradigm hopefully will lead to a better understanding of the pathophysiology, as well as natural history and potential therapeutic approaches.

Keywords:COVID-19; post-covid manifestations; long covid; gastrointestinal disorders; dysbiosis; dyspepsia; microbiome; probiotics

Introduction

Early medical research into coronavirus disease 2019 (COVID-19) focused predominantly on the acute presentation, management, and treatment of what was initially viewed to be only a respiratory illness. However, progressive case analysis demonstrated that the COVID-19 clinical presentation frequently included gastrointestinal (GI) manifestations, diarrhoea being the most common by affecting up to 33.7% of COVID-19 positive patients [1,2]. Also known as SARS-CoV-2, this variant was found to have a similar prevalence of GI symptoms as SARS-CoV-1 and MERS-CoV [3]. Additionally, this disease was associated with frequent reports of nausea, vomiting, and abdominal pain often preceding the respiratory sequela or in some cases, evident as the only symptom. [1,2,4]. Typically, these GI symptoms last between 1-14 days after acute onset [5]. Longitudinal follow-up of patients has demonstrated a notable subset with a wide-range of persistent COVID-19 symptoms, maintained for extended time after the initial acute presentation. Collectively, this has been defined in the literature as long-haul covid (or long-covid) [6]. Evidence of longcovid has emerged recently in the medical literature. In a multistate telephone survey of 272 patients at 3 weeks after initial diagnosis, 35% of respondents indicated that they had not returned to their usual state of health with greater than 50% of those reporting at least one unresolved symptom [7]. Another study of 177 patients had approximately 30% of their cohort reporting persistent symptoms up to 9 months after diagnosis [8]. In a larger cohort of 1733 patients, looking at 6 month follow-up from diagnosis found that the most common persisting symptoms included fatigue or muscle-weakness, loss of sense of smell or taste, sleep disruption, and anxiety or depression [9]. These symptoms were found to be evident even in patients with relatively mild initial symptoms [8]. The clinical course also varied over time from recurrent and relapsing to constant symptoms. With extended follow-up of these “long haul” COVID-19 infected patients, there is increasing awareness of persistent GI involvement. A study of the national healthcare databases of the US Department of Veterans Affairs analyzing the 6-month data beyond the first 30 days of COVID-19 diagnosis showed significant evidence of excess GI-disease burden per 1000 patients compared to non-COVID patients with an increase in diagnosed esophageal disorders, gastrointestinal disorders, and abdominal pain [10].Furthermore, there was noted to be an increased use of laxatives, antiemetic agents, histamine antagonists, antacids, and antidiarrheal agents [10]. Thus, many of the GI complaints and disorders that healthcare providers have recently encountered or will see in the office through this COVID-19 era may be related to COVID-19 manifesting disease and must be considered in this context. This paper will discuss the current understanding of long-covid related GI-disease.

Underlying mechanisms for “long haul” GI COVID

The GI mucosa consists of mucin producing goblet cells as well as a protective barrier of intestinal epithelial cells to protect from exogenous harm and to prevent infection [11,12]. The breakdown of this natural barrier and persisting inflammation are hallmarks of SARS-CoV-2 GI manifesting disease. These are thought to be implicated in systemic disease manifestations, multi-organ involvement and possibly play a large role in “long-haul” COVID.2 Angiotensin converting enzyme 2 (ACE2) receptors are evident in many locations in the body including the renal tubules, lungs, brain, heart, luminal GI tract, and the liver [13]. Notably, the majority of the body’s ACE-2 receptors are found in the brush border of intestinal epithelial cells.2 SARS-CoV-2 infects epithelial cells through binding of its spike glycoprotein (S protein) to the ACE2 receptor [2,11- 12]. The binding causes fusion of the cellular membranes and a downstream effect that allows for internalization of the virus into the host cell. This subsequently leads to viral replication, viral shedding, and release of inflammatory cytokines [2].

Importantly for the gut, this binding has wide-ranging effects. The intestinal ACE2 receptor has a unique role in the stabilization of neutral amino acid transporters (e.g., B0AT1) which are responsible for uptake of amino acids (e.g., glutamine and tryptophan), the downstream metabolic products of which are important in maintaining immunity and healthy gut microbiota [13,14]. It has been shown in murine models that ACE2 receptor deficiency resulted in high susceptibility to intestinal inflammation through epithelial damage [15]. Thus, when either deficient in ACE2 or when bound by something such as COVID-19 glycoproteins, this down regulation effect has been shown to be associated with increased gut leakage and an increase in inflammatory markers such as IL-6 and fecal calprotectin [13–15].

The relationship between the systemic effects of COVID-19 and GI disease is complex and likely multifactorial. For example, the well reported respiratory effects of COVID-19 and the robust inflammatory reaction is associated with increased IL-2, IL-7, interferon gamma, tumour necrosis factor alpha, granulocyte colony stimulating factor. These wide-ranging systemic effects include infiltration of these inflammatory cells in the intestinal tract [11- 16]. Similarly, a study of SARS-CoV-2 infected non-human primate models showed either intranasal or intragastric virus inoculation resulted in pathologic changes in both respiratory and digestive tissues [17]. Thus, they concluded that inflammatory cytokines can play a role in development of both disease pathologies without direct inoculation of each respective tissue. To the contrary however is a recent article that analyzed human intestinal biopsy tissue samples from COVID-19 positive patients and found the absence of a pro-inflammatory response in the GI tract despite detection of SARS-COV-2 in the samples.18 This paralleled their results of reduced mortality in COVID-19 patients that had presented with GI symptoms [18]. Clearly, further studies are needed to better understand the pathophysiologic mechanisms, but it seems GI tract integrity and immune response play a large role in COVID-19 outcomes, severity, and likely long-term GI health.

“Long-haul” COVID, the Microbiome, and Dysbiosis

The gut microbiome has been shown to be a key regulator of bidirectional signaling between the enteric nervous system (ENS) and central nervous system (CNS), suggesting that gut function is controlled through a microbiota-gut-brain (MGB) axis [19]. It has been shown that gut bacteria produce metabolites, such as serotonin, tryptophan, and short chain fatty acids, that can influence gut-brain signaling through the MGB axis. Accordingly, disruptions in the microbiota composition have been shown to impact neurodevelopment, mood, and GI motility [2,19]. Dysbiosis, defined as significant shifts in the diversity of commensal microbiota compared to that of healthy individuals, is a common finding in patients with acute diagnosis of COVID-19 [20–22] . A study of saliva samples from 392 COVID-19 patients found that infected patients had less butyric acid-producing bacteria and more lipopolysaccharide-producing bacteria within the oral cavity compared to that of healthy controls [22]. Several fecal studies found similar microbial imbalances within the gut [2,23- 24]. It has been suggested that gut bacteria develop metabolites to modulate the inflammatory response and potentially influence the severity of COVID-19 infections.19 Gu et al. found that patients infected with SARS-COV-2 have enriched microbial communities of Streptococcus, Rothia, Veillonella, and Actinomyces, all of which correlated with elevated levels of the inflammatory markers C-reactive protein (CRP) and D-dimer [19-23].The related longterm effects of COVID-19 and gut dysbiosis is not yet well defined. Yeoh et al. found a correlation between gut microbiota composition and levels of cytokines and inflammatory markers [25] .Relative to healthy controls, COVID-19 patients had depleted commensal and opportunistic bacteria known to be anti-inflammatory and pro-inflammatory, respectively[25] .They noted this change through serial stool samples collected from patients up to 30 days post-diagnosis and found that gut composition remained significantly altered when compared with non-COVID-19 patients. Notably, this gut microbiota composition of 27 patients remained significantly distinct, regardless of whether they had received antibiotics (although, those that did receive antibiotics were more dissimilar). Species found to be significantly altered compared to healthy controls include an increase in Bifidobacterium dentium and Lactobacillus ruminis and a decrease in E. rectale, R. bromii, F. prausnitzii, and Bifidobacterium longum [25] . A small longitudinal study analyzing fecal microbiota samples taken at the time of diagnosis, at 2 weeks after hospital discharge, and at 6 months post-discharge found that microbiota diversity was still limited 6 months after recovery[26]. Interestingly, the patients were found to have lower gut microbiota richness at 6 months as well as higher levels of CRP indicating a relationship between the inflammatory response and the gut dysbiosis observed in COVID-19[26]. Further studies with a larger sample size are needed to better clarify these associations. Although research indicates an association between dysbiosis and the severity of COVID-19 infections, the pathogenic mechanism(s) by which SARS-COV-2 causes microbiota imbalance remains largely unknown [2-4]. As noted previously it is likely that virus effects a dysbiosis by downregulating ACE2 to promote inflammation and inhibit gut immunity. ACE2 controls expression of B0AT1, an apical neutral amino acid transporter whose substrates are responsible for down-regulating pro-inflammatory cytokines, maintaining tight junctions between cells, and promoting release of anti-microbial peptides. Therefore, low ACE2 expression ultimately compromises gut immunity, allowing for opportunistic microbiota to multiply, invade, and activate cytokine storms [2-4].

“Long-haul” COVID and Functional GI Disorders

Functional GI disorders (FGID) are conditions consisting of chronic or recurrent abdominal pain, such as dysmotility or visceral hypersensitivity, that develop through dysregulation of the MGB axis. Irritable bowel syndrome (IBS) and chronic dyspepsia are considered FGID [26,27]. Studies have found that more than 10% of individuals with infectious enteritis develop post infectious-IBS (PI-IBS) [2,28]. Although COVID-19 has been found to cause bowel inflammation, there is currently a paucity of studies regarding the incidence of post-acute FGID in COVID-19 patients [29]. Research has shown incidences of acute ileus (53%), diarrhea (28.8%), and constipation (39.4%) in infected patients who are critically ill [30]. Based on prior modeling data, COVID-19’s median length of 12 days increases the risk of PI-IBS development by 10-fold [2,31]. Taken together, a wave of FGID cases as a by product of the COVID-19 pandemic should be anticipated [2,29].

SARS-COV-2 addresses many factors that contribute to individual susceptibility to post-infectious FGID, including gut inflammation, intestinal microbiota composition, and mood. FGID most commonly occurs after a bout of generalized gut inflammation, a condition associated with SARS-COV-2 infection [2,29,30-32]. A recent study looking at 347 adults (164 COVID-19 positive and 183 controls) identified persistent GI symptoms and chronic fatigue through a web-based questionnaire about 5 months after infection. They found that after resolution of infection, severity of abdominal pain, discomfort, diarrhoea, and incontinence were greater in COVID-19 recovered patients compared with controls (31.7 vs 13.7%, p<0.001). They postulated the MGB axis playing a large role in these patients [31]. While eliciting an inflammatory response, SARS-COV-2 potentially inhibits gut immunity and compromises epithelial integrity to allow for dysbiosis [2,4]. COVID-19 patients with altered microbiota composition are linked to elevated inflammatory markers, such as CRP and D-dimer, suggesting that dysbiosis may promote subclinical inflammation long after the course of COVID-19 [2,4,29]. Interestingly, a systematic review has recently shown that dysbiosis within the small bowel is associated with functional dyspepsia, which is a type of FGID [32]. COVID-19 and other coronaviruses can cross the blood-brain barrier to affect the brain and mood, thus increasing the risk of FGID. [2,33-34]. Approximately 30% of COVID-19 patients experience neurological symptoms such as dysgeusia, disorientation, nausea, and neuralgia. Mechanisms through which this occurs are currently poorly understood.34 Esposito et al. proposed that SARS-COV-2 could potentially infect the ENS and ascend vagal afferent fibers to reach the CNS [35].This proposal was substantiated by a histological study of post-mortem COVID-19 patients that discovered expression of ACE2 and TMPRSS2 by small and large bowel enteric neurons and choroid plexus epithelial cells [2,34].Other proposed pathways to CNS invasion involve the circulatory and lymphatic system.33 Regardless of the route of neurologic invasion, SARS-COV-2 poses a threat to the gut-brain axis and has been shown to alter mood.2,36 In a clinical study of patients 1 month after recovering from COVID-19, 31%, 28%, and 42% of patients scored within ranges diagnostic for depression, anxiety, and PTSD respectively.36 Because inflammatory dysregulation contributes to the pathogenesis of many mood disorders, these findings suggest that COVID-19 may have psychopathological consequences [36,37].There is a strong link between IBS and mood, given that IBS patients are three times more likely to have depression or anxiety when compared to healthy patients [19,38]. However, two-thirds of comorbid patients were diagnosed with IBS prior to experiencing mood symptoms, suggesting that both systems influence each other bidirectionally [19]. Although Ha et al. reported that serotonin levels are elevated in COVID-19 patients with diarrhoea, it is unclear whether elevated levels can be attributed to the effect of SARS-COV-2 on the CNS, gut, or both [4,36] .To further complicate the pathophysiological connection between SARS-COV-2 and FGID, gut microbes are also known to produce serotonin that can potentially influence gut motility [19].Therefore, much remains unclear as to the causality specifics between COVID-19 dysregulation of the MGB axis and resultant FGID.

“Long-haul” COVID, the Liver, and Biliary System

Liver injury is a common manifestation in patients with COVID-19, with up to 72% of patients with acute infection demonstrating liver impairment through transaminitis. Approximately 6% of patients develop severe liver injury, defined as alanine aminotransferase (ALT) >5x the upper limit of normal [39]. Severe acute liver injury has been associated with poorer disease outcomes, including increased intensive care unit admissions, mechanical ventilation, and mortality [39] . In addition to elevated aminotransferases, markers of liver function affected in severe liver injury include decreased albumin, elevated INR. Bilirubin typically is non-elevated to modestly elevated, overall suggestive of a hepatocellular pattern of injury [39]. Long-term effects of COVID-19 on the liver are still being elucidated. One study looking into liver tissue of 60 patients that died of COVID-19 found that with vascular injury from the disease and subsequent necrosis, there was an activation of intrahepatic stem cells and showed signs of aberrant regeneration [40]. Another study of 5 patients that recovered from infection showed residual viral antigens detected in both intestinal and hepatic tissues up to 180 days after testing negative for SARSCoV- 2 [41]. In addition to factors such as direct ACE2-mediated viral entry into cholangiocytes with cytokine-mediated damage, the use of medications during acute infection may confound the pattern of disease-related liver injury through drug-induced liver injury (DILI) [42,43]. Most commonly, acetaminophen/paracetamol is used to manage fever and body aches. COVID-19 therapies utilized, including hydroxychloroquine, antivirals (lopinavir, ritonavir, remdesivir), and JAK inhibitors (baricitinib), can all contribute to hepatocellular injury, and combination of multiple hepatotoxic medications with ongoing disease can potentiate this effect [43]. Population studies further out from COVID-19 diagnosis can help determine the long-term effects of liver injury and clinical implications at risk due to COVID-19 disease. Alternatively, about 12% of patients with acute COVID-19 develop cholestatic injury, with bilirubin > 3x upper limit of normal [44]. Some patients with cholestatic injury have persistence of jaundice and cholestasis following recovery from acute infection, suggestive of cellular damage to the biliary ductal cells in the pattern of secondary sclerosing cholangitis in critically ill patients (SSC-CIP) [45]. SSCCIP following COVID-19 has been referred to as post-COVID-19 cholangiopathy and has been associated with rapid progression to cirrhosis [46]. Various causes have been proposed for pathogenesis of this disease pattern, including DILI, hypoxic injury, direct viral effects, and damage from systemic inflammation (i.e. cytokine storm) [47]. Limited treatment options exist for SSC-CIP, with the exception of liver transplantation. One center has demonstrated successful orthotopic liver transplantation in a patient with post- COVID-19 cholangiopathy [48].

