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The demand for liver transplantation in the Kingdom of Saudi Arabia (KSA) is associated with the country's high burden of liver disease. Trends in the epidemiology of liver transplantation indications among recipients in KSA have changed over 20 years. Non-alcoholic steatohepatitis has eclipsed the hepatitis C virus in the country due to the effective treatment strategies for HCV. Risk factors for NASH, like type 2 diabetes mellitus, obesity, and hyperlipidemia, are becoming a major concern and a leading indication for liver transplantation in the KSA. There is also a significantly increased prevalence and incidence of genetic adult familial liver diseases in KSA. New immunosuppressive agents and preservation solutions, improved surgical capabilities, and early disease recognition and management have increased the success rate of liver transplant outcome but concerns about the side effects of immunosuppressive therapy can jeopardise long-term survival outcomes. Despite this, indications for liver transplantation continue to increase, resulting in ongoing challenges to maximize the number of potential donors and reduce patient mortality rate while expecting to get transplanted. The Saudi Center of Organ Transplant is the recognized National Organ Donation Agency for transplantation, which renders important support for procurement and allocation of organs. This guidance document aims to help healthcare providers in managing patients in the liver transplant setting.

Infection with hepatitis B virus (HBV) remains an important public health problem with a high burden worldwide. The Saudi Association for the Study of Liver diseases and Transplantation formed a working group to develop HBV practice guidelines in Saudi Arabia. The methodology used to develop these guidelines was based on reviewing the available evidence, local data, and major international practice guidelines on the management of HBV. The aim of these guidelines is to assist healthcare providers in the management of HBV in Saudi Arabia. These updated guidelines summarize the latest local studies performed on HBV epidemiology, major changes in the prevalence of this virus, and advances in disease management.

Background: No virologic cure exists for hepatitis B virus (HBV) infection, and existing therapies are designed to control viral replication. We aimed to estimate the national prevalence of HBsAg in 2017 and study the impact of an enhanced diagnosis rate and universal treatment administration on HBV-related outcomes in Saudi Arabia. Materials and methods: A dynamic transmission and disease burden model was developed to estimate the future economic burden of HBV infection. The infected population was tracked by age and gender-defined cohorts; direct costs (healthcare, screening, diagnostics and treatment) and indirect costs (disability-adjusted life years and the value of a statistical life year) were calculated. The impact of two intervention scenarios (Achieve WHO Targets: diagnose 90% of infections and treat 80% of high viral load patients by 2030; and Diagnose and Treat All: diagnose and treat all infected patients by 2022) were compared against the Base Case scenario (no policy action), with near-universal vaccination coverage rates held constant. A sensitivity analysis of future treatment cost was also conducted. Results: In 2017, HBsAg prevalence was estimated at 1.7%, corresponding to 574,000 infections. The same year, there was an estimated incidence of 490 cases of decompensated cirrhosis, 1500 cases of hepatocellular carcinoma (HCC) and 1740 liver-related deaths (LRD). HBsAg prevalence was 0.1% among 5-year-olds and

In December 2019, a novel coronavirus was identified in patients in Wuhan, China. The virus, subsequently named severe acute respiratory syndrome coronavirus-2, spread worldwide and the disease (coronavirus disease 2019 or COVID-19) was declared a global pandemic by the World Health Organization in March 2020. Older adults and individuals with comorbidities have been reported as being more vulnerable to COVID-19. Patients with chronic liver disease (CLD) have compromised immune function due to cirrhosis and are more susceptible to infection. However, it is unclear if patients with CLD are more vulnerable to COVID-19 and its complications than other populations. The high number of severe cases of COVID-19 has placed an unusual burden on health systems, compromising their capacity to provide the regular care that patients with CLD require. Hence, it is incredibly crucial at this juncture to provide a set of interim recommendations on the management of patients with CLD during the current COVID-19 outbreak.

Several peripheral blood mononuclear cell (PBMC) defects have been linked with hepatitis C virus (HCV) infection, including alterations in cytokine secretion and increased cell death. This study was performed to investigate the expression levels of signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 1 (IRF-1), and caspase 3 in PBMCs of patients infected with HCV. STAT1, IRF-1, and caspase 3 expression levels were compared in PBMCs from 19 untreated (naïve) HCV+ patients, 8 treated (sustained responder [SR]) HCV patients, and 20 HCV- healthy controls. Moreover, PBMCs from naïve HCV+ patients and SR-HCV patients were also evaluated for HCV RNA expression. The expression levels of STAT-1 and IRF-1 were significantly downregulated in PBMCs from naïve HCV+ patients (P Keywords: PBMC; hepatitis C virus; STAT1; IRF-1; caspase-3.

