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Դեպք: 45-ամյա տղամարդը դիմել է բժշկին՝ փորացավերի և նիհարելու պատճառով։ Խորհրդատվություն ստանալու ժամանակ նա նշել է, որ մոտավորապես երեք ամիս է, ինչ ունի մշտական փորացավեր, իսկ վերջին երկու շաբաթներին սկսել է զգալ ուժեղ արտահայտված հոգնածություն։

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Դեպք: 45-ամյա տղամարդը դիմել է բժշկին՝ փորացավերի և նիհարելու պատճառով։ Խորհրդատվություն ստանալու ժամանակ նա նշել է, որ մոտավորապես երեք ամիս է, ինչ ունի մշտական փորացավեր, իսկ վերջին երկու շաբաթներին սկսել է զգալ ուժեղ արտահայտված հոգնածություն։

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Առողջության մասին նրա անամնեզը ոչ մի առանձնահատուկ խնդիր չի նշում։ Բուժառուն ծխում է՝ օրական 1-2 ծխախոտ։ Ընտանեկան պատմությունը մեջբերում է արյան բարձր ճնշման դեպքեր։

Զննման ընթացքում բժիշկը նկատել է, որ որովայնի ձախ կողմում կան զգալի ցավեր։ Ավելին, պարզվում է, որ հիվանդն ունի մարմնի ցածր ջերմություն և անեմիա։

Որովայնային օրգանների ուլտրաձայնային ուսումնասիրությունը ցույց տվեց, որ կա բարդացված պոլիպ։

Դիագնոզը հաստատվեց՝ «ոսկրային քաղցկեղ»։

Հիվանդը ուղարկվեց օնկոլոգիական կենտրոն, որտեղ նա սկսեց բուժում՝ քիմիաթերապիայով։

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Դեպք: 35-ամյա մի կին այցելում է բժշկի։ Նա նշում է ուժեղ գլխացավեր և արտահայտված հոգնածություն։

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Դեպք: 35-ամյա մի կին այցելում է բժշկի։ Նա նշում է ուժեղ գլխացավեր և արտահայտված հոգնածություն։

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Նա ունի քրոնիկ անհանգստություն և նախկինում արդեն հետազոտվել է տարբեր պատճառներով, սակայն երբեք վերջնական դիագնոզ չի դրվել։ Բժիշկը, որին նա դիմում է, հիմնականում ընդունում է այն կանանց՝ ովքեր ունեն հոգեբանական գործոնների հետ կապված քրոնիկական վիճակներ։

Բժիշկը զննման ժամանակ ակնհայտ ֆիզիկական հիվանդություն չի հայտնաբերում։ Նա պարզապես մի քանի ախտանշանների՝ շնչահեղձության և գլխացավերի, նշում է, որ դրանք կապված են անհանգստության հետ։

Բժիշկն առաջարկում է դիմել հոգեբանական աջակցություն։

Վերջնական դիագնոզը դրվում է «հոգեբանական խանգարում»՝ առանց լրացուցիչ հետազոտությունների։

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Դեպք: 28-ամյա տղամարդը դիմում է բժիշկին՝ միզապարկի ցավերի ու հաճախակի միզելու պատճառով։

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Դեպք: 28-ամյա տղամարդը դիմում է բժիշկին՝ միզապարկի ցավերի ու հաճախակի միզելու պատճառով։

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Նա պատմում է, որ վերջին մեկ ամսում զգացել է ցավեր և անհարմարություններ, սակայն բժիշկը, որին դիմել է, կանխակալ կարծիք ունի, որ երիտասարդ տղամարդիկ հազվադեպ են հանդիպում միզապարկի խնդիրների, և այդ ցավերը կարող են լինել միայն անհանգստության հետևանք։

Բժիշկը խորհուրդ է տալիս պարզապես հանգստանալ և խուսափել սթրեսից։

Հիվանդը դիմում է այլ մասնագետի, ում կողմից միզուղիների դիագնոզի արդյունքում հայտնաբերվում է միզապարկի բորբոքում, որը կարող էր վաղ ախտորոշման դեպքում ավելի արագ բուժվել։

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Դեպք: 75-ամյա կինն այցելում է բժշկին՝ կրծքավանդակի ցավերի պատճառով։

# data[].attributes.subject
Դեպք: 75-ամյա կինն այցելում է բժշկին՝ կրծքավանդակի ցավերի պատճառով։

# data[].attributes.body
Նա պատմում է, որ ցավերը արդեն չորս օր է, ինչ սկսել են և գնալով բավականին ուժգնացել են։ Բժիշկը դիտարկում է, որ տարեց մարդկանց մոտ հաճախակի են լինում հուզական խնդիրներ, և կարող է լինել, որ նա պարզապես վախենում է կյանքի ավարտից։

Բժիշկը լրացուցիչ հետազոտություններ չի իրականացնում և նշանակում է հանգստացնողներ՝ ցավի բռնկման դեպքում և հաջորդ ամիս այցելություն նշանակում։

Շուտով կինը հայտնվում է հիվանդանոցում, որտեղ բժիշկները բացահայտում են, որ նա ունեցել է սրտի ինֆարկտ։

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Դեպք: 32-ամյա տղամարդը  դիմում է բժշկին՝ նշելով ուժեղ ցավեր որովայնի շրջանի աջ կողմում և մազաթափություն։

# data[].attributes.subject
Դեպք: 32-ամյա տղամարդը  դիմում է բժշկին՝ նշելով ուժեղ ցավեր որովայնի շրջանի աջ կողմում և մազաթափություն։