Therapeutic options for “long-haul” GI-COVID-19

Although there are currently no approved therapeutics preventing post-COVID-19 GI diseases or symptoms, there have been proposed options similar to those targeting the lungs, as the virus’ binding and internalization mechanisms are similar in both organ systems [2]. Promising drugs that are currently in clinical trials include recombinant human ACE2, Ang 1-7 agonists, monoclonal antibodies targeting the ACE2 receptor, and a TMPRSS2 inhibitor known as camostat mesylate [4,13]. As stated previously, the underlying mechanism of GI COVID-19 involves the ACE2 receptor which is important for viral invasion. Thus, utilizing pharmaceuticals to bind to these receptors may help alleviate the direct invasion and the systemic down-stream effects that the infection can cause the body. Currently, treatment of post-COVID-19 GI disease most aligns with rest, nutritional support, and case-bybase symptom management. As stated prior, there has been an increased use of laxatives, antiemetic agents, histamine antagonists, antacids, or anti-diarrheal agents seen recently, but care should be taken to ensure that the medications are not potentially prolonging infectiousness by modulating gastric pH or affecting the microbiome adversely [10]. Widespread treatment protocols using of these drugs have not been shown to have great efficacy. For example, a male COVID-19 patient with persistent diarrhoea successfully recovered while on a regimen of lopinavir-ritonavir, IFN-α2b, and acetylcysteine [49]. However, a clinical trial of 199 patients found lopinavir-ritonavir to have no therapeutic benefits for COVID-19 [50]. Given the role of the microbiome in the pathogenesis of postcovid dysbiosis, potential treatment options may include targeted probiotic treatment. The utility of these lies in the production of antiviral metabolites as well as the support of adaptive immunity [2,51]. The Chinese University of Hong Kong recently reported use of an oral microbiome formula which is targeted specifically for COVID-19. Although the formula is patent pending, and thus the contents is not public knowledge, the researchers working on it have mentioned that it contains several strains that were found missing from COVID-19 positive patients. Some of these strains may be Fecalibacterium prausnitzii, Lachnospiraceae bacterium, Eubacterium rectale, Ruminococcus obeum, and Dorea formicigeneran [52]. In an unpublished study, hospitalized patients with COVID19 showed resolution of symptoms and reduced proinflammatory markers in patients who received the reported formula [51]. Furthermore, Chinese National Health Commission has recently recommended probiotics to maintain intestinal microecological balance and prevent secondary bacterial infections [53]. Despite this, the rationale behind probiotic use is based on indirect evidence as animal studies failed to show changes in ACE 2 receptor expression after inoculation with lactobacilli and bifidobacterial [16]. More robust pre-clinical and clinical studies are needed to better define the role of probiotics and COVID-19.

Conclusion

There is evolving data from extended longitudinal follow-up of patients affected by COVID-19, that there is a significant cohort with persistent GI symptoms (including abdominal pain, discomfort, diarrhoea, and incontinence) even after resolution of respiratory symptoms and outside the infectious window of acute disease. The spectrum of long-haul COVID-19 has not been well characterized in the medical literature, particularly as it pertains to gastrointestinal pathophysiology. It appears that COVID-19 virus enters a variety of different GI tissues including the liver, biliary tree, and epithelial cells lining the GI tract. The resulting dysbiosis of the GI tract leads to disruption to the MGB axis and can affect the acute illness, severity, and ability to recover from disease. It may also lead to wide-ranging clinical presentations of functional GI disorders, with symptoms persisting many months, hence a new recognition of “long haul” GI COVID. It is imperative for clinicians to be aware of post-COVID-19 GI manifestations in patients who have a history of either confirmed COVID-19 or a suspected clinical history. Recognizably, COVID- 19 infection may not have initial typical symptoms but it is unclear if these cases may still result in more “long haul” consequent effects. It is also unclear as to the duration of these “long haul” symptoms and pathophysiologic changes. Clearly some of the effects such as loss of gustatory or olfactory function can have major effects on quality of life. Future research is clearly needed, but at present, there is even more rationale for disease prevention by vac

cination!

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Lupine Publishers | Acute Upper Gastrointestinal Bleeding (UGIB) In A Resource Limited Setting Highly Endemic for Viral Hepatitis B: Which Etiologies for Which Real Clinical Practices?

Abstract

Aim : To determine the aetiologies of acute upper gastrointestinal bleeding (UGIB) in a setting highly endemic for hepatitis B and to describe actual clinical practices in a resource-limited setting.

Patients and methods: This study was conducted in two parts. The first part was retrospective from January 1st 2010, to December 31st 2019 on the epidemiological profile of UGIB and the second was a prospective study from December 1st 2017 to May 31st 2018 to evaluate, in a blinded experiment, the actual clinical practices in front of an acute UGIB at the emergency units in Yaounde (Cameroon), and included: recognizing UGIB, assessing for severity, taking emergency measures and prescribing emergency Eosogastroduodenal endoscopy (EGDE).

Results : During the retrospective period, 506 patients (prevalence of acute UGIB in the services 5.6%) were included of which 71.3% were men (sex ratio 2.5). The mean age was 49.9 +/- 8 years. Haematemesis was inaugural in 350 patients (69.1%), nonsteroidal anti-inflammatory drugs were the main risk factor in 297 (43.6%), in 78 (15.4%), this was a second episode. Clinical parameters showed initial instability in 435 patients (85.9%) and haemoglobin (Hb) was <7g/dl in 359 (83.4%). EGDE was performed in 203 patients (40.2%), the main causes of UGIB were lesions of portal hypertension in 111 (44.7%), followed by peptic ulcers in 108 (43.5%). Treatment was mainly medical. However, 94 patients (84.7%) with portal hypertension lesions received endoscopic treatment, mainly by injection of sclerosing agent (69.1%), as well as 13 (1.2%) with peptic ulcers, mainly by isolated injection of dilute adrenaline (1: 10,000) in 11 (84.6%). A total of 75 patients (14.8%) died. The second part concerned 74 patients admitted for acute UGIB at the emergency services of five hospitals in Yaounde. To recognize UGIB, a digital rectal examination was done in 43 patients (58.1%), no patient received a nasogastric tube. For assessment of severity, blood pressure was taken in 73 patients (98.6%), pulse rate in 61 (82.4%), respiratory rate in 17 (23%), saturation in 17 (23%), no patient had prognostic scores in their record. For resuscitation measures, 10 patients (13.5%) received a double peripheral venous line, 20 (27%) were filled with crystalloids, restrictive blood transfusion (Hb < 7 g /dl) was carried out in 24 out of 27 patients (88.9%), 9 (12.2%) received nasal oxygen therapy. EGDE was carried out in 43 patients (60.6%), all beyond 24 hours and none had a prognostic score (Forrest or Rockall).

Conclusion: Rupture of oesogastric varices plays a significant role in the occurrence of UGIB in areas with high hepatitis B endemicity, with exceptional severity and high mortality among young people. The lack of qualified human resources and insufficient technical facilities constitute a serious problem. Locally applicable protocols are needed. In the long term, eliminating viral hepatitis B and C should reduce the prevalence of UGIB

Keywords:Gastrointestinal Bleeding; Hepatitis B Virus; Portal Hypertension; Limited Resources; Endoscopy; Clinical Practice.

Background

Acute gastrointestinal bleeding is one of the major medical and surgical emergencies whose severity should never be underestimated [1]. In approximately 80% of cases, acute gastrointestinal bleeding is of high origin, i.e. the aetiology of the bleeding is located upstream of the duodenojejunal angle or Treitz angle [2]. Acute upper gastrointestinal bleeding (UGIB) is the most frequent emergency in hepato-gastroenterology and remains a major cause of mortality, despite improvements in technical facilities, the mortality rate remains stable at about 10-15% [1-4]. The UGIB is exteriorized in 66% of cases in the form of hematemesis and the aetiologies involved are varied [2,5-7]. In the West, the proportion of peptic ulcers is significantly high. Indeed, the most common causes of acute UGIB are non-varicose (80-90%) and include gastric and duodenal ulcers in 20-50% [2,3,5-7]. Contrarily, in sub-Saharan Africa, the proportion of portal hypertension lesions is significant [8,9]. The impact of chronic hepatitis B virus (HBV) infection in this highly endemic area is significant. In highly endemic countries, ≥8% HBsAg positivity, the HBV-related disease burden is due to liver cancer and cirrhosis in adulthood, responsible for portal hypertension. The majority (80%) of the world population lives in high- or intermediate-endemic areas [10]. The way to handle acute UGIB is well codified. Gastrointestinal bleeding must be recognised, its severity assessed, and blood loss compensated. Finally, the cause of the bleeding must be found and treated [1,2,7,11]. The diagnostic approach, non-specific measures to prevent or treat haemorrhagic shock and specific haemostasis measures according to the aetiology of UGIB are often not all implemented in resources limited countries and this has an impact on evolution and prognosis. Based on data collected in the files of patients admitted in emergency and those obtained following the daily clinical practice of emergency staff, the study aimed to highlight the epidemiology and actual management of acute UGIB in our context dominated by HBV infection and limited resources.

Methods

A retrospective collection of data contained in the files of patients admitted for acute UGIB at the Yaounde Central Hospital (Cameroon) between January 1st2010 and December 31st2019, was carried out. Located at the heart of the city of Yaounde, the Yaounde Central Hospital (YCH) was created in 1930. It is the largest public referral hospital in Cameroon with capacity of …. Beds that also acts as a teaching hospital. It houses several services including the Hepato-gastroenterology service with a capacity of 34 beds, three university specialists, four general practitioners and several permanent workers and residents. This service has an upper and lower gastrointestinal endoscopy room and endoscopy equipment. The variables recorded included: demographics (age, sex); clinical and biological characteristics (onset of UGIB, history of bleeding, physical parameters of bleeding severity, and haemoglobin levels on admission); Esogastroduodenal endoscopy (EGDE) findings; specific management of the cause of the bleeding and outcomes (Table1).

The second component, cross-sectional and observational blinded experiments, conducted from December 1st 2017 to May 31st 2018, assessed the diagnostic approach and actual management of patients admitted for acute UGIB in five hospitals of different categories (1st to 3rd) of the Cameroonian health pyramid, in the city of Yaounde. Twenty (20) doctors and 39 nurses in the emergency service who managed 74 patients admitted for acute UGIB were followed. The elements to take care of acute UGIB included recognition of acute UGIB by placing a nasogastric tube or performing a digital rectal exam; assessment of severity by clinical criteria (taking blood pressure (BP), pulse rate (PR), respiratory rate (RR) and room oxygen saturation (SPO2), Glasgow- Blatchford score; fluid resuscitation and transfusions (double venous line, crystalloids filling, proton pump inhibitors (PPI) or vasoactive treatment, oxygenation, restrictive blood transfusion (haemoglobin (Hb) <7 g/dl), hourly monitoring of vital signs and neurological status) and finally, the performance of EGDE and the Rockall and Forrest scores.

Statistical Analysis

Data was analysed using Statistical Package for Social Sciences (SSPS Inc, Chicago, Illinois, USA) version 23.0. Means ± standard deviation was used for quantitative variables; Categorical data was expressed as numbers and proportions. A p value of less than 0.05 was considered statistically significant.

Results

During the retrospective period, 506 patients (prevalence of acute UGIB in the services 5.6%) were included of which 361 men (71.3% and 145 women (28.7 %), given a 2.5 sex ratio. The mean age was 49.9+/- 8 years (maximum 14-96 years) and the peak of bleeding was in the 55-65-year age group. Haematemesis was the initial complaint in 350 patients (69.1%), non-steroidal antiinflammatory drugs (NSAIDs) constituted the most important risk factor in 297 patients (43.6%), in 78 (15.4%). This was a second episode. On admission, clinical parameters relevant to severity were systolic BP <100 mmHg in 122 patients (39.8%); HR >100 beats/ minutes in 435 (85.9%) and RR >20 cycles/minute in 435 (85.9%). Hb was <7g/dl in 359 patients (83.4%). EGDE was performed in 203 patients (40.2%), the major causes of bleeding were: portal hypertension lesions in 111 patients (44.7%) followed by peptic ulcers in 108 (43.5%). Treatment was mainly medical. However, 94 patients (84.7%) with portal hypertension lesions received endoscopic treatment, mainly by injection of sclerosing agent (69.1%), as well as 13 patients (1.2%) with peptic ulcers, mainly isolated injection of dilute adrenaline (1: 10,000) in 11 (84.6%). A total of 75 patients (14.8%) died during hospitalization (Table 2).

The second part concerned the assessment of care offered to 74 patients admitted for acute UGIB (mean age 55 years; sex ratio 2.1). For the recognition of bleeding, digital rectal examination was performed in 43 patients (58.1%) and no patient received nasogastric tube. Regarding the assessment of severity by clinical criteria, BP was taken in 73 patients (98.6%), HR in 61 (82.4%), and RR in 17 (23%), no patient had prognostic scores in the record, including the Glasgow-Blatchford score. Only 17 patients (23%) had SPO2 measurements. Regarding intensive care measures, only 10 patients (13.5%) received a double peripheral venous line, the majority of which was a small-bore venous line. Twenty patients (27%) were filled with crystalloids; restrictive blood transfusion was performed in 24 out of 27 patients (88.9%) with Hb < 7 g / dl. Only 9 patients (12.2%) received nasal oxygen therapy. EGDE was performed in 43 patients (60.6%), all beyond 24 hours after admission and none had a prognostic score after endoscopy (Forrest or Rockall).

Discussion

The study showed that acute UGIB is an emergency with exceptional severity in our environment, as mortality is very high at around 15%. In this study, it was found that acute UGIB affected two and a half times more men than women with a mean age of about 50 years. This is the case in studies conducted in Mali (sex ratio 2.78; mean age 47.45 years), and in Côte d’Ivoire (sex ratio 3.38; mean age 47 years) [8,12]. Indeed, in the sub-Saharan African region, the occurrence of acute UGIB often involves relatively young patients. This can be explained by the fact that the causes of bleeding are often dominated by portal hypertension lesions, especially in young patients, as reported in Mali in a rural area [8]. As opposed to sub-Saharan Africa, in the West, the age of onset of acute UGIB is higher than 70 years due to the use of NSAIDs in the elderly population. Of chronic NSAID users, 25% develop an ulcer, of which 2-4% are complicated by bleeding [2,7,13,14]. The male predominance is universal, and reverses in the West after the age of 80 years due to the higher life expectancy in the female population [2,4,6-9, 11,13,14].

As in several studies reported in literature, hematemesis was the most common initial clinical presentation [2,6,7,15,16]. This initial clinical presentation can be explained by the different lesions found on endoscopy. In fact, portal hypertension lesions, led by oesophageal varices, were the most frequent, alongside peptic ulcers. The frequency of the various aetiologies varies from one region to another [5,6,8]. Thus, in the sub-Saharan African region, several studies report very high frequencies of portal hypertension lesions. This is the case of the study by Diarra et al. in Mali in 2007 [8]. The authors reported a frequency of 55.2% in favour of ruptured oesophageal varices, far ahead of peptic ulcers which represented 16%. The frequency of portal hypertension lesions is also high in Burundi (28.2%) [16] and Gabon (29.5%) [17]. These various countries have liver diseases related to chronic HBV infection in common. Indeed, sub-Saharan African countries are located in a zone of high endemicity according to the World Health Organisation (WHO), i.e. the prevalence of hepatitis B is 8-20% of the general population [10]. Cirrhosis, which causes portal hypertension, is often the result of chronic HBV infection acquired at birth or in early childhood [18]. The annual incidence of varicose veins is approximately 5% [19]. UGIB from ruptured esophageal varices accounts for 70% of gastrointestinal bleeding in cirrhosis, with an estimated overall 2-year bleeding risk of 20% [19]. The aetiological approach to acute UGIB in high- and intermediate-endemic areas where the majority (80%) of the world population lives should therefore consider this high frequency of portal hypertension lesions and bleeding complications.

Regarding the severity of the bleeding, more than 85% of patients were initially unstable with clinical and laboratory signs of severity, despite the absence of Glasgow-Blatchford and Rockall scores in their records. This initial haemodynamic instability can be explained, on the one hand, by the causes of bleeding, in particular the rupture of oesogastric varices, which are exceptionally serious, but also, on the other hand, by the late arrival in hospital structures due to distance, cultural considerations or difficulties of mobility in our country.

Treatment was essentially medical. PPI treatment was most often initiated on admission, even if this treatment did not always fully comply with current recommendations in Europe and Asia [2,7,20,21]. Contrarily, in cases of suspected acute UGIB related to rupture oesogastric varices, vasoactive therapy to reduce portal blood flow was never initiated on admission, in line with international recommendations, including those adapted by the European Society of Gastrointestinal Endoscopy to be applicable to resource-limited settings, including some African countries [2,7,22-24]. Patients with bleeding peptic ulcers have rarely benefited from endoscopic haemostasis, unlike those with portal hypertension lesions. Late arrival at hospital would explain why in sub-Saharan Africa Forrest scores IIc and III, i.e. pigmented stain or clean base of the ulcer, are most frequently found [25]. For the Forrest classification guiding the choice of endoscopic treatment modality for ulcers, there is no endoscopic treatment for these scores [2,3,7,26]. The practice of injecting adrenaline alone instead of combined adrenaline and bipolar coagulation or endoclips was inappropriate. This could be explained by factors such as excessive procedure costs, insufficient training of practitioners and limited logistic equipment.

The mortality rate of upper GI bleeding varies between 2-10%, and is increased by the presence of associated diseases, but also rupture of oesogastric varices with a specific mortality rate of 15- 25% [2,27,28]. Because of the predominance of portal hypertension lesions in our series and the liver failure accompanying cirrhosis, mortality was high compared to other countries in the sub-region, 5% in Togo [15], 3.8% in Gabon [17] and 9.4% in Côte d’Ivoire [12]. On the other hand, it was close to the mortality found in Burundi, 22.9% [16]. The lack of primary prevention of varicose vein rupture could also explain this high mortality. However, this factor has not been studied (Table 3, 4).

The quality of care is key to improving prognosis [2,3,7, 8,29- 31]. The actual care in the studied setting was assessed. The priority in the care of acute UGIB is to ensure haemodynamic stability with crystalloid or balanced infusions and possible transfusions [2- 5,29-31]. For this purpose, bleeding should be recognised either by nasogastric tube placement or by digital rectal examination. Also, the severity should be assessed by prognostic scores, in particular the Glasgow-Blatchford score (GBS), based on clinical and biological criteria, validated to identify low-risk patients with a sensitivity of 99% and a specificity of 32% [2,30,32]. From these recommendations, it was observed that the recognition of bleeding and the assessment of its severity were insufficient. Recording clinical parameters was neglected. Neither digital rectal examination nor nasogastric tube placement to aid diagnosis was rarely done if the patient was not present at the time of the blood loss. Oxygen therapy, even for initially unstable severe cases or cases with comorbidities, was often not effective. This may be due to the lack of oxygen in some hospitals or because of outdated or non-existent anaesthesia and intensive care equipment. The current guidelines, recommending a transfusion threshold of 7 g/dl [2,30,33,34], were met in about 90% of patients in this case. It should be noted that the Yaounde Central Hospital, which had the largest number of patients, has a certification for its blood bank. Treatment with venous PPI was started early in the majority of cases regardless of the suspected aetiology. Given the significant proportion of portal hypertension lesions, vasoactive drugs should be integrated into local protocols for the care of acute UGIB, since this is not currently the case. Helicobacter pylori testing and eradication is also not integrated into the care of acute UGIB in the setting. And yet, this is a validated approach [35]. Helicobacter pylori infection plays a major role in the development of ulcers in the studied environment, affecting approximately 70-80% of the population [36].

EGDE with or without endoscopic therapeutic procedures is an integral part of the care of UGIB and has been shown to improve patient outcomes in terms of morbidity and mortality [2,7,26,31]. However, the ideal time for its performance is unclear. Recommendations agree that it should be performed within 24 hours of admission [2,3,7,37]. Early endoscopy within 12 hours would not influence clinical outcomes, mortality, recurrence of bleeding or the need for surgery [20,31]. In our resource-limited environment, not only is there a shortage of qualified human resources, but there is also inadequate technical equipment. While it is accepted that an EGDE should be performed in every patient with acute UGIB, the rate of completion was only 40-60.6% in both study arms. This procedure is relatively expensive in relation to people’s income. Endoscopy was most often performed beyond 24 hours after admission. Thus, therapeutic endoscopic procedures were rare. If performed early, it seems to have an influence on hospital resources and costs, by identifying low-risk patients and allowing them to return home quickly [31,37]. This would be appropriate in our resource-limited environment.

Conclusion

Contrary to Western countries, ruptured oesogastric varices play an important role in the occurrence of gastrointestinal bleeding in areas with high hepatitis B endemicity. UGIB is exceptionally severe in these areas, as it has a high mortality. The lack of qualified human resources and insufficient technical facilities constitute a serious problem. For this reason, the improvement of clinical practice in relation to acute UIGB should consider the significance of portal hypertension lesions, on the one hand, and the limitation of resources on the other. Therefore, locally applicable protocols need to be devised. In the long term, the elimination of viral hepatitis B and C should considerably reduce the prevalence of UGIB. A multicentre study is therefore expected to establish protocols adapted to our health and limited resource settings.

What Is Known

a) 80% of gastrointestinal bleeding are upper. The most common causes of acute UGIB are non-variceal (80-90%) and include gastric and duodenal ulcers in 20-50%.

b) The age of onset of UGIB is around 70 years.

c) UGIB remains an important cause of morbidity and mortality.

The mortality rate has remained stable at around 10-15%.

d) The improvement of the prognosis depends on the care quality and treatment of acute UGIB is well codified.

e) The assessment of the severity of UGIB is based on prognostic scores, in particular the Glasgow-Blatchford score (GBS) which is based on clinical and biological criteria, validated to identify low-risk patients with a sensitivity of 99% and a specificity of 32%.

f) If acute UGIB is suspected in relation to rupture oesogastric varices, vasoactive therapy to reduce portal blood flow should be given as early as possible. In cases of suspected ulcerrelated UGIB, high-dose PPI therapy should be started early.

g) The priority in the care of acute UGIB is to ensure haemodynamic stability with crystalloid or balanced infusions and possible transfusions. Current guidelines recommend a transfusion threshold of 7 g/dl.

h) Helicobacter pylori testing and eradication is incorporated into the care of acute HDH.

i) It is accepted that an EGDE should be performed in all patients with acute UGIB. There is consensus that endoscopy should be performed within 24 hours of admission (12 hours in the case of portal hypertension related UGIB).

j) The Forrest classification guides the choice of endoscopic treatment modality for bleeding ulcers.

k) Haemostatic endoscopy is the first-line treatment for bleeding ulcers.

Relevance of the study

a) The causes of acute UGIB in areas of high hepatitis B endemicity are dominated by variceal bleeding in young patients.

b) The age of onset of UGIB is around 50 years.

c) The mortality rate is very high, around 15%.

d) The actual clinical practice is based on a non-codified care.

e) The prognostic scores of UGIB, notably those of Glasgow- Blatchford (GBS), Forrest and Rockall, are rarely used.

f) In case of suspected acute UGIB related to rupture oesogastric varices, vasoactive treatment is not often prescribed.

g) Not all emergency intensive care measures are followed, including oxygen therapy and monitoring.

h) Helicobacter pylori testing and eradication is not included in the care of acute UIGB.

i) The rate of completion of EGD is very low (40-61%) and it is done beyond the required 24 hours.

j) Haemostatic endoscopy is not the first-line treatment for bleeding ulcers, only in 1.2%.

Abbreviations and acronyms:

Upper gastrointestinal bleeding (UGIB); hepatitis B virus (HBV); HBV surface antigen (HBsAg); blood pressure (BP); pulse rate (PR), respiratory rate (RR); room oxygen saturation (SPO2), oesogastroduodenal endoscopy (EGDE); haemoglobin (Hb); proton pump inhibitors (PPIs); University of the Mountains (UdM); World Health Organisation (WHO); Institutional Ethics Committee of the University of the Mountains (CIE-UdM).

Declarations

a) Ethical considerations

We obtained ethical clearance from the Institutional Ethics Committee of the University of the Mountains (CIE-UdM) under the number No. 2018/149/UdM/PR/CIE of 19 March 2018.

b) Consent to publish

All authors gave their approval for publication.

c) Availability of data and materials

The datasets used during the current study are available from the corresponding author on reasonable request.

d) Competing interests

The authors declare no conflict of interest for this study.

e) Funding

The authors did not receive any fund for this study.

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Lupine Publishers | Improvement of Liver Function by a Short-term Administration of Luseogliflozin in Patients with Type 2 Diabetes: A Single-arm Study and the Mini-literature Review

Abstract

Background: Non-alcoholic fatty liver disease is not simply the hepatic manifestation of obesity and diabetes but also linked to hepatocellular carcinoma. Yet, its effective treatment has not been established. In this study, we evaluated the effect of a short-term administration of luseogliflozin to patients with type 2 diabetes having non-alcohol fatty liver disease. Luseogliflozin is a unique sodium-glucose cotransporter 2 inhibitor which is metabolized in and excreted by the liver in addition to the kidney. Therefore, the drug might possess an additional effect on other agents of the same class which are exclusively metabolized in the kidney.

Methods: Using alanine aminotransferase >20 IU/L as a diagnostic basis for non-alcoholic fatty liver disease, 19 patients, not taking alcohol, with type 2 diabetes (male/female 15/4, the median age 57 years) was treated with 2.5 mg luseogliflozin for 12 weeks.

Results: Pre- and post-treatment median values for alanine aminotransferase were 51 IU/L and 33 IU/L (p = 0.001), and the corresponding values for the fibrosis index based on the four factors [age (years) ∙ alanine aminotransferase (IU/L)] / [platelets (109/L) ∙ alanine aminotransferase (IU/L)1/2)] were 1.669 and 1.314 (p = 0.043). There was no adverse effect of the drug. Our findings were essentially compatible with the results of the previous studies reviewed.

Conclusion: We conclude that sodium-glucose cotransporter 2 inhibitor could be the choice for the pharmacological treatment of non-alcoholic fatty liver disease. Especially, a short-term administration of it is consistently effective in mild cases.

Keywords: SGLT2 inhibitor; NAFLD; Fibrosis-4 index; GPR-index; APRI.

Abbreviations: SGLT2i: sodium-glucose cotransporter 2 inhibitor; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; T2DM: type 2 diabetes mellitus; AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: gammaglutamyl transpeptidase; Fib-4 index: Fibrosis-4 index; GPR-index: gamma-glutamyl transpeptidase to platelet ratio; APRI: aspartate aminotransferase to platelet ratio

Introduction

Obesity or overweight is the motherland of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) [1]. Accordingly, with increasing trend of body weight worldwide, the number of patients with the liver problem is relentlessly increasing [2]. Recently, NASH has also been attracting the attention as a cause of hepatoma [3,4]. Under such yet, treatment of NAFLD (NASH and NAFLD are collectively called NAFLD hereafter in this communication), irrespective of presence or absence of diabetes, has not been established. Results of treatment of patients with type 2 diabetes (T2DM) having NAFLD with sodium-glucose cotransporter- 2 inhibitor (SGLT2i) appears promising [3-7], the effectiveness of a short-term treatment, such as 12 week-treatment, has not been established. Here, we evaluated effectiveness of a short-term administration of SGLT2i, luseogliflozin, that is metabolized not only in the kidney but in the liver [8]. A mini literature review on this issue was also performed to resolve the current inconsistency. This study was approved by the Clinical Research Ethics Committee of Aizawa Hospital (No. 2019-094).

Subjects and Methods

Subjects  

Consecutive 29 patients with T2DM who took luseogliflozin for 3 months or longer between January 1, 2019 to May 31, 2020 were initially registered. Because the purpose of this study was to investigate the effect of luseogliflozin on NAFLD/NASH, 8 with alanine aminotransferase (ALT) less than 20 IU/L [9], and other 2 with a habitual alcohol drinking of 20 g/day or more were excluded, and the remaining 19 were analyzed. The study was a single-arm, add-on study. Namely, 2.5 mg luseogliflozin was additively prescribed on top of the hypoglycemic agents already taken by the patients, which are shown in Supplemental Table 1. The data before and 12 weeks after luseogliflozin administration was critically compared.

Laboratory measurements

In addition to the routine clinical chemistries, indices of the hepatic fibrosis including Fibrosis-4 index (Fib-4 index), gammaglutamyl trans peptidase (GGT) to platelet ratio (GPR-index), and aspartate aminotransferase (AST) to platelet ratio (APRI) were calculated10: the unit for AST, ALT, GGT as IU/L, platelet counts as 109/L and age as a year. Equations for each index were as follows [10].

Fib-4 = [(AST) ∙ (age)] / [(Platelet counts) ∙ (ALT)1/2] GPR index = 100 ∙ (GGT) / (Platelet counts) APRI = 100 ∙ (AST) / (Platelet counts)

Statistical analysis

The data were collected retrospectively and analyzed cross-sectionally and longitudinally. We evaluated the effect of luseogliflozin on the liver function tests and the indices of liver fibrosis. In addition, delta, i.e., the basal value minus 12 week-value for the indices of liver fibrosis was calculated for each study subject, and correlation between the delta values of fibrosis indices and the basal plasma glucose (PG), glycosylated hemoglobin (HbA1c), AST, ALT, GGT, body weight (BW) and body mass index (BMI) were examined. Furthermore, the delta value of the liver fibrosis indices and the delta value of PG, HbA1c, AST, ALT, GGT, BW and BMI were also examined. The statistical analysis was performed using JMP ver.15. Wilcoxon rank-sum test, Wilcoxon signed rank test and Spearman rank correlation were used as needed.

Literaturereview

Representative 10 original reports published in the English language on the treatment of patients with T2DM having NAFLD by SGLT2 inhibitors [6,7,11-18] were summarized to provide a current overview of the issue. In these literature, five kinds of SGLT2i agents were prescribed, with the number of the patients ranging from 9 to 32 and the treatment duration from 12 to 48 weeks.

Results

Baseline characteristics of the patients

Values are median and interquartile ranges except for sex and the observation period: the latter was shown as mean and SD. sBP, systolic blood pressure; dBP, diastolic blood pressure; HR, heart rate; Hct, hematocrit; Plt, platelet count; T.Bil, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyl transpeptidase; Al-P, alkaline phosphatase; Alb, albumin; eGFR, estimated glomerular filtration rate; HDL-C, high density-lipoprotein cholesterol; LDL-C, low density-lipoprotein cholesterol; TG, triglycerides. N.A., not applicable. *Wilcoxon signed-rank test.The study patients were male dominant (the proportion of males, 79%), middle-aged Japanese adults with the median BMI of 28.0 kg/m2 which was larger than the representative value in the Japanese patients with T2DM in general11(Table 1A). The median HbA1c value of the entire group before luseogliflozin was 8.8% (77 mmol/mol) so that the level of glycemic control was unsatisfactory (Table 1A). Regarding the hypoglycemic agents used before subscribing luseogliflozin, Dipeptidyl Peptidase-4 (DPP-4) inhibitors and biguanide were most frequently employed (Supplemental Table 1), which was typical for the Japanese patients [19].

Values are median and interquartile ranges except for sex and the observation period: the latter was shown as mean and SD. sBP, systolic blood pressure; dBP, diastolic blood pressure; HR, heart rate; Hct, hematocrit; Plt, platelet count; T.Bil, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyl transpeptidase; Al-P, alkaline phosphatase; Alb, albumin; eGFR, estimated glomerular filtration rate; HDL-C, high density-lipoprotein cholesterol; LDL-C, low density-lipoprotein cholesterol; TG, triglycerides. N.A., not applicable. *Wilcoxon signed-rank test. Liver function and indices of hepatic fibrosis following luseogliflozin administration Elevated serum level of ALT was an inclusion criterion, so that the ALT was clearly elevated as a group with the median value, 51 IU/L. As well expected, administration of luseogliflozin significantly decreased PG and HbA1c (Table 1, A and B, before and after luseogliflozin, respectively). In addition, it significantly lowered the serum level of AST, ALT, GGT, and alkaline phosphatase (ALP). The degree of lowering was 12%, 34%, 35 and 42% for the respective enzyme levels. Importantly, the luseogliflozin treatment also significantly lowered the values for Fib-4 index, GPR index, and APRI (Figure 1).

Correlation between delta Fib-4, GPR index, and APRI and baseline and delta values of liver function and the body weight and BMI

The delta Fib-4 index was significantly and positively correlated associated with higher baseline AST and ALT levels; the delta GPR index was correlated with baseline AST and GGT; the greater delta APRI was associated with higher baseline AST and ALT (Table 2A). Correlation between the delta values and the baseline of liver function was absent for BW and BMI (Table 2A).

On the other hand, there was an inverse correlation between ‘delta Fib-4 and delta AST and delta ALT’, ‘delta GPR index and delta GGT’ and ‘delta APRI with delta AST and delta ALT’ (Table 2B). There was no significant correlation between delta values of the fibrosis indices and the delta of BW and BMI (Table 2B).