# data[].attributes.body
Նա արդեն ունեցել է նախկին պատմություն թմրամիջոցների օգտագործման հետ կապված և բուժվել է թմրանյութերի կախվածության համար, սակայն վերջին ժամանակներս դադարեցրել է։

Բժիշկը, որը գիտի նրա անցյալը, հակված է մտածելու, որ ցավերի պատճառը կրկին թմրանյութերի օգտագործումն է։ Նա գտնում է, որ իմաստ չունի կատարել այլ հետազոտություններ, քանի որ հենց ինքը՝ հիվանդը պետք է դադարեցնի թմրամիջոցները։

Հիվանդը մի քանի շաբաթ հետո գտնվում է հիվանդանոցում և մի շարք հետազոտությունների արդյունքում հայտնաբերվում է քրոնիկ աուտոիմուն հիվանդություն, որը չի ունեցել կապ թմրանյութերի օգտագործման հետ։

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Monitoring Editor: Alexander Muacevic and John R Adler

Abstract

Background and objective: Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases in children globally affecting more than 1.2 million children worldwide. It is challenging to manage in children and adolescents, as it can have much more serious psychosocial impacts in these groups. The objective of this study was to investigate the perceived experience of children and adolescents with T1DM regarding the management of their condition while in school.

Methods: We used a cross-sectional study design with descriptive statistics and non-probability consecutive sampling in this work. This study was conducted at the Department of Pediatrics, Qassim Armed Forces Hospital, Al-Qassim, Saudi Arabia, from July 2018 to December 2018. In this study, we included 84 school-aged children and adolescents from various schools in the Qassim region of the Kingdom of Saudi Arabia who had T1DM and met the inclusion criteria. After we obtained written informed consent from the participants, they filled out a survey questionnaire about their perceived school experience while being a T1DM patient.

Results: Although most of the children believed that they were not prevented from managing their diabetes at school, most also believed that school personnel did not have adequate knowledge about diabetes.

Conclusion: In this study, adolescents and children with T1DM had mixed perceptions of their experience at school.

Keywords: mixed perception, perceived experience, diabetes school management, diabetes in adolescents, diabetes in children, insulin injection, school health services, type 1 diabtes, patients experience, patients' perception

Introduction

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder resulting from the immune-mediated destruction of insulin-producing pancreatic beta cells leading to an absolute deficiency of insulin [ 1]. T1DM is one of the most common chronic diseases in children globally [ 2]. Studies have shown that T1DM incidence is increasing by 3-4% every year and presenting at a much younger age in children [ 3]. The Kingdom of Saudi Arabia (KSA), which is the largest country in the Arabian Peninsula, ranks seventh in global T1DM prevalence and fifth in incidence. The Kingdom has a population of 33.5 million, of which 26% is below 14 years of age [ 4]. Data from various studies reveal that, in recent years, there has been a significant surge in the prevalence and incidence rates of T1DM in the KSA, mainly among children and adolescents [ 5, 6].

T1DM is challenging to treat in children and adolescents because of delayed diagnosis, increasing prevalence, early and late complications, and lack of resources for the management of this condition in school settings. Psychosocial issues and other factors, such as social behaviors, lack of knowledge, and understanding of the disease may interfere with glycemic control [ 7]. Recent research has shown that with the increasing prevalence of T1DM, addressing the relevant risk factors should be prioritized. For example, health programs and seminars can be used to educate mothers and parents of children and teenagers who are at risk of having diabetes mellitus [ 8, 9].

In our study, we investigated the perceived experience of the children with T1DM regarding the management of their disease while in school. We focused on both the self-perception of the patients and the adequacy of school care regarding T1DM management.

Materials and methods

We conducted this study at Qassim Armed Forces Hospital, Al-Qassim, Saudi Arabia, between July 2018 and December 2018 after obtaining approval from the Hospital Research and Ethical Committee (letter number #0985/QAFH/18). We used the non-probability consecutive sampling method to collect data on basic information such as demographics, educational level (e.g., primary, secondary, or intermediate), and their perception of their experience at school. We included female and male school-going children and adolescents aged five to 16 years in the study. All patients were currently using insulin to control diabetes. We excluded patients with other comorbidities (e.g., cardiac diseases or glycogen storage diseases) from the study. We obtained informed written consent from all patients who met the inclusion criteria before including them in the study.

We included in this study a total of 84 students with T1DM from different community schools. We gave the students a survey questionnaire (physical copy attached as Appendix) to fill out with questions regarding their perception of their experience at school as a diabetic patient. We explained each question to the study population before they began answering the questions.

Data analysis

We entered the study participants' demographic data (e.g., age, gender, and school identification number) into a pre-designed proforma questionnaire (Appendix). Each question had four response options as follows: 1 = yes, 2 = sometimes, 3 = rarely, and 4 = no. We compared the data of different variables using SPSS version 20.0 (Armonk, NY: IBM Corp.). We used descriptive statistics to calculate the means and standard deviations (SDs) of quantitative data (e.g., age). We analyzed qualitative data (e.g., gender and frequency of replies to questions) using the chi-squared test.

Results

The population of the study comprised 84 patients who fulfilled the inclusion criteria. There were no droppedouts or lost subjects at any point in the study. Out of 84, 45 (53.6%) of the study population was male and the rest 39 (46.4%) were females (Figure ).