Values are median and interquartile ranges except for sex and the observation period: the latter was shown as mean and SD. sBP, systolic blood pressure; dBP, diastolic blood pressure; HR, heart rate; Hct, hematocrit; Plt, platelet count; T.Bil, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyl transpeptidase; Al-P, alkaline phosphatase; Alb, albumin; eGFR, estimated glomerular filtration rate; HDL-C, high density-lipoprotein cholesterol; LDL-C, low density-lipoprotein cholesterol; TG, triglycerides. N.A., not applicable. *Wilcoxon signed-rank test. Literature review In the previous studies, SGLT2i was administered for the relatively small number of patients with type 2 diabetes having NAFLD (up to 32) for the relatively short period (up to 48 weeks) for patients with T2DM having NAFLD (Table 3). In general, the agent effectively ameliorated the hepatic fat accumulation as indexed by the liver function tests, the fibrosis indices, the morphological tests such as computed tomography (CT) scan, magnetic resonance imaging (MRI) or biopsy. However, the detailed analysis of the reported data of the short-term therapy exhibited inconsistency. According to the report by Eriksson JW et al [7], in one population with the treatment duration of 12 weeks, liver function was improved and fat accumulation in the liver decreased, and in the other, the hepatic fat was not decreased by the 12 weektreatment with SGLT2i [7]. Morphological evaluation of the liver was not carried out in the third study [14]. Taken together, twentyfour weeks was the shortest period needed to firmly demonstrate improvement of hepatic morphology indicating attenuation of fat accumulation [12,17]. No clear-cut difference on the basis of species of SGLT2i was observed.

Discussion

In this study, we analyzed effect of 2.5 mg luseogliflozin given for 3 months to patients with T2DM having NAFLD, judged by ALT 20 IU/L or higher. We confirmed the substantial lowering, generally 30-40%, of elevated liver enzyme levels and, moreover, decrease in the established indices of liver fibrosis such as Fib-4 index, GRP index, and APRI, by this short-term SGLT2i treatment in the group. Elevated delta Fib-4 was significantly associated with higher basal Fib-4 values, and as expected from the definition of Fib-4, delta Fib-4 and delta AST well correlated each other. The degree of improvement of the indices of hepatic fibrosis was much less than that of glycemia, and our preliminary data suggested that lowering of delta Fib-4 correlated with improvement of insulin sensitivity indexed by lipids and BMI [20] (data not shown). Absence of correlation between the drug effect on the indices of fatty liver and its effect on the BW strongly suggested that BW reduction was not the primary conveyer of SGLT2i’s favorable effect on NAFLD, at least under our treatment protocol. Importantly, the average change of the three fibrosis indices corresponded to the range observed in patients whose alteration of the hepatic fibrosis proven by biopsy or ultrasonography [10]. A significant lowering of Fib-4 after treatment with SGLT2i was not recognized in some of the previous studies (Table 3). A clear-cut luseogliflozin effect within a short period on the liver in our study might be due to the stringent selection of study participants using ALT ≥ 20 IU/L as an entry criterion. The mini review can be summarized as, 1) favorable outcome of SGLT2i treatment on NAFLD may be a class effect, 2) the hepatic enzymes may be relatively sensitive as indicators of improved NAFLD showing significant attenuation within 12 weeks, and 3) for measurable reduction of hepatic fat, approximately 10 more weeks of luseogliflozin treatment are needed. Hepatic triglycerides (TG) accumulation might be excessively stimulated by an abundance of substrate, hyperglycemia, and hyperinsulinemia in T2DM patients with NAFLD [21], and SGLT2i might suppress this circle by lowering PG and serum insulin at the same time through improved insulin sensitivity [22,23]. Results of randomized, largescale, prospective studies with measurements of insulin and newer markers are strongly awaited to fully understand the significance of SGLT2i in NAFLD or NASH.

Conclusion

Short-term (twelve-week) add-on administration of luseogliflozin lowered plasma glucose in patients with type 2 diabetes having NAFLD. In addition, the treatment effectively suppressed markers of fatty liver likely through improved insulin sensitivity. Through the literature review, luseogliflozin’s effect on fatty liver appears to be comparable to other SGLT2i.

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Lupine Publishers | Is there a utility of Nordin’s Index in the evaluation of osteoporosis in patients with post viral cirrhosis? Results of a pilot study in Cameroonians

Abstract

Background: Metabolic bone disorders are frequent in patients with cirrhosis. These two conditions are usually misdiagnosed in Sub-Saharan Africa before the onset of complications. A full evaluation of metabolic bone disorders in patients with liver cirrhosis is difficult in our milieu and osteodensitometry is rarely available. In this preliminary study, we sought to determine the necessity of a cost-effective method, the Nordin’s Index, in the evaluation of osteoporosis in patients with liver cirrhosis.

Methods: This was a prospective cross-sectional study from January to May 2017 in Yaoundé. We compared the data of 19 patients (15 men, 4 women) with post viral liver cirrhosis and 17 controls (13 men, 4 women) paired with age, gender and body mass index (BMI). Data collected included vitamin D levels, serum and urine concentrations of calcium and phosphorus, Nordin’s Index and results of the bone mineral density using an x-ray absorptiometry scan. Statistical analysis was performed using the software SPSS 21. A p value of less than 0.05 was considered to be statistically significant.

Results: The mean age of patients was 38 ±15 years, with a mean BMI of 25 ±8 kg/m². Three of the four women were on menopause. Etiologies of cirrhosis were viral hepatitis B (8 patients), viral hepatitis B and D coinfection (7 patients), and viral hepatitis C (4 patients). The median duration of cirrhosis was 19 [8; 48] months, and 14 patients were classified grade A in Child Pugh classification. There was no statistical difference in the serum and urine concentrations of calcium and phosphorus. Osteoporosis was more frequent in cirrhosis (31.6% versus 11.8%, p<0.05). Nordin’s Index was significantly elevated in patients with cirrhosis compared to controls (0.12 [0.06; 0.13] mg/mg, versus 0.03 [0.01; 0.08] mg/mg, p<0.05), and in patients with cirrhosis associated to osteoporosis compared to those without (0.13 [0.09; 0.13] mg/mg versus 0.07 [0.03; 0.08] mg/mg, p<0.05). Vitamin D deficiency was more observed in controls (13/17 versus 7/19, p<0.05). Factors associated with osteoporosis were disease duration, elevated Nordin’s Index and elevated serum level of transaminases.

Conclusion: The Nordin’s Index, a simple and inexpensive tool for exploration of the phosphocalcic metabolism, could be useful for the evaluation of osteoporosis during viral cirrhosis. However, its performance has to be evaluated in a larger sample.

Keywords: Cirrhosis, chronic viral hepatitis, osteoporosis, Nordin’s Index, Vitamin D.

Abbreviations: ALAT: Alanine Aminotransferase; ALP: Alkaline Phosphate; ASAT: Aspartate Aminotransferase, BMD: Body Mass Density; GGT: Gamma Gluthamyl Transferase

Introduction

Cirrhosis is the outcome of most chronic liver diseases. It remains a major public health problem in Sub-Saharan Africa and particularly in Cameroon, where chronic viral hepatitis is highly endemic [1-3]. In fact, sixty percent of cirrhosis in Africa are attributable to viral hepatitis B and C [4]. In Cameroon, 70.9% of cirrhosis cases are due to chronic viral hepatitis B and 25.5% to chronic viral hepatitis C [5]. The hallmark of cirrhosis is hepatocellular insufficiency and portal hypertension, resulting in impaired liver function and subsequent systemic abnormalities. Bone damage is one of the systemic abnormalities frequently seen in cirrhosis, regardless of etiology, and is known as hepatic osteodystrophy [6]. Hepatic osteodystrophy is a combination of osteoporosis and osteomalacia, the latter being rare during cirrhosis [6]. According to the World Health Organization (WHO), osteoporosis is a diffuse disease of the skeleton, characterized by a decrease in bone mass and an alteration of the micro-architecture of bone tissue, leading to increased bone fragility and an increased risk of fractures [7]. Its pathogenesis during cirrhosis is complex and leads to an increase in bone resorption by osteoclasts to the detriment of its formation by osteoblasts [8]. The prevalence of osteoporosis during cirrhosis is between 12% and 55% [9]. In Africa, more precisely in the Maghreb region, it has been estimated to 28.26% [10]. Osteoporosis is almost asymptomatic until complications. It is a real public health problem as it causes low energy fractures in more than 40% of cases, affecting the morbidity and quality of life of patients with cirrhosis [8]. Several factors are associated with the occurrence of osteoporosis during cirrhosis, including vitamin D deficiency with a prevalence of 32% in Europe and 32.6% in Africa during cirrhosis [10,11]; Elevated Child and Pugh Score, duration of disease, etiology of cirrhosis, low body mass index, with some controversy in the literature [12]. Considering the risk of osteoporosis being high during cirrhosis, it is necessary to have an evaluation of bone mineral density in these patients [13,14]. However, this is rare in our context because of the cost and accessibility of this examination. With the absence of hepatic transplantation in our environment to cure cirrhosis, there is a long duration of cirrhosis and, therefore, an increased risk of complications including osteoporosis. It is therefore important to use simple and inexpensive tools to make the diagnosis or at least to detect high-risk subjects. Nordin’s Index is calculated by the calciuria/creatinuria ratio. It is an old marker of bone resorption, which correlates with post-menopausal osteoporosis and its risk of fracture [15,16]. However, its usefulness in cirrhosis especially post viral has been little studied to the best of our knowledge. In this study, we sought to determine the utility of Nordin’s Index as a cost-effective method in the evaluation of osteoporosis in people suffering from post-viral cirrhosis in a highly endemic area for chronic viral hepatitis and limited access to bone mineral density assessment.

Patients and Methods

Study design  

The study used a cross sectional design with a prospective data collection.

Study setting

This study took place from January to May 2017 at the Yaoundé Central Hospital and Cathedral Medical Centre (CMC) at Yaoundé, where the participants were recruited. Laboratory analysis were conducted at the University Hospital Centre of Yaoundé. Bone mineral density measurements were carried out at the Autonomous Centre for Radiology and Medical Imaging (CARIM) at Yaoundé.

Participants

The sample was made up of 19 adult volunteers (15 men and 4 women) followed for a cirrhosis of viral cause (chronic viral hepatitis B, C, and D). They were matched with 17 adult volunteers (13 men and 4 women) without any chronic or acute disease/ condition, paired with age (±2 years), gender and body mass index (BMI; ±2 kg/m²). The diagnosis of liver cirrhosis was based on clinical and biological signs of portal hypertension and chronic liver failure, ultrasonographic signs of chronic liver disease and endoscopic signs of portal hypertension. Ultrasonographic signs included irregular liver outline, heterogeneous echo structure, dysmorphic liver, enlarged portal vein and presence of collateral venous circulations. The controls were recruited from among the patients’ caregivers to ensure equal exposure to environmental and nutritional factors that may contribute to osteoporosis. We did not include any participants who presented pathologies with known repercussions on bone and/or phosphocalcic metabolism, such as: chronic renal disease, thyroid and parathyroid disorders, Cushing Syndrome, diabetes, HIV infection and cancer. We did not include participants receiving treatment with known effects on bone and/ or calcium phosphorus metabolism such as: hormone replacement therapy, biphosphonates, calcium, vitamin D, corticosteroids, antimetabolites, anticoagulants, anticonvulsants, thyroxine. Pregnant women instead of women with amenorrhea, participants with diabetes, tobacco and alcohol consumers were not included.

Sample size calculation

The sample size was estimated using the formula in Whitley et al. to compare proportions between groups [17]. The parameters used for the calculation of the standardized difference were derived from the study of Goral et al [18]. They found a mean T-score of -1.6 SD in patients with cirrhosis and -0.25 SD in controls, with a standard deviation of 1.3 SD. In our study, the level of significance was set at p 0.05 and the power at 80%. The minimum sample per group was 15.

Procedure

Ethical considerations  

We obtained research authorizations in the selected health care facilities and the approval of the Institutional Review Board of the Faculty of Medicine and Biomedical Sciences. All the participants read and signed an informed consent form.

Clinical data

Sociodemographic (age, gender) and clinical data were collected through a questionnaire. Clinical variables were anthropometric parameters (weight and height) for BMI calculation, the history of cirrhosis (duration, etiology, complications, current Child and Pugh’s Score, treatment), suggestive signs of osteoporosis and its complications (history of pathological and or low energy fracture), comorbidities, menopause for women and its duration, and family history of osteoporosis.

Laboratory Analysis

For laboratory analysis, 10 mL of peripheral venous blood sample was collected from each participant after eight hours of fasting. The blood samples were centrifuged for 5 minutes at 3000 rpm using the Humax 14K Germany centrifuge. 500μl of serum was then extracted for the determination of calcium (mg/L), phosphorus (mg/L), albumin (g/L) by colorimetric method and for the determination of creatinine (mg/l), total alkaline phosphatase (U/L), transaminase (Aspartate amino transferase (ASAT), Alanine amino transferase (ALAT), in U/L), gamma gluthamyl transferase (GGT, U/L) by kinetic method, using the Mindray model BS 120 spectrophotometer. The remaining serum was stored at -20° Celsius and used to determine 25(OH) vitamin D (ng/mL) levels by ELISA using the BioTek EL×800 ELISA chain. Serum creatinine was used to estimate the glomerular filtration rate using four parameters’ MDRD formula in mL/min for 1.72m². The measured calcemia was corrected using albuminemia. Hypercalcemia was defined for a corrected Calcemia > 104 mg/L, while Hypocalcemia was defined below 81 mg/L [19]. Hyperphosphatemia was defined as blood phosphorus > 50 mg/L in adults while hypophosphatemia was defined below 25 mg/L [19]. Vitamin D Status was assessed according to the classification of Holick et al [20].

Laboratory Analysis

After consumption of 200 ml of low calcium water (Volvic® type: Ca<10 mg) in a fasting individual with a previously empty bladder, calciuria and creatininuria was measured on the urine collected 2 hours later. Nordin’s Index was calculated: calciuria/ creatininuria (mg/mg). The normal value of the Nordin’s Index is lower than 0.11 mg/mg. An increase in the index indicates hyperresorption of bone. Calcium, phosphorus and creatinine in urine were determined using the same methods as in the plasma.

Bone Mineral Density (BMD)

Bone mineral density was measured by biphotonic X-ray absorptiometry scan using the Hitachi® lunar prodigy DXA system, with 37 Micro SieVert (μSV) dose per measurement site. Bone mineral density was measured at the lumbar spine, the neck of the left femur and the distal end of the left radius. Data on bone mineral density were expressed in g/cm², T-score and Z-score. Osteoporosis was defined as T-score <-2.5 for patients aged 50 years and older or a Z-score <-2 for patients under 50 years of age for measurement of the lumbar spine, femoral neck or distal end of the radius [21].

Statistical analysis

Statistical analysis was performed using SPSS version 21.0. Quantitative variables were expressed as mean ± standard deviation or median and interquartile range [25th and 75th quartiles]. Qualitative variables were expressed as effectives and proportions. The Mann-Whitney test was used to compare the means, while medians were compare using the Median’s test. Fisher Exact Test was used to compare proportions. We searched for associations between continuous variables and bone mineral density on various sites by calculating the Pearson’s Correlation Coefficient to determine the factors associated with the decrease in BMD. For all the tests, the statistical significance level was set at 0.05.

Results

Clinical characteristics of the study samples

The mean age of patients was 38.6 ±15.9 years, while that of controls was 37.8 ±15.9 years (p>0.05). Participants’ ages ranged from 23 to 73 years. There were respectively 2/4 and 2/4 women on menopause in the patients and control groups. Between cases and controls, there was no statistical difference in body mass index (p>0.05) (Table 1). The median duration of cirrhosis was 19 months, range from one to 120 months. The causes of liver cirrhosis were chronic viral hepatitis B (42%), hepatitis C (31%), and B-delta (37%). There was no coinfection with viral hepatitis B and C. Most of the cases were classified on stage A (n=14), while 3 and 2 cases were respectively on-stage B and C in Child and Pugh classification.

Bone and calcium-phosphate metabolism

Between patients and controls, there was no difference in serum levels of ASAT, ALAT, GGT. Albuminemia was significantly lower in cirrhotic patients (33.7 ±8.6 g/L versus 42.6 ±2.5g/L, p<0.001). Serum total alkaline phosphatase levels were significantly higher in patients with cirrhosis (141.4 ±60.9 U/L versus 72.2 ±28.9U/L, p<0.001). There was no difference in serum and urinary excretion of calcium and phosphorus. Vitamin D levels were higher in patients with cirrhosis (22.8 ±7.1ng/mL versus 11.3 ±5ng/mL, p<0.05), and the frequency of vitamin D deficiency was significantly high in controls (14 (82.3) versus 7 (36.8), p<0.05). The median of Nordin’s Index was significantly higher in cases compared to controls (0.12 [0.06; 0.13] mg/mg versus 0.03 [0.01; 0.08] mg/mg, p<0.05) and in patients with cirrhosis who have osteoporosis compared to those without (0.13 [0.09; 0.13] mg/mg versus 0.07 [0.03; 0.08] mg/mg, p<0.05) (Table 1).

Osteoporosis and associated factors

The frequency of osteoporosis was three times higher in the test group (31.5%) than in the control group (11.7%) (p<0.05). The most frequent site of osteoporosis was radius (6/19 for cases and 2/17 for controls). There was only one case of osteoporosis on the femoral neck in controls, and one case on the lumbar region in cases. Several biomarkers were found to be associated with the decrease in BMD at the different sites. These included the duration of cirrhosis, which was weakly and inversely correlated with decreased BMD at the femoral head and distal end of the radius. We found a weak and moderately negative correlation between the Nordin’s Index and the BMD at the femoral and lumbar levels respectively. There were also weak correlations between transaminases levels (ASAT, ALAT), corrected calcemia and phosphoremia, with BMD values at the radial and lumbar levels. These associations are presented in (Table 2).

Discussion

Osteoporosis is by far the most frequent bone complication during cirrhosis irrespective of the etiology. Thus, it remains a concern for the specialist. Osteodensitometry is the exam of choice in the investigation of osteoporosis in cirrhotic patients. However, due to its high cost and low availability, it is not commonly prescribed. There is also no subsidies for paraclinical examinations of patients affected by cirrhosis in our context, which is highly endemic with chronic viral hepatitis. We conducted this study as a pilot study with the aim of evaluating markers and indices that are common, accessible and easy to perform in order to investigate bone metabolism abnormalities in post viral cirrhosis. Our results show that in addition to transaminase abnormalities, whose high levels are associated with a decrease in BMD, the Nordin’s Index could be an evaluation tool, as it is better correlated with a decrease in BMD. Being the main constituents of bone, we first explored markers of phosphocalcic metabolism. We found a similar plasma and urine calcium-phosphorus profile between the cirrhotic patients and the controls. As previously reported in the literature, despite the alteration in BMD, there is an increase in parathyroid hormone that is not related to secondary hyperparathyroidism, but rather to the alteration of liver function [22]. Thus, ensuring calciumphosphorus balance. This explanation was confirmed by Fisher et al., who found that despite vitamin D deficiency in patients with cirrhosis, their calcium-phosphorus metabolism was balanced, and they did not present secondary hyperparathyroidism [23]. The level of 25(OH) vitamin D which is a reflection of vitamin D storage, was significantly increased in patients with cirrhosis. 25(OH) vitamin D is synthesized from 7-dehydrocholesterol under the action of 25 hepatic hydroxylase. Hepatic failure observed during cirrhosis leads to a defect in vitamin D hydroxylation and a defect in the production of albumin and vitamin D binding proteins (VDP) with a consequent drop in vitamin D levels [24,25]. The higher incidence of vitamin D deficiency in the control group may be a reflection of their diet which was not assessed in our study. More so, there are several other exogenous factors associated with vitamin D deficiency namely: lack of sunlight (main cause), lack of oral vitamin D intake, and black skin [26, 27,28]. We assessed bone formation by evaluating serum total alkaline phosphatase levels. The significant elevation of alkaline phosphatases, coupled with gamma GT would, however, be more a reflection of cholestasis accompanying liver damage rather than a disturbance on bone metabolism. We also observed a weak and negative correlation between transaminase levels and BMD in people with cirrhosis in some sites. This result is similar to that found by Turkeli et al. and Karan et al [29,30]. However, since these markers are not markers of bone and calcium-phosphorus metabolism, this correlation would be more reflective of the cytolysis induced by viral hepatitis. Evaluation of bone status requires biological assays of bone remodeling and measurement of bone mineral density by biphotonic X-ray absorptiometry. However, the bone resorption could be evaluated with the Nordin’s Index. This marker was elevated in 63.2% of patients with cirrhosis compared to 11.8% in the control group, with a significant increase in patients with cirrhosis. This result is similar to those found in the literature suggesting increased bone resorption in patients with cirrhosis. Bone mineral density assessment by biphoton X-ray absorptiometry found a greater frequency in osteoporosis in cirrhotic patients, and correlates literature findings which reported a prevalence between 15 and 55% [9]. The high risk of having osteoporosis during cirrhosis is explained by an increase in bone resorption in these patients as found in our study and described in the literature [8,24]. The most affected site in our study was the distal end of the radius followed by the lumbar spine and femoral neck, respectively; similar to the findings of Diamond et al [31]. However, few authors assessed bone mass at the distal end of the radius in their study. The predominance of osteoporosis at the distal end of the radius and lumbar spine is explained by the fact that they consist of 60% and 50% trabecular bone, respectively, compared to the femoral neck, which is 60% cortical bone [32]. Indeed, trabecular bone has an accelerated metabolism and early demineralization during pathologies with repercussions on bone metabolism as opposed to bone that has a slower metabolism and slow demineralization. In association with decrease in BMD, disease duration, an elevated Nordin’s Index were negatively correlated. However, vitamin D levels, transaminases levels and the other markers were either weakly or not at all correlated. The evaluation of the Nordin’s Index may be carried out during post viral cirrhosis in low-income countries. However, the interpretation of the results of our study must be done with certain reservations, notably the small size of our sample and the absence of multiple assays knowing that the concentrations of the biomarkers evaluated could vary over time. A study on a larger sample would thus be necessary to better specify these results.

Conclusion

The estimation of the Nordin’s Index could be helpful for the evaluation of osteoporosis in patients with chronic liver disease. However, its performance has to be evaluated in a large sample.

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Lupine Publishers | Validity of Serum Markers for Fibrosis Staging in Chronic Hepatitis B and C Patients

Introduction

According to latest report globally about 350 million people are affected by Hepatitis B virus and about 686,000 die every year from Hepatitis B related diseases[1,2]. Similarly, more than 185 million people around the world are infected with Hepatitis C virus, of whom 350,000 die each year[3,4]. Hepatic fibrosis, regardless of the underlying a etiology, is a consequence of accumulation of extracellular matrix components in the liver. This process is caused by persistent liver damage and consequent wound healing reaction, leading to cirrhosis, portal hypertension, and hepatocellular carcinoma (HCC), all these cumulatively leading to increased morbidity and mortality [5,6]. Thus accurate assessment of liver fibrosis is essential for successful individualized disease management for people with chronic hepatitis B and C7. Although liver biopsy, till date, remains the gold standard for diagnosis of liver fibrosis but it is far from optimal because of many associated complications [8,9,10]. To overcome these limitations multiple noninvasive modalities have been introduced. Various non-invasive parameters which could replace the biopsy of the infected liver include: - FIB-4[11], APRI[12], AST/ALT ratio[13], Kings Score[14], Frons index[15], Elastography[16] and Fibro scan[17]. Our study included the following three parameters as alternative to liver biopsy: FIB-4, APRI (Aspartate Aminotransferase to Platelet Ratio Index) and AST/ALT Ratio (Aspartate transaminase)/ (Alanine transaminase).

Materials and Methods

The current study was a hospital based prospective study which was conducted in the Department of Internal Medicine and Department of Gastroenterology, Government Medical College, Srinagar, J&K (INDIA). The study was approved by the respective ethical committees of the college. The study was conducted over a period of 36 months starting from August 2014 to July 2017. The study was approved by the respective ethical committees of the college. A total of 262 patients were included and out of them 172 were infected with hepatitis B and 90 patients were infected with hepatitis C. All Chronic Hepatitis B (CHB) and Chronic Hepatitis C (CHC) patients seen in the OPD or admitted in IPD were enrolled and investigated as per the study design. Patients were explained about the liver biopsy procedure, its advantages and possible adverse effects. Patient’s history was taken, and physical examination was carried out. Written informed consent was obtained from each participant. Patients were ≥ 18 years of age of either sex. All patients’ laboratory data (alanine aminotransferase [ALT], aspartate aminotransferase [AST], platelet count) were collected. FIB-4[12], APRI[13]were calculated by sterlings[11]and wai’s[12] formulas respectively:

Fibrosis stage was calculated by abstraction from liver biopsy reports. Fibrosis scores from different scoring systems (IASL[18], Metavir[19], Ishak[20], Knodell[21]) were mapped to a F0–F4 equivalency scale: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis (Table 1). If the patient had more than one biopsy, the earliest biopsy with the highest fibrosis stage and available laboratory results was used for this analysis[18].

Statistical Analysis

We first validated predefined serum markers then developed and validated cut-offs of the serum markers for classification of cirrhosis (F4) or advanced fibrosis (F3–F4). The serum markers of interest were as follows: APRI, FIB-4 and ALT/AST ratio, as defined in the previous section. The endpoints of interest were the presence of advanced fibrosis (F3–4 vs F0–2) and the presence of cirrhosis (F4 vs F0–3) in case of Chronic Hepatitis C. However, in our study, in patients with chronic hepatitis B infection who underwent liver biopsy, no patient had a histological grade of F3 or F4. In such scenario, comparison was made between those with few bridges or septa (F2) and no fibrosis (F0). The data was entered in Microsoft Excel Spreadsheet. Continuous variables were summarized as mean and standard deviation (SD). Categorical variables were summarized as percentages. Radius of Curvature (ROC) curves were constructed for APRI and FIB-4 scores and AST/ ALT ratio. Liver biopsy results was taken as standard. Area under ROC curve was reported along with its 95% confidence interval for APRI, FIB-4 and AST/ALT ratio. A p-value of <0.05 was considered as statistically significant.

Results

Out of 90 CHC patients, 18 belonged to 18-30-year age group, 36 patients belonged to 31-45 age group. Twenty-three patients were between 46-60 years of age whereas thirteen patients belonged to 61-75-year age group. Similarly, out of 172 CHB, 34 belonged to 18-30-year age group, 68 patients belonged to 31-45 age group. Fifty-five patients were between 46-60 years of age whereas fifteen patients belonged to 61-75-year age group. In our study out of 172 patients of CHB, 107 were male and 65 were females with male to female ratio of 1.6:1. Similarly out of 90 patients of hepatitis CHC, 56 were males and 34 were females and the male to female ratio was 1.6:1. On combining the two groups, out of 262 patients there was slight male preponderance with total male to female ratio of 1.6:1.

A. Chronic Hepatitis C

We compared AUROCs of the FIB-4 index with those of the other indices for the classification of advanced fibrosis and cirrhosis, respectively (Figure-1&2, Table 2&3).

The AUROC for FIB-4 in differentiating F3–F4 from F0–F2 was 0.940 (95% CI: 0.788–0.994) when compared with AST/ALT Ratio with p value of 0.019 and AUROC for APRI was 0.856(95% CI: 0.680–0.957) when compared with FIB-4 with p value of 0.321 for CHC. The AUROC for FIB-4 in differentiating F4 from F0–F3 was 0.926 (95% CI: 0.769–0.989) when compared with AST/ALT Ratio with p value of 0.007 and AUROC for APRI was 0.070(95% CI: 0.721–0.974)) when compared with FIB-4 with p value of 0.374 for CHC.

B. Chronic Hepatitis B

In case of CHB, comparison was done between AUROCs of the FIB-4 index with those of the other indices for the classification of those with few bridges or septa (F2) and no fibrosis (F0); and fibrous portal expansion (F2 vs F0-F1)(Figure-3,Table 4). The AUROC for FIB-4 in differentiating F2 from F0–F1 was 0.839 (95% CI: 0.667–0.944) when compared with AST/ALT Ratio with p value of 0.038 and AUROC for APRI was 0.801(95% CI: 0.614– 0.915) when compared with FIB-4 with p value of 0.732 for CHB.

Cut-off Values for Predicting Fibrosis and Cirrhosis Using FIB-4 in CHC

Based on the AUROC analysis in the previous section, FIB- 4 had the best overall utility for prediction of advanced fibrosis and cirrhosis in a chronic hepatitis C population compared with the other two markers, as FIB-4 score outperformed the other serum markers and was superior to AST/ALT ratio and almost similar to APRI. We next derived optimal cut-off values of FIB-4 for distinguishing the lower end of liver stage (F0–F2) and upper end of liver stage (F3, cirrhosis) for CHC. The optimal cut-off of FIB-4 in distinguishing F3,F4 vs F0-F2 was >2.30 with sensitivity and specificity of 91.7% and 88.9% respectively. For APRI, optimal cut-off was >1.66 with sensitivity and specificity of 75% and 91.4% respectively and for AST/ALT ratio optimal cut-off was >1.35 with sensitivity and specificity of 50% and 83.9% respectively. Similarly, the optimal cut-off of FIB-4 in distinguishing F4 vs F0- F3 was >2.50 with sensitivity and specificity of 100% and 81.8% respectively. For APRI, optimal cut-off was >1.74 with sensitivity and specificity of 87.5% and 82.4% respectively and for AST/ALT ratio optimal cut-off was >1.43 with sensitivity and specificity of 57.5% and 80.9% respectively.

Cut-off Values for Predicting few bridges or septa (F2) and no fibrosis (F0); and fibrous portal expansion (F2 vs F0-F1) in CHB

Similarly, the optimal cut-off of FIB-4 in distinguishing few bridges or septa (F2) and no fibrosis (F0); and fibrous portal expansion (F2 vs F0-F1) was >1.33 with sensitivity and specificity of 86.3% and 78.5% respectively. For APRI, optimal cut-off was >0.68 with sensitivity and specificity of 80.1% and 82.9% respectively and for AST/ALT ratio optimal cut-off was >0.54 with sensitivity and specificity of 71.2% and 73.6% respectively[Table 5].

Discussion

While analysing our results for these markers, FIB-4 was found out to be a better marker for detecting the degree of fibrosis in CHC. In early stages of fibrosis (F0-F2), keeping a cut-off value >2.3, the sensitivity and specificity of FIB-4 was 91.7% and 88.9% respectively. At further advanced degree of fibrosis i.e., cirrhosis, the sensitivity of cut-off value of >2.5 for FIB-4 reaches 100%. The cut-off valve obtained of APRI score 1.66 was similar to study conducted by [22]where the cut-off valve of APRI has been 1.5, the sensitivity and specificity of APRI has been more than 75% and 91.4% for F0-F2 and F3, F4 (significant fibrosis) score. The APRI score in similarity with FIB-4 score is quite valuable in advanced stage of fibrosis (cirrhosis), but in early stages of fibrosis the APRI score has not been of much significance, though the effect can be attributed to very less number of patients in this group. The higher sensitivity and specificity pattern obtained from FIB-4 and APRI score was not reflected by AST/ALT ratio in our study, with the sensitivity and specificity falling to 50% and 37% to stages F3 and F4 respectively.

The superiority of FIB-4 and APRI with AST/ALT ratio in predicting the fibrosis is validated by the study conducted by [23]. However in case of CHB,FIB-4 has definitely being shown to be almost close to liver biopsy in predicting the histopathology of liver. The other two scoring systems like APRI and AST/ALT ratio have not proved to be better than FIB-4. The results of the study conducted by Yilmaz et al. [24] reported that APRI had acceptable accuracy for assessment of fibrosis with CHC but same was not applicable for CHB, though we had no patients of advanced fibrosis, but even on comparing the patients of mild with moderate fibrosis, APRI was not as significant marker with AUC of 0.644 and 95% CI of 0.455 to 0.804. FIB-4 again served as a significant marker to distinguish patients of mild fibrosis (F0, F1) from patients with moderate fibrosis with AUC of 0.839 and 95% CI (0.667 to 0.944) and p-valve of 0.038. The studies conducted by Zhang et al. [25] in the past revealed FIB-4 as a diagnostic marker to discriminate between patients of early fibrosis and advanced fibrosis. The advantage of our study was its prospective design and adoption of strict inclusion and exclusion criteria. The disadvantage of our study was the small sample size.

Conclusion

Thus, our study suggests that FIB-4 and APRI are excellent surrogate markers for liver fibrosis while ASL/ALT is not a very sensitive marker. Among all these scores FIB-4 is the best. On the basis of our results, we recommend use of FIB-4 as a surrogate marker for liver fibrosis across all age groups. We further recommend that larger number of patients to be undertaken in future studies.