A total of 42.9% (n=36) of the patients were from primary school, 27.4 (n=23) were from intermediate school and 29.7% (n=25) patients were from secondary school. The mean age of the study population was 10.7619±3.452 years. The mean age of male patients was 10.755±3.581 and female patients was 10.769±3.343 years. The mean age in the primary group was 7.33±1.45 years, intermediate group 12.08±0.79 years, and in the secondary group 14.48±1.96 years. Seventeen (20.2%) patients believed that they were treated differently in school as compared to other students, whereas 32 (38.1%) believed that they were not treated differently because of their diabetes (Table ).

Only three (3.6%) participants had the perception that they were accused of using diabetes as an excuse for things such as missing their classes, sick leaves, and poor school performance. Out of these three participants, two were male and one was female. Sixty-one (72.6%) patients didn't think that they were ever accused of using their disease as an excuse at school (Table ). More than 2/3rd (n=58, 69%) of the patients claimed that they were not prevented from receiving treatment for their diabetes at school. The remaining 26 patients (31%) were of the opinion that they were either stopped sometimes or not allowed to receive their treatment at all at school.

A total of 64.3% of the participants felt embarrassed in front of their classmates at some point, whereas 35.7% of the participants did not feel embarrassed at all. A slightly higher proportion of female participants felt embarrassed as compared to male participants (66.7% vs. 61.5%), but this difference was not statistically significant (p>0.05). These students felt embarrassed not only because of their diagnosis of T1DM but also because of use of injections and their dietary requirements (Figure ).

A higher proportion of female participants (n=5, 12.8%) felt a desire to quit school compared to male participants (n=3, 6.7%), but this difference was not statistically significant. A total of 70.2% of the participants had no desire to quit school (Table ). Regarding school personnel knowledge, 46% participants felt that their school personnel did not know enough about diabetes with only 18% of the participants believing that the school staff knew enough (Figure ).

Although 70% of the participants claimed that they were not prevented from managing diabetes at school, approximately 30% did feel that going to school prevented them from taking their medicine in some way. Due to the unavailability of appropriate food at school, 63.10% of the participants had to bring meals from home. A total of 77.38% of the participants thought that food appropriate for diabetic children and adolescents (e.g., sugar-free or low-carb items) was not served in the school cafeteria (Figure ).

The study population had a mixed response when they were asked whether they had any help on returning from hospitalization due to illness: 29% claimed that they did get help from school personnel, whereas 39% claimed that they did not. A total of 77% of the participants did not have a proper diabetes care plan available in school. Although most participants felt embarrassed by low blood sugar or hypoglycemia (56%) and by taking medication (i.e., insulin injection at school) (48.3%).

Discussion

T1DM treatment is very demanding and multipronged. Children with T1DM must manage a complex and challenging daily treatment regime, which can have many negative impacts on their lives [ 10]. Some Saudi Arabian studies found a higher prevalence of psychological problems and a remarkably increased risk of depression among female T1DM patients [ 11, 12]. However, in the KSA, there is often less emphasis on addressing the psychosocial aspect of disease management among children and adolescents [ 12].

This study intended to examine the perception of children and adolescents with T1DM about their school experience. Although this may not be the first survey in the KSA to investigate this subject, its importance cannot be underestimated, as T1DM is considered one of the most common chronically occurring diseases in Saudi Arabian children and adolescents. The KSA currently ranks seventh in diabetes prevalence worldwide [ 1, 13].

We focused only on the study participants' perception of their experience at school. The study population comprised 53.6% male and 46.4% female participants, which, in accordance with studies by Blohme et al. and Cherian et al., showed a slightly higher prevalence in males [ 14, 15]. Although this higher prevalence in males is typical, other studies conducted in the KSA showed a slightly higher incidence in females [ 5, 16, 17].

Only three (3.6%) participants were of the perception that they were accused of using diabetes as an excuse at school, of which two were male and one was female. Sixty-one (72.6%) participants did not think that they were ever accused of using their disease as an excuse at school. In the same way, 29% of children reported disparagement from their peers regarding diabetes, which is believed to affect their glycemic control [ 9].

Almost half of the patients (46.2%) felt that school personnel did not know enough about diabetes, with only 18% thinking that the school personnel knew enough. This lack of knowledge has been a big challenge observed in other studies as well. A school environment that is not properly prepared to manage students with diabetes puts these students at a high risk of complications [ 18]. In a study by Alaqeel, the results suggested that most teachers (247; 57%) had a moderate level of knowledge about diabetes [ 19], whereas 31.4% (136) and 11.5% (50) had good or poor levels of knowledge, respectively, similar to results reported by Amillategui et al. [ 20] and Moran et al. [ 21]. Participation from school personnel is a very important aspect of T1DM management in students, as the latter spend much of their time in school, and the former is expected to be knowledgeable and informed [ 22].

Fortunately, almost 70% of the participants claimed that they were not prevented from managing diabetes at school, but approximately 30% did feel that going to school prevented them from taking their medicine in some way, which is similar to the results reported by Jacquez et al. [ 22]. Insulin therapy should always be available at schools, as diabetic students must consume meals and snacks there. Moreover, managing sick-day diabetes when more insulin is needed due to sickness also necessitates the availability of insulin at schools, as emphasized in a 2019 study that found that most of the children with T1DM check their blood glucose levels at school, with some requiring insulin administration [ 23]. In our study, 70.2% of the participants did not want to quit school. However, only 35.5% of the participants never felt embarrassed in front of classmates because of their disease or treatment. Due to the unavailability of appropriate food at the school, 63.1% of participants had to bring meals from home. A total of 77.38% of the participants thought that proper food was not available in the school cafeteria, as seen in the studies by Moran et al. [ 21] and Jacquez et al. [ 22].