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Lupine Publishers | Case of Application of Syrolimus in a Patient with Progressing Pultifocal Pepatic Nodular Hyperplasia

Abstract

Introduction: A case presented to the public demonstrates the possibility of treatment with Sirolimus in a patient with progressive multifocal liver Focal Nodular Hyperplasia (FNH) with progressive growth and a tendency to formation of liver function insufficiency after splenorenal shunt for portal hypertension.

Material and Methods: Patient E. 08.03.2001 year of birth c Diagnosed with multifocal bilobar nodular liver hyperplasia after splenorenal bypass surgery for portal hypertension, established in 2018/ Sirolimus treatment was prescribed from 06.22.18 to the present.

Conclusion:  As a result of the treatment with Sirolimus, a normalization of the level of liver enzymes, bilirubin in the blood is noted. According to radiation methods, a reduction in liver size and FNH size is up to 30%.

Keywords:Multifocal liver Focal Nodular Hyperplasia (FNH); Sirolimus

Introduction

Today, FNH is regarded as a benign vascular formation of the liver. VNG is the second most common benign liver neoplasm [1]. Edmonton first described it in 1958 [2]. FNH most often occurs as a monofocal lesion, in more rare cases there are two or more nodes [3]. FNH is believed to be a hyperplastic response of liver tissue to arterial malformation, and not a true tumor. When conducting radiation diagnostics, the central scar is determined in 44% of cases. The central scar with T2-weighted MRI is hyperintensive [4]. It is possible to determine the filling of blood formation from the center to the periphery, which distinguishes it from monofocal liver hemangiomas. As a rule, in the case of PF, the risk of complications is low; there is no risk of malignancy. Therefore, a patient with VNF rarely requires their surgical removal. The most common indication for removal is pain, which usually occurs with FNH greater than 7 cm in distance [5]. The presence of more than five nodes are characterized as multiple FNH. This is very rare and only a few cases are described in the literature [6]. With progressive multiple FNH, we did not find any treatment recommendations in the literature other than liver transplantation. Therefore, we decided to present a case of treating multiple liver FNHs in a patient using Sirolimus therapy. We also did not find such articles in the literature and therefore we bring this case to the public.

Materials and Methods

Patient E. 08.03.2001 year of birth. Born from the first pregnancy, proceeding against the background of chronic intrauterine hypoxia of the fetus. Childbirth - emergency cesarean section. Height at birth 51 cm, weight 3118 grams, Apgar score of 8 points. In the neonatal period: pneumonia, urinary tract infection, perinatal hypoxic encephalopathy of the fetus, intraventricular hemorrhage. Grew and developed according to age. In August 2008, he suffered bleeding from the dilated veins of the esophagus and stomach. Bleeding is stopped conservatively. The diagnosis of portal hypertension syndrome, cavernous portal vein transformation. In October 2008, surgical treatment was carried out: the formation of spleno-renal anastomosis “side-byside” (Figure 1). No more bleeding was noted. In February 2018, during a control study, multiple FNHs were identified in C1, C4, C8 with dimensions of 87x61 mm, in C7 with dimensions of 51 by 43 mm, 50 by 40 mm (Figure 2). Diagnosed with multifocal bilobar nodular liver hyperplasia after splenorenal bypass surgery for portal hypertension. Blood test for alphafetoprotein 1.66 IU / ml. During the control examination in July 2018, an increase in FNH sizes to 90 by 70 mm, an increase in blood transaminases (Table 1), alkaline phosphatase up to 218.00 IU / L (N 42 - 110), a moderate increase in bilirubin were noted. The patient complained of chronic fatigue, weakness, moderate pain in the liver. lack of appetite.

After examining the child, we came to the conclusion that the observed progression of the disease can lead to the replacement of the liver parenchyma with the subsequent occurrence of organ failure. This could endanger the patient’s life, but there is no possibility of surgery due to the prevalence of the lesion. Sirolimus (Pfizer, USA) from 06.02.2018 was prescribed orally daily at a dose of 3 mg / day until a therapeutic concentration of the drug in blood serum of 6-15 ng / ml was achieved. Due to the excess of the therapeutic interval, the dose of Sirolimus was consistently reduced from 11/06/2018 to 1 mg / day, 02/05/2019 the concentration of Sirolimus was 7.8 ng / ml.

Résultats

As a result of the treatment with Sirolimus, a normalization of the level of liver enzymes, bilirubin in the blood is noted. According to radiation methods, a reduction in liver size and FNH size is up to 30%. Now the patient is feeling well. There is no pain in the liver. Playing sports. Reception of sirolimus continues to date.

Discussion

Multifocal FNH is a rare form of this disease. An even rarer situation arose in our patient, there was a progression of the disease with signs of emerging hepatic cell failure. There was a high risk of severe disease with subsequent liver transplantation. There is an interesting fact that the physiological characteristics of the patient appeared after application of a splenorenal shunt for portal hypertension. Apparently, in the growth stimulation of the nodes, the FNH played the role of impaired portal blood flow. In the available literature, we found only recommendations for liver transplantation in such patients. Teaching ability of Sirolimus to suppress vascular growth through inhibition of M-TOP, we suggested the possible effectiveness of this therapy. After an explanation with the patient and his legal representatives, we started therapy with Sirolimus at a dose of 3 mg / day, then we reduced it to 1 mg / day taking into account the concentration in the blood. The patient had no complications associated with Sirolimus therapy. After a year of treatment, we noted a clear positive trend. The patient’s condition improved, there was no pain, blood counts returned to normal (Table 1).

Conclusion

Of course, this question still requires research in other patients with multiple progressive FNH, in order to draw conclusions about the effectiveness and safety of Sirolimus. But with this patient, we got encouraging results.

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Lupine Publishers | The Failure Bauhinias Damper as a Possible Cause of Chronic Autointoxication and the Development of Psoriasis

Abstract

The goal is to assess the impact of biogenetic on the condition of patients with psoriasis

Materials and Methods: The study group included 415 patients aged 19 to 65 years (34% of men and 66% of women), in whom irrigoscopy revealed the injection of contrast into the ileum, i.e., the insolvency of the baugine flap (NBZ) was diagnosed, 74 of them suffered from psoriasis. For the detection of chronic intoxication were evaluated the data of clinical manifestations, indican urine, level of middle molecules, blood serum, lipid metabolism, microbial resistance, the hydrogen breath test.

Results: NBZ is a chronic endointoxication, which regresses in collaboration with the clinical manifestations of psoriasis after biogenetic.

Conclusion: Hypothesized that NBZ is one of the causes of psoriasis, and biogenetica – link in etiopathogenetic method of treatment.

Keywords: Insolvency bauhinias dampers; Chronic endo intoxication; Psoriasis; surgery

Introduction

Recognizing the harmfulness of dysfunction of such barrier structures as cardia, pylorus, sphincter of Oddi, heart valves, venous valves of the lower extremities, etc., modern medicine ignores the failure of the ileocecal locking system (Bauhinia valve) as a possible cause of the pathology of the digestive system and associated various extraintestinal diseases [1]. But it is worth paying attention to the opinion of I.I. Grekova [2] “Despite a number of works devoted to the proximal colon, the pathology of this department is still not sufficiently explained because in these works the role of the bauhinia valve was completely ignored.” Bauhinia valve (BZ) distinguishes between the functions of the small and large intestines, isolates the small intestine from the reflux of the colonic contents, which differs sharply in chemical composition, physical condition and bacterial spectrum [3-5]. According to LG Peretz [6], in 1 ml of intestinal contents there are up to 5000 microbes, and in 1 g of the contents of the large intestine there are about 30-40 billion [6]. With the failure of the Bauhinia Damper (NBZ), billions of colon microbes are thrown into the small one [4,6], colonization of the small intestine with allochthonous (alien) microorganisms occurs, excessive bacterial growth syndrome (SIBO) or enteric dysbacteriosis develops [7,8].

Absorbing the blood products of microorganisms (indole, phenol, cresol, skatole, pyrocatechin, carbolic acid, hydrogen sulfide, mercaptan, ethane, methane, etc.) causes autointoxication phenomena that cannot be sufficiently arrested, especially for liver diseases [7,9-11]. The development of putrefactive and fermentation processes in the small intestine - The consequence of the SIBO. The lymphoid tissue in the course of the gastrointestinal tract suffers because of a violation of the barrier function of the intestinal wall [4,12], resulting in a deficiency of immunoglobulins A and M. In 70% of patients with chronic enterocolitis there is a marked decrease in the body’s immunological reactivity the body becomes less protected before microbial aggression - in patients with chronic colitis [5]. Recognizing NBZ as one of the anatomical causes of SIBR, nevertheless, the authors do not have a therapeutic effect on it [13,14], although they assign SIBOs key pathogenetic mechanisms in many diseases of the digestive tract and associated extradigestive conditions [7,10].

The interrelation between the pathology of the gastrointestinal tract (GIT) and the development of dermatosis is a well-known fact. The small intestine is the organ of the digestive canal, the most responsible for the development of dermatosis. The relationship between the intensity of skin manifestations and the activity of ileocolitis Roberts et al. [15] with psoriasis was detected in 2/3 of patients with enterocolitis [15]. Sensitization to intestinal autoflora was revealed. So sharply positive were skin tests, primarily to Escherichia coli-up to 97% [16]. Allergic dermatosis, rosacea, seborrhea, food allergy, urticaria, neurodermatitis were found in 176 (22%) of 800 patients with diseases of the alimentary canal [17]. In the etipathogenesis of dermatosis, the following enterocolitic links are distinguished [18]. a. The most responsible for the development of dermatosis is the small intestine. The immune complexes formed in the intestine penetrate the blood and settle in various tissues, including the skin with the development of immediate and delayed hypersensitivity types. b. There is a shortage of many substances as a result of malabsorption in the small intestine, in particular vitamins, whose participation in the pathogenesis of dermatosis is large. c. The use of sorbents, hemosorption, plasmapheresis significantly improves the effect of therapy, which confirms the role of endogenous intoxication in the development of dermatoses. The goal is to assess the effect of Bauhinoplasty on the condition of patients suffering from psoriasis.

Materials and Methods

The study group included 415 patients aged from 19 to 65 years old (34% of men and 66% of women), in whom a reflux of contrast into the ileum, i.e. diagnosed NBZ (Figure 1). In 111 patients, reflux of the radiopaque substance to the ileum was regarded by doctors as the norm. But all surveyed to the question: “Do you consider yourself ill?” answered in the affirmative. From the onset of the first signs of the disease, 15% of those examined passed from 1 year to 5 years, 32% have from 5 to 10 years, and 53% have more than 10 years. Of the 415 patients with NBZ, 74 suffered from psoriasis. Previously, they identified: chronic gastritis - in 62.5%, chronic cholecystitis - in 37%, chronic gastroduodenitis - in 12.5%, chronic colitis - in 12.5%, chronic pancreatitis - in 6%, duodenal ulcer - 6%. In 6% of patients with a history of appendectomy.

Research methods

Irrigoscopy: It is important to note that the refusal to hold a tight filling of the cecum at NBZ can lead to a false-negative conclusion. A repeated X-ray examination immediately after a bowel movement is of fundamental importance, since during a bowel movement a maximum pressure is created in the bowel, which at the NBZ will be accompanied by a pronounced reflux of the radiopaque substance into the ileum (Figures 1-3).

Chronic autointoxication was detected by such studies as urine indican (Obermeyer was tested for this purpose.), The level of the average serum molecules was measured according to N.I. Gabrielyana, lipid metabolism. Microbial resistance was determined by the content of antibodies to peptidoglycan Staphylococcus aureus (method of Professor A.N. Mayansky). Peptidoglycan is the most common element of the cell wall of all bacteria, which makes it possible to indirectly judge the content of anti-peptidoglycan antibodies in general. The content of antibodies to peptidoglycan Staphylococcus aureus (strain 885, solubilized by ultrasound) was determined. Each sample was placed in 3 repetitions, calculating the average result. Negative controls were the wells in which the stage of treatment with the antigen (peptidoglycan) was omitted. Indicators of negative control from the results of the experiments were subtracted. A pool of 25 sera from healthy donors was used as a positive control. The results are statistically processed on the IBM / AT-286 computer using the following criteria: determination of averages, Fisher criterion, Wilcoxon-Whitney-Mann criterion.

Operation - Bauginoplasty (BP) - RF patent №2253378 - imparting reflux to the ileocecal junction [19]: Omitting the details of the operation, we note its essence:

a) A non-absorbable thread is embedded in the loose strand of the greater omentum (Figure 4), forming a structure (ligature-omental tape) to ensure the refluxity of the ileocecal junction. b) Ligature-and-omental tape is carried out through the mesentery of the terminal ileum 2-3 cm proximal to the ileocecal fistula and behind the ascending colon 2-3 cm distal to the ileocecal fistula (Figure 5). c) The terminal ileum for 6-7cm is fixed with interrupted sero-muscular sutures for the free tape of the ascending colon (Figure 6). d) By tying the ends of the ligature, we finally form the reflux structure (Figure 7), the diameter of which is equal to the diameter of the large intestine (positive decision on the application No. 2015107214 for the invention “Bauginoplasty Method”. Authors: Martynov V.L., Khairdinov A.Kh., Semenov AG), which is exactly what makes refluxing.

The functioning design to ensure the refluxity of the ileocecal junction works autonomously

a) Pressure in the lumen of the colon below or equal to the pressure in the lumen of the ileum, the ileum is not onstricted; the contents of the small intestine may enter the colon (Figure 8). b) Pressure in the lumen of the colon is higher than the pressure in the lumen of the small intestine, the ileum is squeezed by the ascending intestine on the ligature-stuffing cage; the contents of the colon in the small intestine does not enter (Figure 9).

Determination of hydrogen in exhaled air by the Gastrolyser apparatus (Figure 10) with a lactulose load. The advantages of VDT are: the ability to diagnose the entire small intestine for the presence of SIBO, a high level of correlation between the rate of production of H2 in the intestine and the rate of its elimination by the lungs [20,21], speed and non-invasiveness, a clear distinction between the metabolic activity of bacteria and their host, and the ability to assess the effectiveness of treatment SIBR [13].

The diagnosis of SIBR before the operation was made to 20 patients (12 women, 8 men) with NBZ and psoriasis no earlier than a month after taking antibiotics or putting enemas, which can give false negative results. Statistical processing of the results was carried out according to Fisher’s exact test, the Shapiro-Wilk, Wilcoxon test, descriptive statistics performed using Excel.

Results

Of the 415 patients, only 14 (2.5%) did not show enterocolitic complaints, the rest noted that they determined the diagnosis of irritable bowel syndrome (Table 1). After performing the operation, Bauginoplasty (PD) showed a significant regression of clinical manifestations, which suggests their cause, namely, NBZ (Table 1).

Of 415 patients with NBZ, the qualitative response of urine to indican was positive in 95% of cases (normally this reaction is negative). Before and after surgery, this reaction was determined in 24 patients. In all 24 before the operation, the qualitative response of urine to indican was evaluated as positive, after Bauginoplasty (BP), this reaction was positive only in 4 (5%) patients (p = 0.00272). The level of medium molecules (USM) is increased in 82% of patients with NBZ with Me = 0.34 (the normal rate of USM serum according to NI, Gabrielyan is 0.24±0.02). Serum serum before and after BP is determined in 20 patients. Normal values before and after PD were found in 1 case. USM decreased compared with preoperative in 16 patients. Of the 16 studied with a decrease in USM serum in 7, this decrease reached normal values, in 9 the norm was not achieved. When checking the normality of the distribution of the values of the level of average serum molecules (the Shapiro – Wilk criterion was used) the following data were obtained: prior to the operation, the Shapiro – Wilk criterion W = 0.42929, p = 0.0005; after W = 0.92497, p = 0.12353, i.e. the distribution of the values of the level of the average serum molecules after the operation can be approximately considered normal, and the distribution of the studied trait before the operation differs from the normal one. Before operation: Me - 0.34 (interquartile range from 0.31 to 0.36); after surgery: Me - 0.29 (interquartile range from 0.26 to 0.32). In this regard, when analyzing the presented data (two related samples by quantitative trait), we used the Wilcoxon test (p = 0.017). The results obtained allow us to accept the hypothesis of the existence of statistically significant differences between groups for the trait under study. When NBZ due to chronic intoxication, the liver also suffers [22], which violates lipid metabolism, which is normalized by PD (Table 2).