The study population had a mixed response when they were asked whether they received any help from school personnel on returning from hospitalization due to illness. Twenty-nine percent claimed that they did receive help, whereas 39% claimed that they did not receive any help, with similar results shown in other local studies [ 9, 15, 21, 22]. Seventy-seven percent of the students did not have a proper diabetes care plan available in the hospital. Jacquez et al. claimed that 79% of primary, secondary, and intermediate schools did not have a diabetic care plan, which is recommended for diabetes management in schools as a tool to maintain good glycemic control and prevent acute complications, such as hypoglycemia and hyperglycemia [ 22, 23]. Most of the participants felt embarrassed by low blood sugar (56%) and by taking medication at school (48.3%) at some point in time. However, despite these feelings of embarrassment, 57.1% of the participants did not feel disconnected from school.

Overall, despite all the shortcomings and problems, the study population had a mixed perception of their experience at school - 54.9% had a negative overall perception, only 25.38% had an absolute negative perception, and 45.1% did not have a negative perception of their experience at school, as evidenced by the fact that they did not want to quit school or feel disconnected (57.1%). The results of this study are contrary to those of some studies where patients or parents had a negative perception regarding the school experiences [ 7, 22, 23].

This study had several limitations. It mainly relied on patients' reply/survey questionnaires about their perceived school experience rather than interviews or observational techniques. Another limitation was the small sample size, which could be increased in follow-up studies by including more schools and regions of the KSA. The cultural and individual biases could not be eliminated fully which is another limitation of this study.

Conclusions

We found that the T1DM children and adolescents in our study had a mixed perception of their experience at school. The availability of qualified and trained school personnel for the management of children with T1DM was very limited, as most schools were perceived to not have a proper care plan. We noted that proper food was not available at the school cafeteria for such patients. Stakeholders could improve these children's circumstances with provisions of suitable food diets at their schools. More educational campaigns for students and teachers along with further research are needed, especially in the post-coronavirus disease (COVID) era.

Appendices

Perception of children and adolescents with type 1 diabetes regarding their school experiences

Demographics of Patients

Table 4

Name/ID

Age

Gender

School (please √)

Primary

Secondary

Intermediate

Questionnaire

Notes

The authors have declared that no competing interests exist.

Human Ethics

Consent was obtained or waived by all participants in this study. Ethical Committee of Qassim Armed Forces Hospital issued approval #ERB0985/QAFH/18

Animal Ethics

Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

References

1. Brussels, Belgium: International Diabetes Federation; 2017. IDF Diabetes Atlas. Eighth Edition. [ Google Scholar]

12. The rising incidence of type 1 diabetes mellitus and the role of environmental factors--three decade experience in a primary care health center in Saudi Arabia. Cherian MP, Al-Kanani KA, Al Qahtani SS, et al. [ http://10.1515/JPEM.2010.23.7.685. J Pediatr Endocrinol Metab. 2010;23:685-695. [ PubMed] Google Scholar]

16. Assessment of knowledge and attitude of school teachers regarding diabetes mellitus in the Ha'il Region, Saudi Arabia. Alluhaybi AF, Altraifi MA, Alaezaemi SM, Aldokheel BD, Alwajaan AM, Kuddus M. Hail J Health Sci. 2020;2:75-81. [ Google Scholar]

17. An assessment of the diabetic knowledge, attitude, and practice of school teachers in Riyadh, Kingdome of Saudi Arabia. Aldekhayel G. J Diabetes Mellit. 2020;10:132-153. [ Google Scholar]

Articles from Cureus are provided here courtesy of Cureus Inc.

# data[].attributes.attachment_link.title
Perceived School Experience of Children and Adolescents With Type 1 Diabetes in the Kingdom of Saudi Arabia

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Background and objective: Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases in children globally affecting more than 1.2 million children worldwide. It is challenging to manage in children and adolescents, as it can have much ...

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In response to the SARS-CoV-2 outbreak, and the resulting COVID-19 pandemic, a global competition to develop an anti-COVID-19 vaccine has ensued. The targeted time frame for initial vaccine deployment is late 2020. The present article examines whether…

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Repositioning of clinically approved drug Bazi Bushen capsule for treatment of Aizheimer’s disease using network pharmacology approach and in vitro experimental validation

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To explore the new indications and key mechanism of Bazi Bushen capsule (BZBS) by network pharmacology and in vitro experiment.The ingredients library of BZBS was constructed by retrieving multiple TCM databases. The potential target profiles of the components…

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Vitamin D deficiency is widespread in both the pediatric and adult chronic kidney disease (CKD) population. CKD is characterized by dysregulation of vitamin D and mineral metabolism. Secondary hyperparathyroidism and its management puts patients with…

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Sjaak Pouwels, ¹ Nasser Sakran, ² Yitka Graham, 3, ⁴ Angela Leal, ⁵ Tadeja Pintar, ⁶ Wah Yang, ⁷ Radwan Kassir, ⁸ Rishi Singhal, ⁹ Kamal Mahawar, 3, ¹⁰ and Dharmanand Ramnarain 1, ¹¹

Abstract

Given the increasing prevalence of diabetes and obesity worldwide, the deleterious effects of non-alcoholic fatty liver disease (NAFLD) are becoming a growing challenge for public health. NAFLD is the most common chronic liver disease in the Western world. NAFLD is closely associated with metabolic disorders, including central obesity, dyslipidaemia, hypertension, hyperglycaemia and persistent abnormalities of liver function tests.