The content of antibodies to peptidoglycan Staphylococcus aureus was higher than in practically healthy people (positive control) in 8 patients (40%), it was less in 12 patients (60%). An increase in the antibody content of more than 2 times compared with healthy ones was observed in 3 patients (15%). Based on this study, it can be assumed that the majority (60%) of patients with NBZ have a decrease in the intensity of immunity to microbial antigens. After surgical correction of the NBZ in 1-2 years, the same patients had higher levels of antibodies to peptidoglycan than practically healthy people (positive control) in 14 (60%) patients (p = 0.028), less - in 8 (40% ) patients (p = 0.172). The antibody content is more than 2 times higher than in healthy patients in 9 patients (41%). Of these patients, 74 suffered from psoriasis. They also made a surgical correction NBZ - Bauginoplasty. For histological examination, skin biopsy specimens were taken from the surgical wound area, which were evaluated by Dr. med. Professor N.S. Torgushinoy. The changes found were reduced to three groups of features [23]: A. Obligatory for all drugs were dystrophic changes (horny dystrophy of the epithelial layer, manifested in para- and hyperkeratosis, mucoid swelling of the fibrous structures of the papillary and reticular layers of the dermis, especially expressed under the basal membrane. hyalinosis, more in the reticular layer; atrophy of the skin appendages - sweat sebaceous glands). B. Cell proliferation, first of all, capillary endothelium. The endothelium became high, juicy; often formed multi-row layers, almost completely overlapping the vessel lumen. This reaction is not associated with inflammation and can be regarded as a manifestation of changes in the overall composition of the blood. Changes in the integumentary epithelium are determined in the form of acanthosis foci. C. Diffuse or focal dermatitis in the form of productive inflammation with the prevalence in the cellular composition of lymphocytes, with a moderate admixture of segmented leukocytes. Inflammatory phenomena, as a rule, were combined with an intensive reaction of the vascular bed, edema and extravasation. Inflammation in skin biopsies was most often assessed as moderate. According to the results of the hydrogen respiratory test (VDT) for SIBO with lactulose load in 20 patients suffering from psoriasis, before performing PD (Figure 11), all subjects under study revealed SIBO of 1–3 degrees (Table 3) with slowed orocecal clearance (large intestinal peak on 90th minute) and significant reduction of SIBR already on the 7th day after the operation (Figure 11).

The presence of SIBR of the small intestine in patients with NBZ and psoriasis is confirmed by our research, coincides with the data given by foreign authors [3,21] and fits into the framework of the pathogenesis of reflux of the contents of the large intestine into the lumen of the small intestine. In the immediate postoperative period, patients with psoriasis showed a positive trend in the form of regression of skin manifestations and, accordingly, related complaints, namely: reduction or disappearance of itching, reduction in the area of lesions and their severity, reduction of desquamation and in some cases the complete disappearance of pathological elements on skin, which can be regarded as the onset of remission. After 3-12 months after surgery, patients underwent a control outpatient examination by a dermatologist. In all, the condition is defined as sustained remission during dermatoses (Figures 12-15). Also noted a decrease or disappearance of complaints of the gastrointestinal tract, presented before the operation.

Conclusion

When NBZ patients develop SIBR, chronic autointoxication, the organism’s antimicrobial resistance decreases, which can be the cause of many pathological conditions and nosological forms, including psoriasis. Bauginoplasty is the etiopathogenetic method of their correction. We put forward a working hypothesis: the inconsistency of the Bauhinia valve is a link in the etiopathogenesis of psoriasis, and Bauhinoplasty is a surgical method for its correction. In 1970, Marks and Shuster [24] proposed the term “dermatogenic enteropathy”. Based on the foregoing, we propose the term “enterogenous dermatopathy,” since it more reveals the causal relationship between the gastrointestinal tract and dermatoses [1].

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Lupine Publishers | Non-Alcoholic Fatty Liver Disease and its Interplay with Various Metabolic Disorders

Abstract

Nonalcoholic fatty liver disease (NAFLD) is described as exposition of multiplex liver metabolic disturbance interconnected with obesity. NAFLD is depicted by steatosis, excessive accumulation of fats in liver, due to triglycerides export and oxidation of fatty acid from plasma and de novo synthesis. Hepatic steatosis can therefore be explained as biochemical outcome of inconsistency between interfused mechanisms of lipid biotransformation. This condition is allied to a range of various modifications in lipoproteins, fatty acids, and glucose metabolisms in organism. So, above metabolic disfunctions are suspected to be the origin of possibility for adverse cardiometabolic risk agents related to NAFLD, like dyslipidemia, Type 2 diabetes mellitus (T2DM), and insulin resistance. Reactive oxygen species (ROS) generation participates as known inducer of inflammation and oxidative stress, that exacerbate this disease. These disorders are hallmarks that worsen NAFLD complications, so far participate in developing advanced stages of NAFLD and incline the body to CVD and T2D. The reciprocal risks exist among these diseases. Given the sharp growing prevalence and persistence of NAFLD, and its complexity that provoke additional metabolic syndrome, this review discusses various mechanisms of developing NAFLD, interaction with other associated hallmarks, aiming to clarify beneficial mechanisms for improvement.

Keywords: Nonalcoholic fatty liver disease; oxidative stress; Type 2 diabetes; noncoding RNAs; cardiovascular disease

Introduction

The liver is known as metabolically complex organ due to its multiple biological activities, involving detoxification of various endogenous metabolites and exogenous toxic substances, formation of biochemicals needed for degradation and the synthesis of protein. The liver also serves an exigent task in metabolisms like lipid homeostasis and glycogen storage regulation [1]. Increased activity of mitochondria consequent to the fatty acids hyper-afflux from oxidation of fatty acid, produce free radicals that generate liver oxidative stress [2]. Abnormal function of liver may engender several metabolic impairments, such as NAFLD (Marrero et al., 2002). NAFLD is explained as the grouping of excess fat into liver cells, that does not result from alcohol consumption. The existence of fats in the liver is normal; however, if the concentration of fats exceeds 5%-10% of the weight of liver, then it is called a fatty liver (steatosis). Thus, NAFLD is explained as the amassing of liver fat of >5% of liver weight with <10g of daily alcohol consumption (Bayne, 2010). Besides these, generation of NAFLD was discovered to be linked with insulin resistance, the latter is known also as a critical risk factor for developing type 2 diabetes (T2D) [3]. NAFLD comprise a large spectrum of manifestations extending from simple steatosis, continuing to nonalcoholic steatohepatitis (NASH) and cirrhosis. Furthest, NAFLD correlates with significant higher risk of developing hepatocellular carcinoma (HCC) [4]. The worse hallmark of this disease is the significant interdependence with various attributes of metabolic syndrome (MetS), such (T2DM), obesity or dyslipidemia [5]. MetS is hallmarked by the aggregation of several impairments involving elevated blood pressure, obesity, dyslipidemia, insulin resistance and proinflammatory activities [6]. Moreover, studies by different researchers elucidated NAFLD as the leading inducer of liver diseases and the main reason for impaired liver function worldwide; also considered as an inherent part of MetS (hypertension, hyperglycemia, central obesity and dyslipidemia) [7,8]. The evolution of MetS has been coincided with a growth in liver disorders including NAFLD, and was revealed to correspond with disorders, like cardiovascular disease (CVD). Particularly, NAFLD has been taken as hepatic exposition of MetS [9].

The NAFLD prevalence increases quickly around the world and noted as a camouflaged epidemic. The Universal estimation of NAFLD prevalence in general population has overpassed 25% [10], See Figure 1. In developing countries such as, China; and India, the number of NAFLD patients has been augmenting sharply over the last decades [11]. However, no medications presently approved for NAFLD. The primary therapeutic intervention in NAFLD, same as in other MetS is gained from lifestyle improvement, promoting equitable low-energy diet, together with promoting physical activity. So, these are prime remunerative approaches for this condition [12,13]. Lifestyle moderation has improved the metabolism syndrome features; however, more effort needs to be made in addressing various MetS components [14]. Thus, to provide better understanding that will help different players involved in management of MetS disorders. This review discusses various mechanisms of developing NAFLD and its interplay with other metabolic disorders, while clarifying beneficial mechanisms for improvement.

The NAFLD prevalence increases quickly in every region in the world as a masked epidemic. The worldly estimation of NAFLD prevalence in general population has surpassed 25% [10] (Figure 2). In region of South and Central America, NAFLD prevalence varies depending on obesity rate, where Belize has the highest obesity prevalence of 35% with NAFLD 29% and Peru has the lowest obesity prevalence of 15% with NAFLD 12.5% [10]. The Occurrence of obesity aggravate NAFLD prevalence. In addition, NAFLD is sharply elevating worldwide, coincident with the augmented prevalence of obesity. Currently NAFLD has become the major chronic liver disease; NAFLD prevalence in adult population of developed countries is approximately 30% [9]. NAFLD has also become a considerable liver disease in children in response to the elevation of childhood obesity prevalence. Obesity may initiate production of excess ROS and systemic oxidative stress [15] which result in protein and lipid oxidation [16] (Figure 3).

The study from sub-region of USA that compared NAFLD in Hispanic from different origins, showed the greatest NAFLD prevalence in Hispanics from Mexican origin (33%) than those from Caribbean origin (Puerto Rica (18%), Dominic Republic (16%)), (P<0.01). The greater NAFLD prevalence remained in Hispanics of Mexicans than Dominican or Puerto Rican origin, even after regulating other factors that discovered to contribute in NAFLD; such as insulin resistance, levels of triglyceride and C-reactive protein, hypertension, serum level of high-density lipoprotein, waist circumference, body mass index (BMI), sex and age [17]. Prevalence of NAFLD might be explained by elevated polymorphism prevalence in the gene encoding patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409 C/G, M148I); especially in Hispanics where it accounts (49%), compared to Non-Hispanics whites (23%) and African-American (17%) [18,19]. Moreover, PNPLA3; rs738409 counts 52% in Hispanics Mexican, 23% in Dominicans [20] (Eric et al., 2019) and 36% in Hispanics Puerto Rican [21]. According to a genome-wide association study [19] elucidated that a non-synonymous sequence variation (rs738409) in PNPLA3 that replaces methionine for isoleucine at residue 148 (I148M) correlates with disproportion in liver lipid profile and the possibility of generating NAFLD. Thus, higher PNPLA3; rs738409 C/G, M148I in Hispanics suggested to take part in fueling NAFLD high prevalence [22] (Figure 4).

BMI correlates with NAFLD, and it has been revealed as a factor that elevates the probability of emerging NAFLD. In years, 1980-2008, the BMI-mean augmented worldwide by 0.4 kg/ m2 for males and by 0.5 kg/ m2 for females per decade. This coincides with obesity prevalence that increased simultaneously from 4.8 to 9.8% for men and from 7.9 to 13.8% for Women [23]. This factor was investigated in the region of European Union and it’s clear that similarly to other regions, in Europe the higher risk of acquiring NAFLD is elevated coincidently with the increases of BMI, 25% (BMI<25kg/ m2), 67% (BMI 25-30 kg/ m2) and 91% (BMI ≥30 kg/ m2) [24]. Together with other risk factors (obesity or T2DM) which more likely associate to sedentary life, are increasing in Europe fueling the NALFD prevalence and further the impairments such as cirrhosis and HCC [25].

The NAFLD prevalence among adults of sub- region Shanghai was considered to show high growing trend of NAFLD with time, it’s obvious that NAFLD prevalence is elevating with time [26]. The research showed diversity of NAFLD prevalence in different subregions of Asian countries, in Taiwan (15%-27%), Korea (24%- 40%), and Japan (9%-18%) [27]. Additionally, prevalence in India has increased from 28% in 2015 to 31% in 2016 in the rural region of Haryana [28]. Timely elevation of Fatty Liver was also revealed in different sub-regions of China [29]. Shanghai with high rate in development that goes together with life behavioral changing; the incremental in NAFLD is seen to increase sharply in adults in recent years. Findings supported by [30-33], shown in Figure 5.

NAFLD Pathogenesis

Numerous researches have reported that metabolic impairment or disturbance is the basic abnormality in NAFLD [34]. At the center of this discovered metabolic abnormality there is insulin resistance, that also known among the initiators of NAFLD. Thereafter, by provoking oxidative stress, fatty liver may evoke inflammation and hepatocyte injury which may cause the disease to tend to NASH and cirrhosis. The overload of triglycerides (TG) as fat droplets in hepatocytes cytoplasm was reported as the main event of NAFLD, which is a precondition for the succeeding NASH, as it was shown by liver biopsy that 5%-10% of hepatocytes have fat droplets [35]. Increased moving of both TG and free fatty acids (FFA) to the liver, reduced hepatic using of FFA, decrease in export of TG from liver, disturbed beta-oxidation of FFA in hepatocytes result in stockpiling of TG within hepatocytes cytoplasm [34,36,37]. Another main stimulus for liver de novo fatty acid synthesis, is the surplus carbohydrate from either dietary origins or hepatic de novo gluconeogenesis [36,37].

Obesity can be defined as a chronic low-grade inflammatory condition. There are cytokines related to obesity, such as interleukin-6 (IL-6), leptin, adiponectin, and tumor necrosis factoralpha (TNF-α) that play a remarkable role in NAFLD evolution. Research findings reported that adipose tissue may be the inducer of inflammatory mediators and adipokines, such as pro-inflammatory ones (IL-6, TNF-α, and leptin) and anti-inflammatory (adiponectin) effects [38]. Even though, these hormones and cytokines may ordinally work in balance, the homeostasis is disturbed in NASH that result in increased TNF-α and reduced adiponectin levels. Several mechanisms that likely involve in hepatocellular injury in setting of NAFLD, many of them produce the ROS. A liver with surplus fat can be more prone to stressors, such as adipokines, reactive ROS, and cytokines than normal liver [39,40].

In the study done by Yang and colleagues, obese mice with fatty liver cleared endotoxins less than nonobese controls [38]. Factors that perform key functions in the evolution of NASH from simple steatosis remain unclear [41-43]. Some known possible ways are oxidative stress through increasing ROS and reduced antioxidants, lipid peroxidation, reactive metabolites, 4-hydroxynonenal and malondialdehyde, adipose tissue products. Other discovered ways are Fas-ligand, transforming growth factors-β1, respiratory chain deficiency along with mitochondrial dysfunction, and intestinal microbiota by augmented intestinal permeability, elevated energy gaining from diet, intestinal leak, bacterial lipopolysaccharides (LPS), TNF-α, and endotoxins [44].

Hallmarks in NAFLD

NAFLD and oxidative stress

Oxidative stress increases the loss of structure and function of healthy cells, DNA and also damage of important macromolecules. These conditions are the main roots for chronic diseases such as cancer, stroke, cardiovascular impairment including diabetes [45]. Oxidative stress has been found to disrupt insulin signaling process, which result in insulin resistance in cell [46]. Yet, impaired insulin signaling mechanism remains unclear [47] (Rains & Jain, 2011). Besides, Elevation of oxidative stress is generally a considerable factor in degenerative diseases, including chronic fatigue neurodegenerative diseases. Moreover, oxidative stress can be suggested to mediates the transition from simple steatosis to steatohepatitis and, disruption of metabolic balance. Furthest, the above cited impairments are the crucial features that lead to steatohepatitis in lipid-laden hepatocytes [48]. Oxidative stress arises due to the lower antioxidant capacity and/or overproduction of the ROS [47]. Various mechanisms by which these two scenarios initiate oxidative stress in organism are described in the following paragraphs.

Several factors initiate oxidative stress in diabetes. The main origin of oxidative stress is mitochondria. Mitochondria use around 98% inhaled oxygen, from which 0.2-2% produce ROS [47,49]. A part of the used oxygen is reduced to water, and the left oxygen converted to oxygen free radicals through oxidative metabolism of mitochondria [50]. Oxygen is required for human life, even though, it may damage and kill the cells when it produces ROS [51]. The ROS are engendered by the reduction of molecular oxygen or from oxidation of water to give products such as superoxide anion, hydroxyl radical, hydrogen peroxide [47]. The hyperglycemia promotes low density lipoprotein (LDL) peroxidation and followed by the production of free radicals [52,53]. The other significant factor in the production of free radicals is glucose oxidation. In its enadiol form, glucose become oxidized in a transition-metal dependent reaction to give enadiol radical anion transformed into reactive radicals [54]. Other mechanism of oxidative stress in diabetes is the engendering of advanced glycated end products (AGEs) [55]. AGEs resulted from the covalent binding of the ketone or aldehyde groups of reducing sugars, in their way to free the amino groups of proteins [47]. Alternatively, Antioxidant may be defined as a substance that delay or inhibit the oxidation of substrate, this scenario comprises many mechanisms pointed out in oxidative stress production pathways. There exist various exogenous and endogenous components which can perform a considerable function in antioxidant defense and help in prevention of oxidative stress in organism including Catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD) [56]. The alteration of endogenous antioxidant defense comes in case of hyperglycemia. In diabetes, both decreases and increases in the activities of major antioxidant enzymes like CAT, SOD, Glutathione reductase (GR), GPx have been noticed [57]. Studies have shown that in pancreatic islets 8-hydroxy-2-deoxyguanosine (8-OH-dG) and 4-hydroxynonenal (4- HNE) levels augmented which support that hyperglycemia might be a key inducer of oxidative stress in the β-cell and oxidative stress induced by glucose [58]. The β-cells of pancreatic islets are vulnerable to the genesis of ROS and the reduction of antioxidant enzymes activities [59]. In Goto-Kakizaki (GK)-rats, the levels of 8-OH-dG and 4-HNE were high in β-cells of pancreatic islets [60]. Many reports have elucidated that the increasing of peroxide content in tissues, plasma, and red blood cells of animals that have chemically induced diabetes [61,62].

NAFLD and Type 2 Diabetes

The apparition of NAFLD exposes to possibility of T2D and in such way exacerbates its complications [63-66]. Multiple factors such as inflammatory adipocytokines and free fatty acids that efficaciously engage in initiation of insulin resistance and NAFLD, are known to be originated from inflamed and inflated visceral adipose tissue [67]. Liver is the prime body organ targeted by accumulation of ectopic fat, and superfluous free fatty acid (FFA) flow into the liver support insulin resistance through initiating NF-kB induction, lysosomal instability, and TNFα activation [68] , cAMP/ PKA pathway [69], or by activation of IL-18 production and NLRP3-mediated IL-1β [70]. The activation of c-Jun N-terminal kinase (JNK) and protein kinase Cε (PKCε) are known to be two ways through which intermediate of liver fat synthesis (Diacylglycerol (DAG)) inhibits signaling of liver insulin [3]. The hepatocytes initiate a redemptive procedure by augmenting mitochondrial β-oxidation to stop FFA, as consequence excess lipid will then hinder capacity of mitochondria antioxidant. Furthest, these will promote insulin resistance that lead to leakage of mitochondria and oxidative stress [71].In hepatic insulin resistance, two pathways are proposed to stimulate de novo lipogenesis, either by glucose, via carbohydrate response element-binding protein (ChREBP) [72] or by insulin via sterol regulatory element-binding protein 1c (SREBP-1c) [73]. In addition, insulin resistance obviously known to be induced by the alteration of metabolisms in muscle, liver, pancreas, and adipose tissue that might be initiated from hepatokines. Recently, a number of studies substantiated that secretion of hepatokines with diabetogenic properties become disturbed during liver steatosis condition, See Table 1. Liver steatosis reduces high-density lipoprotein cholesterol (HDL), and increases triglycerides (TG) and low-density lipoprotein cholesterol (LDL). As result, these changes favor the atherogenic dyslipidemia [74]. Likewise, liver steatosis stimulates inflammatory factors and disturbs agents involved in blood coagulation and circulation, which also predispose to CVD risk See Table 1. All these scoped out mechanisms related to NAFLD pathogenesis are proposed to augment the risk of microvascular and macrovascular diabetic complication. Notably, improvement of NAFLD has been revealed to be a manner of modifying probability of generating diabetes [75].

Existing of T2D promote the possibility of NASH generation by two- to three-fold (Portillo-Sanchez et al., 2015). In T2D patient’s lipogenesis is high in liver [72,73], accompanying fatty acid oxidation and production of triglyceride. On the other hand, very low-density lipoprotein cholesterol (VLDL) will decrease [76], in this manner, the two incidence NAFLD and T2D often coexist. Primarily, sympathetic fat liver accumulation arises as a defense response to lipotoxicity of free fatty acids that induce metabolic stress [77]. Even though, continual liver free fatty acid influx augment in background, resulting hepatic intracellular triglycerides activate different inflammatory pathways [48]. There are still several outrages in NAFLD patients with T2DM that through different mechanisms initiate the proceeding of NAFLD to NASH, cirrhosis, and HCC [78]. FFA like, ceramides, cholesterol, palmitic acid, and lysophosphatidylchloline; their extra influx in liver of T2D patients, directly lead to lipotoxicity and finally give rise to liver inflammation and fibrosis [79,80]. Metabolism of excess FFAs and oxidation in liver generate oxidative stress [81], which in combination with endoplasmic reticulum (ER) stress [82] lead to hepatocellular injury and apoptosis. Moreover, extra hepatic FFAs, the dissemination of inflammatory mediators (like TNFα, IL- 6, and MCP-1) from disordered adipose tissue [80], and endotoxins emanated from gut [83], are obviously mentioned in diabetic patients with NAFLD. As result, these will activate Kupffer cells in liver [84] and release hepatic inflammatory mediators (IL-1β, IL-6, TNFα) that will consequently fuel inflammation and liver damage [85].

The generated hepatocellular damage actuates necrotic and apoptotic hepatocyte death pathways [86], so the continuation of this mechanism finally activates liver stellate cells, deposits of collagen, and liver fibrosis [87]. In another way, with no influence of liver stellate cells activity, liver fibrosis can be generated from insulin resistance by mediating lysyl oxidase-like 2 (Loxl2) [88]. In parallel, oxidative stress, liver inflammation, insulin resistance, ER stress, and hepatocyte death may also induce the regenerative procedure through a lines of growth factors that activate a number of oncogenic signaling pathways, such as JAK/STAT, PI3K/PTEN/ Akt, mTOR, NF-kB, NRF-1, and 4HN. And these mechanisms disclosed above contribute to the generation of HCC [89]. NAFLD and Blood Vessels Impairment Liver is regarded a central organ, that favor its interrelation with various system like cardiovascular and others such as gut, visceral and subcutaneous adipose tissue, and muscle tissues [103]. Circumstances like long-term lipid and glucose metabolism disturbance, oxidative stress, insulin resistance can promote vascular endothelial dysfunction, which is related to endothelial cell damage originated from biological and physical changes including hypoxia and ischemia, hemodynamics, and lipid deposition [104,105]. The lipid overaccumulation and hypercholesterolemia induced by NAFLD can so far, result in endothelial dysfunction subsequent to vascular diseases (VD). Undetermined endothelial function is an early stage in the acquisition of atherosclerosis, ahead of development of plaque inflammation or fatty streaks [106] and hence crucial in CVD development. Postprandial lipid status is consistent with atherogenic form through augmented chylomicron remnants, small quantity of HDL particles and more LDL [107] (Roche and Gibney, 2000). In case of NAFLD patients, the postprandial pathway is hallmarked by enlarged VLDL particles and excess levels of triglyceride-rich [50,108]. Suggested mechanisms through which NAFLD intervene in CVD remain complex and heterogenous. As far as NAFLD obviously known as part of systemic disease and expression of MetS in liver its intercorrelation with CVD could be drawn from the fact that, liver plays an important function in lipid and glucose homeostasis, and hence, is the center of cardiometabolic disease. One of the beginning points is possibly a disparity in calorie-intake and expenditure, overfilling the adipose tissue capacity of storage resulting to the buildup of ectopic fat, involving hepatic fat [42].

Liver enzymes elevation are correlated to stroke [109]. NAFLD Patients expose endothelial malfunction of conducting vessels, along with microvasculature [110]. Arterial stiffness known as a well-recognized marker of CVD anteceding arterial hypertension, and NAFLD remain independently allied to rising of vascular stiffness [110]. Discrepancy of living condition, glycaemic control and body weight may substantially influence disease progression. A make for the effective carotid plaque burden/generalized atherosclerotic burden known as carotid intimal media thickness (cIMT) interplays with NAFLD [111]. In case of cirrhosis, intrahepatic and mesenterial endothelial irregularity are encountered [112]. Same as in NAFLD, intrahepatic dysfunction appeared [113] yet, interestingly, no inflammation or fibrosis reported [114,115]. So, this is implicated as an early phenomenon that proposed to lead to disease progression. Even though is more pronounced in NASH, Endothelial dysfunction of systemic circulation has been also found in NAFLD [116]. An endogenous antagonist of nitric oxide synthase (NOS) known as Asymmetric dimethyl arginine (ADMA) was discovered to be positively allied to CVD. Reduced breakdown, in which liver perform a vital function [117], is suggested to result in elevated ADMA levels [77]. Moreover, NAFLD patients show elevated quantity of circulating ADMA, a coalition ceasing after the reparation for metabolic risk factors [117]. Other numerous markers involved in endothelial dysfunction (like, endocan) have been also found to elevate in NAFLD [118] \. An undisturbed endothelial monolayer is fundamental for normal vessel wall performing. Ruination of this layer performs a role in atherogenesis, that is marked by endothelial microparticles (EMPs) elevation, showing disruption of endothelial. Apart, the endothelial progenitor cells (EPCs), reported to indicate endothelial repairmen, their circulating levels decreased, and their adhesive activity also weakened in NAFLD [119].

Liver microvasculature manifest a remarkable modification in NAFLD condition, these are: deformation of the sinusoidal pattern, sinusoids compress by fat-burdened hepatocytes and fenestrae ruination [120]. And these distortions appear due to the generation of fibrosis and inflammation as a sign of preliminary phenomenon [114]. These disproportions in structure are known to take part in accelerating portal pressure observed in non-cirrhotic NAFLD, in humans and animals [114]. In arterial stiffness condition that increases relating to NAFLD and CVD, there is alteration in structure of ‘media’ in large arteries: its crosslinking and collagen content increases, contrarily elastin fibres decrease, so as to get fractioned [121]. Quantities of metalloproteinases, same as serum elastase are connected with arterial stiffness [121]. Interestingly, in NAFLD this arterial stiffness was found to be elevated [122], others made a proposition of a potential activity of TGF-β [123]. The role of preventing the formation of atherosclerosis done by laminar flow on vascular endothelium known to be induced by Nrf2 activation (Kim et al. 2012). Furthest, Nrf2 has been yet reported to extenuate neointimal hyperplasia originated from vascular injury [124]. Non-Coding RNAs Improve NAFLD Non-Coding RNAs (ncRNAs) is a set of molecules that is regularly incorporated in NAFLD pathogenesis. ncRNAs typically shows high cellular or tissue specificity, allowing them great potential for predicting disease progression. In case of NAFLD as well as in other diseases ncRNAs may have a critical role as appropriate biomarkers and good indicators in assessing the severity of disease [125].

Most examined non-coding RNAs are miRNAs. Times ago, panels encompassing several serum miRNAs and other biochemical indicators, unveiled miRNAs to have high diagnostic indices for NAFLD and a higher predicted NASH potential compared to biomarkers [126,127]. In addition, miRNAs have been discovered to intervene in lipid metabolism, inflammation, insulin resistance, fibrosis, as well as HCC generation. Knowing their correlation with severity of disease, miRNAs can be biomarkers used in early noninvasive diagnosis and evaluation of NAFLD severity. Sensitive biomarker for early detection is accessed through assessing miRNAs serum levels [125]. Therefore, some critical points and pathways are scoped out in the following paragraphs. First point investigates the role of miR-155, this has shown the ability to regulate some proteins and cytokines obviously known to participate in NAFLD progression, as cleared in following discussion. The Cytokines TNFα, IL-6 have been suggested to perform a greater role in NAFLD pathogenesis [128], as their elevation and secretion have been discovered to be increasing in serum of NASH patient (Kassel et al., 2010). Again, Park et al. unveiled that pro-inflammatory cytokines IL-6 and TNFα are crucial for the progression from steatosis to steatohepatitis in obese mice, and that absence of IL-6 or TNFR1( receptor that bind TNFα) decreased lipid accumulation in liver, as well as reduction of macrophages and neutrophils influx in high fat fed diet mice [129]. Beyond this, in their absence, levels of reactive oxygen were also lowered, together with the AKT, mTOR and COX2 proteins. The findings of Qu et al. have reported similar suppression of IL-6 and IL-1b in response to miR-155 or miR-21 inhibitors, showing that these inflammatory factors are regulated positively by miR-21 or miR-155. In addition, obesity and NAFLD in another way can develop in response to elevated white adipose tissue mass corresponding to miR-155 deficiency/downregulation. Furthest, hepatic steatosis augmented in miR-155 mice fed with HFD for 6 months [130].Second point investigates the role of miR-22, for its elucidated potentiality in revealing different degrees of liver abnormalities in NAFLD, as cleared in this paragraph. The research findings revealed that the serum level of miR-122 in mice with a methionine-choline deficiency (MCD) diet has augmented 40-fold, overstepping serum alanine aminotransferase (ALT) (4.8-fold) and aspartate aminotransferase (AST) (3.3-fold) [131]. Additionally, it was explicated that increased levels of serum miR-122 occurred in NAFLD rats even without elevated ALT augmentation [132]. Hence, the sensitivity of miR-122 is better than the one of cytokeratin (CK)- 18, ALT, or AST while detecting NASH and predicting liver fibrosis in patients with NAFLD [133].

Another complication that commonly involve in pathogenesis of several diseases is the abnormal cell proliferation. So, the inhibition of this pathological process has been clarified as critical way in treating precited disease [134], through targeting miRNA, lncRNA, or ceRNA crosstalk. In case of elevated quantity of PPARα, its target gene carnitine palmitoyltransferase 2 (CPT2) and the acyl-CoA binding domain containing 3 (ACBD3) or the solute carrier family 27A (SLC27A) become activated, and the steatosis is lowered [134]. Therefore, scircRNA/miR-34a/PPARα Pathway is suggested to be incorporated in progression of NAFLD. Moreover, the critical role of noncoding RNAs in NAFLD was investigated in a number of studies which explained that both circRNA 0046367 and circRNA 0046366 the endogenous regulators of miR-34a [134, 135] block miRNA/mRNA cooperation with miRNA response element (MRE) and lastly can extinct inhibitory effect on PPARα. These enabled to propose that dysregulation mechanism of circRNA 0046366 or circRNA 0046366/miR-34a/PPARα signaling pathway may be a novel mechanism that lead to hepatic steatosis [134].

Conclusion

NAFLD is etiologically correlated with systemic distortion of various metabolisms, of which their impairment result in multiple disorders such as: insulin resistance, hyperglycemia, hyperlipidemia and other complications correlated with obesity and diabetes. Insulin resistance is illustrated like a central root that likely initiates the coexistence of diabetes and NAFLD. Moreover, mitochondria hyperactivity and shortage in antioxidants initiate liver oxidative stress. That induce inflammation which aggravate the liver cell damage by accelerating the progression from simple steatosis to NASH, that progress to other irreversible forms of NAFLD. Besides, cytokines related to obesity, such as interleukin-6 (IL-6), leptin, adiponectin, and tumor necrosis factor-alpha (TNF-α) work in harmony, but their homeostasis is disturbed in NASH, that also worsen NAFLD. The prevalence of NAFLD elevated the risks of acquiring other diseases either related to Insulin resistance, as co-inducer (such as Type 2 diabetes) or from subsequent damages (such as cardiovascular diseases, from vessels damage). The management of NAFLD rely on early detection and severity quantification, the noncoding RNAs have shown these abilities with high sensitivity. Obesity and NAFLD can also develop in response to elevated white adipose tissue mass, derived from miR-155 deficiency/downregulation. These facts allow us to suggest also that noncoding gene can play role in handling the disease. Moreover, also many other different mechanisms involved in developing NAFLD, and interconnecting pathways with other metabolism complications (such as diabetes, obesity and cardiovascular diseases) are encompassed in this study. However, currently no specific medication for NAFLD, future researches can base on advancing analysis that amalgamate findings on NAFLD in its complexity and its interrelation, like current study, to further in management of NAFLD and in case diverse disorders involved to aggravate condition.

Acknowledgement This study was supported by National Natural Science Foundation of China (30725045).

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