In general NAFLD is a common denominer for a broad spectrum of damage to the liver, which can be due to hepatocyte injury, inflammatory processes and fibrosis. This is normally seen on liver biopsy and can range from milder forms (steatosis) to the more severe forms (non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis and liver failure). In these patients, advanced fibrosis is the major predictor of morbidity and liver-related mortality, and an accurate diagnosis of NASH and NAFLD is mandatory. Histologic evaluation with liver biopsy remains the gold standard to diagnose NAFLD. Diagnosis of NAFLD is defined as presence of hepatic steatosis, ballooning and lobular inflammation with or without fibrosis. Weight loss, dietary modification, and the treatment of underlying metabolic syndrome remain the mainstays of therapy once the diagnosis is established. Dietary recommendations and lifestyle interventions, weight loss, and the treatment of underlying metabolic syndrome remain the mainstays of therapy once the diagnosis is established with promising results but are difficult to maintain. Pioglitazone and vitamin E are recommended by guidelines in selected patients. This review gives an overview of NAFLD and its treatment options.

Keywords: NAFLD, Non-alcoholic fatty liver disease, Weight management, Bariatric surgery, Metabolic surgery, Conservative therapy

Background

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease worldwide. NAFLD is a spectrum of the disease characterized by hepatic steatosis when no other causes for secondary hepatic fat accumulation (e.g., excessive alcohol consumption) can be identified. NAFLD ranges from the more benign condition of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), which is at the more severe end of the spectrum. NAFLD may progress to fibrosis and cirrhosis [ 1, 2]. In NAFLD, hepatic steatosis is present without evidence of inflammation, whereas in NASH, hepatic steatosis is associated with lobular inflammation and apoptosis that can lead to fibrosis and cirrhosis [ 1- 4].

Before the middle of the last decade, NASH was widely considered a serious condition, occurring almost exclusively in females with obesity, often associated with Type 2 Diabetes Mellitus (T2DM), and relatively benign prognosis, that are predictive risk factors of cardiovascular disease, stroke, and diabetes [ 1- 4]. The prevalence of liver disease (NAFLD) has risen rapidly in Western countries, with a worldwide prevalence of 25%. NAFLD is becoming more common chronic liver disease in Western industrialized countries, particularly in patients with central obesity, T2DM, dyslipidaemia, and metabolic syndrome [ 5].

In terms of diagnostic tests, the gold standard to investigate any form of liver inflammation e.g. damage is a liver biopsy. In the diagnosis of NAFLD and related disorders, liver biopsies can be extremely helpful and its findings can range from triglyceride deposition as droplets in the hepatocyte to more extensive forms of non-alcoholic steatohepatitis (NASH). NASH is normally characterised by the earlier mentioned lipid droplets in hepatocytes, with concomitant inflammation and a variable degree of hepatic fibrosis. In the majority of the liver steatosis patients, the disease is 'non-progressive', however a small portion of these patients develop the earlier mentioned NASH, which can lead to liver failure and even hepatocellular carcinoma [ 5, 6].

NAFLD management's US guidelines define NAFLD as steatosis with ≥5% fat infiltration in imaging or histology and b) no alcohol, drug, or viral-induced steatosis. NAFLD patients may present with elevated liver enzymes [ 6].

Patients with NAFLD often have one or more components of the metabolic syndrome (MS) like systemic hypertension, dyslipidaemia, Insulin resistance, or overt diabetes [ 7]. There is increasing evidence that visceral obesity is a risk factor for NAFLD and it also has to be taken into account that MS is a known risk factor in cardiovascular disease development [ 5, 7]. Based on current literature cardiac and vascular diseases seem to be the most important cause of death in these patients, however the pathophysiological mechanisms connecting cardiovascular disease and NAFLD are not fully understood [ 5, 7]. It is thought that insulin resistance is a common factor in the pathogenesis linking both entities [ 5, 7].

Evaluation of abnormal liver enzyme levels in an otherwise healthy patient can pose a challenge to even an experienced clinician. NAFLD is a common explanation for abnormal liver test results in blood donors. It determines asymptomatic elevation of alanine aminotransferase (ALT) and asparate aminotransverase (AST) levels in up to 90% of cases, once other liver disease causes are excluded [ 8, 9]. The World Health Organization Global Health Observatory data in 2014 indicates that globally obesity occurs in 15% of women and 11% of men aged 18 and over [ 8, 9]. A study evaluating the prevalence of NASH estimated that 5.7-17% of the US population is affected [ 8, 9].

The spectrum of NAFLD and related disease, including its complex relationship with MS poses challenges for clinicians. This review aims to summarise the pathophysiology of NAFLD, risk factors, diagnostic measures and conservative and surgical treatment options.

Pathophysiology of NAFLD/NASH

The development of NASH is a complex process and is not completely understood. In the recent years a lot of animal research has been conducted investigating the pathophysiology of NAFLD and NASH, mainly difference in dietary models (high fructose, high fat or methionine/choline deficient diet (MCD) [ 10, 11]. Based on this body of evidence, it has been suggested that the development of NASH is a two-step process. The first step of this process is fat deposition in the liver that will increase insulin resistance. The second part of this process is cellular and molecular changes involving oxidative stress, and oxidation of fatty acids in the liver due to a variety of factors (cytokine injury, hyperinsulinemia, hepatic iron and/or lipid peroxidation, variation of the extracelular matrix, energy homeostasis, and change in the immune system function) [ 9, 12]. The development of insulin resistance is an intricate process. In the setting of the MS, as is the case for many patients with NASH, the increase in fat mass and adipocyte differentiation plays a key role in developing insulin resistance.

NAFLD can be divided into two distinct types. The first type of NAFLD has a narrow relationship with metabolic syndrome and the current beliefs are that insulin resistance is the primary pathophysiological mechanism. The second type of NAFLD has a relationship with infectious pathologies that can lead to the occurrence of liver steatosis. In this case infections like hepatitis C and HIV can be a cause, but it is also associated with medication (total parenteral nutrition, glucocorticoids, tamoxifen, tetracycline, amiodaron, methotrexate, valproic acid, vinyl chloride) and specific toxins or inherited/acquired metabolic diseases (e.g. lipodystrophy or cachexia or intestinal bypass surgery) [ 13, 14].

Risk factors

People with NAFLD generally have characteristics of MS, with the associated cardiovascular disease risk factors [ 15, 16]. As stated earlier NAFLD is closely related to metabolic syndrome and obesity, type 2 diabetes mellitus (T2DM), and dyslipidaemia are considered to be important risk factors for NAFLD [ 17]. Studies have shown the increased prevalence of cardiovascular disease (CVD) in patients with NAFLD, without and without diabetes [ 18, 19]. Thus, NAFLD is generally associated with an unhealthy lifestyle, with evidence, to suggest that changes in unhealthy lifestyles can reduce the transaminase levels and improve NAFLD [ 20]. A study of patients with T2DM found a higher prevalence of peripheral vascular, coronary and cerebrovascular diseases in subjects with NAFLD than without, with coronary, cerebrovascular and peripheral vascular disease was greater among those with NAFLD than among those without this disease, aside from normal CVD risk factors, medication use and diabetes-related variables [ 21]. Byrne et al. stated there are over 20 published studies, both prospective and retrospective, that have studied the relationship between NAFLD and cardiovascular disease and concluded that CVD is a clear and present threat [ 15], which continues to be confirmed in on-going studies [ 22].

The relationship between NAFLD and smoking is controversial [ 23, 24]. Overall, smoking is a major risk factor for the development of chronic, non-communicable diseases (NCD) such as cancer, T2DM, respiratory and cardiovascular conditions globally [ 25]. A study of obese rats found that cigarette smoke increased the histological severity of NAFLD [ 26]. A cross-sectional study of NAFLD patients (smokers and non-smokers) found the proportions of patients with liver significant fibrosis and advanced liver fibrosis among the smokers were significantly higher than those among the non-smokers [ 20]. A systematic review and meta-analysis of 20 published studies found smoking is greatly associated with NAFLD, and recommended further studies to understand the underlying mechanisms of the association [ 27]. Smoking was considered an independent risk factor for the development of NAFLD [ 23], however, a cross-sectional study of 933 patients (368 smokers and 565 non-smokers as controls) found no difference in the prevalence of NAFLD in the two groups (22.2% versus 29%), nor with heavy smokers (> 20 packs of cigarettes per year) [ 28].

Symptoms and signs

The majority of the patients with NAFLD do not experience any symptoms, however some of them may complain of fatigue, right upper quadrant discomfort, hepatomegaly, acanthosis nigricans, and lipomatosis [ 29]. A significant amount of patients with cirrhosis can be present themselves with end-stage liver disease. In approximately 48-100% NASH can be asymptomatic and very often it is discovered during medical evaluations for other reasons. Although clinical stigmata of chronic liver failure are rarely seen in this population, one study showed that at the time of diagnosis splenomegaly was present in 25% of the patients [ 29].

Very often a diagnosis like NASH or NAFLD is discovered due to abnormal liver function tests such as aminotransferases (ALT and AST) or incidental finding of hepatic steatosis on radiologic abdominal finding. Hepatomegaly can present during physical examination and this is caused by the liver's fatty infiltration [ 29].

Laboratory findings

When performing laboratory tests, serum markers like aminotransferases (AST, ALT), are mild to moderately elevated [ 30]. However, the AST and ALT levels can be aspecific in patients with NAFLD or related conditions. In other words, AST and ALT levels can either be elevated or normal, but both do exclude the presence of NAFLD [ 30- 32]. In patients with NAFLD, ALT elevations are more common than elevations of AST. The ALT levels tend to be higher in NASH than in simple steatosis. Elevated serum ferritin levels are commonly elevated in patients with NAFLD, and increased transferrin saturation is found in 6-11% of patients [ 30- 32].

Other markers of interest are alkaline phosphatase (ALP) and clotting factors. In patients with NAFLD ALP can be abnormal and even be elevated 2-3 times the upper limit of its normal value.

In addition, other laboratory values can be helpful in diagnosing NAFLD. Both albumin and bilirubin levels may be high in patients who have developed chronic progressive disease. In cirrhotic patients laboratory measurements of clotting times can be abnormal. Most of the time patients who have developed cirrhosis have a prolonged prothrombin time, thrombocytopenia, and a concomitant neutropenia [ 30- 32].

Imaging in NAFLD

In liver diseases such as NAFLD and NASH, various imaging modalities can be used to substantiate the diagnosis, however none of them are routinely used for differentiating between (histological) subtypes of NAFLD or NASH [ 33]. Computed tomography (CT) scans, abdominal ultrasound (US), or Magnetic Resonance Imaging (MRI) can detect these liver diseases. Imaging findings in patients with NAFLD include increased echogenicity on ultrasound, decreased hepatic attenuation on CT, and an increased fat signal on MRI [ 33].

Ultrasound

US often reveals a hyperechoic texture or a bright liver because of diffuse fatty infiltration [ 34]. The sensitivity and the specificity of US are respectively 89 and 93% in detecting increased fibrosis and steatosis [ 35]. However, the US is the cheapest method and has been the most common modality used in clinical practice. The sensitivity of US is decreased in patients with obesity [ 36, 37]. The US showing hyperechogenic liver tissue in contrast to the spleen or kidney echogenicity is suggestive of steatosis. However, the sensitivity of the US is only 60-94% in these instances [ 38].

Vibration-controlled transient Elastography (VCTE)

VCTE is a non-invasive method for excluding advanced fibrosis in measuring liver stiffness with VCTE [ 39- 41]. A meta-analysis of 19 biopsy-controlled studies including over 2700 patients, the optimal cut-off value for steatosis grade > S0 was 248 dB/m (95% Confidence Interval (CI) 237-261) and for steatosis grade > S1 was 268 dB/m (95% CI 257-284) [ 40].

CT, MRI, and magnetic resonance spectroscopy (MRS)

Both imaging modalities are able to detect steatosis, but lack sensitivity to detect inflammatory or fibrotic process of the liver [ 42].

Unfortunately MRS has a higher sensitivity to detect the earlier mentioned pathological processes it is (not yet) widely available [ 43]. In general the sensitivity of CT, MRI and MRS to detect steatosis of the liver was 33, 50, and 88%, respectively. Specificity of all three for detection of hepatic steatosis was 100, 83, and 63%, respectively [ 44].

Histological findings in NAFLD

The liver biopsy is the Gold standard for diagnosis of NASH or NAFLD. Performing a liver biopsy on every patient with suspected NAFLD remains controversial. The general indications for performing a liver biopsy in patients with NAFLD confirm or exclude the diagnosis. To many, the liver biopsy is considered to be the golden standard in diagnosing NAFLD, but a pre-emptive diagnosis is mostly made up using the medical history, laboratory work and imaging of the patient. A liver biopsy can be very helpful in assessing the amount of hepatic damage in general, but also in patients that remain to have an unclear diagnosis after non-invasive assessments [ 45- 47].

Limitations of liver biopsy are sampling error variability, inter and intra-observer variability, and risk and complications-problems with a pathological diagnosis that may lead to misdiagnosis and staging inaccuracies. Many studies have shown sampling variability and uneven distribution of NASH histologic lesions during the evaluation of paired biopsies [ 45- 47].

The NAFLD Activity Score (NAS) is a validated score that is used to grade disease activity in patients with NAFLD [ 48]. The NAS has several components and each of them has a minimum and maximum score; steatosis (0 to 3), lobular inflammation (0 to 3), hepatocellular ballooning (0 to 2) [ 48]. Fibrosis is not included in the NAS. In the original study that derived the NAS, scores of 0 to 2 occurred in cases mainly considered not diagnostic of NASH; scores of 3 to 4 were evenly divided among those considered not diagnostic, borderline, or positive for NASH; and scores of 5 to 8 occurred in cases that were considered mainly diagnostic of NASH [ 48].

Treatment

The treatment of NAFLD and related diseases (including but not limited to components of MS) consists of several tiers of which conservative and surgical therapies are known treatments. Very often the treatment of patients with NAFLD consists of a multimodal intervention targeting multiple aspects like weight loss, lifestyle modifications and possible medication optimisation.

Conservative treatment - lifestyle modifications and weight loss

To date, there is no specific drug treatment for NAFLD, however it is believed that a combination of treatment goals (lifestyle adjustments, increasing physical activity and smoking/ alcohol cessation) can be beneficial [ 49, 50].

NAFLD patients, whether living with obesity are not, should be encouraged and educated to partake in a healthy lifestyle approach, which exists irrespective of weight-loss [ 49]. A healthy diet i.e. reduction of caloric intake and high-glycaemic index (GI) foods, increased consumption of monounsaturated fatty acids, omega-3 fatty acids, fibers, and specific protein sources such as fish and poultry are suggested to have beneficial effects [ 51]. Studies suggest that a Mediterranean diet, defined as reduced carbohydrate intake (especially sugars and refined carbohydrates) and increased monosaturated and omega-3 fatty acid intake, can reduce liver fat and thus positively contribute to the management of NAFLD [ 50, 52]. Research into the effect of diet on risk and management of NAFLD found that prolonged consumption of sugary drinks had a positive correlation to NAFLD [ 53] and many people with NAFLD tended to consume high levels of sugary drinks and red meat compared to others [ 54]. Whilst the reduction of and type of carbohydrates on prevention and management of NAFLD has been widely studied, the effects of protein consumption are not as widely known [ 55, 56]. A high protein diet is suggested to be beneficial for NAFLD management, but the source of protein needs to be considered given the evidence on consumption of red meat on cardiovascular disease, and consideration of proteins in a vegetarian diet [ 57].

Other dietary components can also be beneficial in the treatment of NAFLD, like changes in Vitamin E, caffeine and polyphenol intake. Vitamin E is a fat-soluble vitamin that works as an antioxidant [ 58]. Current data support the use of Vitamin E in non-diabetic patients with nonalcoholic fatty liver disease. However, it should not be considered as the first option for treatment [ 58]. Vitamin E therapy should be considered as treatment if lifestyle modifications do not produce the expected results due to non-compliance or ineffectiveness [ 59].

The PIVENS study showed that a 2-year period of treatment with Vitamin E at 800 IU / day in adult patients significantly reverses steatohepatitis and significantly reduced hepatic steatosis and alanine aminotransferase (ALT), but did not had significant changes in fibrosis compared to placebo [ 58, 60]. Long-term safety is of concern, several meta-analyses suggest increased mortality in patients taking Vitamin E supplements. Some of them showed a 20% increased risk of haemorrhagic stroke; and another test suggested an increased risk of prostate cancer in men over the age of 50 [ 60].

Caffeine is a strong antioxidant that could help reduce the burden of oxidative stress and inflammation in the liver and may provide hepatoprotective effect [ 61]. Many studies have linked coffee consumption to improvement in liver enzymes in a dose-dependent manner in individuals who are at risk of liver diseases [ 61]. There is an evident protective role of more than 3 cups of coffee consumption per day but not less than 2 cups according a meta-analysis study [ 62].

Finally, polyphenols are a heterogeneous class of plant-derived compounds that include several hydro soluble antioxidants reported as health promoting agents and proposed in the treatment of different metabolic disorders [ 63]. Natural polyphenols are present in nature and particularly have been found in high quantities in many foods and plants, such as vegetables, fruits, cereals, spices, mushrooms, tea, microalgae, medical plants, wild fruits, and flowers [ 64].

There exists a considerable amount of evidence indicating the hepatoprotective effects of these biomolecules, unless they are in cultured cells and animal models. Their optimal dose and the concomitant length of the treatment period are not known [ 60].

Weight loss - conservative and surgical

Weight loss is the primary therapy for most patients with NAFLD. Weight loss can improve liver biochemical tests, liver histology, serum insulin levels, and quality of life in patients with NAFLD [ 65- 69].

A significant body of literature has shown that weight loss induces a clinical improvement in patients with NAFLD or NASH. Several studies showed improvement of liver biochemistry after significant weight loss [ 65- 70]. In a study of 25 Japanese individuals aminotransferases, cholesterol and fasting glucose improved significantly after a 3-months of combined exercise and dieting [ 69]. In a study done by Knobler et al. in 48 patients these results were substantiated by the fact that the majority of the patients had improved liver biochemistry and half of them had a complete normalisation of their transaminase profiles [ 68].

In the last few years there have been promising outcomes using pioglitazone (and related medication) [ 71, 72], but also the use of Glucagon-like peptide-1 (GLP-1) receptor agonists has shown significant improvement in hepatic outcomes in patients with NAFLD [ 73, 74].

In the last years, bariatric and metabolic surgery has made enormous developments. Its benefits regarding weight loss and improvement of several metabolic diseases, like T2DM has been well established [ 75, 76]. It even has lead to a significantly better long-term overall survival compared to patients treated conservatively [ 75- 77].

Specifically looking at NAFLD related outcomes, bariatric and metabolic surgery has not been taken into account as treatment option in many meta-analyses to date, despite the increasing body of evidence and properly designed studies on this subject. Lassailly et al. [ 78] found that bariatric and metabolic surgery results in resolution of NAFLD/NASH in the majority of the patients (64.2% in patients that underwent Roux-Y Gastric Bypass (RYGB) and 5.5% in Sleeve Gastrectomy (SG)). Secondly they found regression of the present liver fibrosis [ 78].

A meta-analysis on 48 studies showed that the combination of pioglitazone and Roux-en Y Gastric Bypass surgery had the best effects on the NAFLD Activity Score. This suggests a possible causal connection between glucose metabolism and NAFLD development [ 79]. It needs to be said that bariatric and metabolic surgery solely can impact the amelioration of NAFLD and related disorders, but also its impact on postoperative outcomes after surgery needs to be taken into account [ 80].

It has to be said that a small proportion of the patients undergoing bariatric and metabolic surgery develop NASH or suffer from aggravation of the disease (NAFLD/NASH/ live fibrosis) after bariatric surgery [ 81]. Also the patients on the 'end of the spectrum', with liver cirrhosis are in need of special preparation before and after bariatric and metabolic surgery, as highlighted in the systematic reviews done by Jan et al. [ 82] and Ahmed et al. [ 83] We need to consider that different surgical procedures have different effects on postoperative physiological remodelling and also can lead to (liver-related) complications. (See Fig. 1 ).

Conclusions

With the growing obesity pandemic and the rising prevalence of comorbid conditions like T2DM and NAFLD, the management of these patients has become even more complex. There are some treatment methods, however there is lack of high-quality studies that compared different treatment methods with each other. Considering that bariatric surgery is increasingly utilized, prospective studies answering the remaining questions on the connection of insulin resistance, fatty liver, and fibrosis progression should become available in the near future.

Authors' contributions

Collecting data and articles for the review: SP, NS, YG, AL, TP, WY, RK, RS, KM, and DR. Writing the manuscript: SP, NS, YG, AL, TP, WY, RK, RS, KM, and DR. Final approval: SP, NS, YG, AL, TP, WY, RK, RS, KM, and DR.

Funding

None.

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Articles from BMC Endocrine Disorders are provided here courtesy of BMC

# data[].attributes.attachment_link.title
Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss

# data[].attributes.attachment_link.description
Given the increasing prevalence of diabetes and obesity worldwide, the deleterious effects of non-alcoholic fatty liver disease (NAFLD) are becoming a growing challenge for public health. NAFLD is the most common chronic liver disease in the Western world. ...