Simple Summary Hepatocellular carcinoma (HCC) is the most common type of liver cancer and accounts for approximately 6% of all human cancers. In this study, we performed a systematic review and pooled analysis of the conventional transcatheter arterial chemoembolization (C-TACE) compared to drug-eluting beads TACE (DEB-TACE) as two treatment options for patients with unresectable HCC. Treatment with DEB-TACE appears to be non-inferior compared to conventional C-TACE and associated with a better objective response and disease control with fewer severe complications and all-cause mortality. In light of these findings, research efforts should attempt to further characterize the efficacy and safety profile of DEB-TACE as a potential component of unresectable HCC management. Abstract Hepatocellular carcinoma (HCC) occurs in nearly three-quarters of all primary liver cancers, with the majority not amenable to curative therapies. We therefore aimed to re-evaluate the safety, efficacy, and survival benefits of treating patients with drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) compared to the conventional transcatheter arterial chemoembolization (C-TACE). Several databases were searched with a strict eligibility criterion for studies reporting on adult patients with unresectable or recurrent HCC. The pooled analysis included 34 studies involving 4841 HCC patients with a median follow-up of 1.5 to 18 months. There were no significant differences between DEB-TACE and C-TACE with regard to complete response, partial response and disease stability. However, disease control (OR: 1.42 (95% CI (1.03,1.96) and objective response (OR: 1.33 (95% CI (0.99, 1.79) were significantly more effective for DEB-TACE treatment with fewer severe complications and all-cause mortality. The pooled-analysis did not find superiority of DEB-TACE in complete or partial response, disease stability, controlling disease progression, and 30 day or end-mortality. However, results showed that DEB-TACE is associated with a better objective response, disease control, and lower all-cause mortality with severe complications compared to C-TACE treatment. Given that the safety outcomes are based on limited studies with a potential for bias, there was no clear improvement of DEB-TACE over C-TACE treatment.

End-stage liver disease secondary to hepatitis C virus (HCV) infection is a major indication for liver transplantation (LT) worldwide. Previous studies have shown a negative impact of HCV on patient and graft survival leading to an inferior transplant outcome when compared to other liver transplant indications. The percentage of HCV patients infected with genotype 4 (G4) among recipients of OLT varies depending on geographic location. In the Middle East HCV-G4 infection is the most common genotype among transplant recipients. Direct antiviral agents (DAAs) have revolutionized the management of HCV infection in the pre- and post-transplant setting. Recent clinical trials have shown high sustained virologic response rates, shorter durations of treatment, and decreased adverse events when compared with the previous treatment of pegylated interferon (PEG-IFN)-based therapy. However, most of these studies were performed in HCV-G1-infected patients. Due to the low prevalence of HCV-G4 in Europe and the USA, this genotype has not been adequately studied in prospective trials evaluating treatment outcomes. The aim of this chapter is to summarize the natural history and treatment outcome of HCV-G4 in the liver transplant setting, with particular attention to new HCV therapies.

Background Autoimmune hepatitis (AIH) is a rare indication for liver transplantation (LT). Data on the long-term outcomes of living-related LT for AIH are limited and inconsistent. The present study aimed to assess the long-term outcomes of deceased donor LT (DDLT) and living donor LT (LDLT) for AIH. Methods All patients who received transplants for AIH-related cirrhosis from 2001 to 2018 were included in this study. Results Seventy-four patients (31 male, 43 female) received LT. The average follow-up was 7.9 ± 6.9 years (median = 7.2 years), average age was 34.3 ± 13.8 years, and average Model for End-Stage Liver Disease (MELD) score was 23.6 ± 8.5. Thirty-six (49.3%) patients received a graft from a living donor, and 83% of patients were maintained on steroids. The 1-, 3-, 5-, and 10-year survival rates of patients were 91%, 89%, 87%, and 82% and of grafts were 89%, 88%, 86%, and 76%, respectively. In univariate analysis, MELD score (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.17; P = .028), donor age (OR per 5 years, 1.45; 95% CI, 1.07-2.02; P = .021), donor type (OR LDLT vs DDLT, 0.19; 95% CI, 0.04-0.67; P = .017), and renal function (OR glomerular filtration rate Conclusion We have shown the highest reported long-term survival rates in LT for AIH, including a large number of patients who underwent LDLT. Standardized management and immunosuppressive therapy, including the maintenance of a low-dose steroid protocol, may have contributed to this outcome.

Patients with chronic liver disease (CLD) and liver transplant recipients are at increased risk of morbidity and mortality from coronavirus disease 2019 (COVID-19). Although several studies demonstrated the safety and efficacy of COVID-19 vaccines in the general population, data in CLD patients and liver transplant recipients are lacking. Two COVID-19 vaccines were approved by the Saudi Food and Drug Authority and rolled out to several million recipients in Saudi Arabia. These vaccines are mRNA-based vaccine BNT162b2 from Pfizer/BioNTech and adenovirus-based AZD1222 from Oxford/AstraZeneca from three manufacturing sites (EU Nodes, Serum Institute of India, and South Korea Bio). The Saudi Association for the Study of Liver diseases and Transplantation (SASLT) has reviewed the available evidence and issued interim recommendations for COVID-19 vaccination in CLD and liver transplant recipients. Since there is no evidence contradicting the safety and immunogenicity of the currently approved COVID-19 vaccines in patients with CLD and hepatobiliary cancer and liver transplant recipients, the SASLT recommends vaccination in those patient populations. CLD and hepatobiliary cancer patients and liver transplant recipients should be prioritized depending on the risk factors for severe COVID-19. In transplant recipients, the optimal timing of vaccination remains unknown; however, immunization is recommended after the initial immunosuppression phase. Patients with CLD and liver transplant candidates or recipients should be closely monitored after COVID-19 vaccination. These patient populations should be included in future clinical trials to provide further evidence on the efficacy and safety of COVID-19 vaccines.

Background: Kidney transplant (KT) recipients have a high rate of hepatitis C virus (HCV) infection, which can impact long-term graft and patient survival rates. Although direct-acting antivirals (DAAs) are effective for treating HCV, there is limited data on their use in post-KT patients with HCV genotype 4 infection. Objectives: To evaluate the effectiveness and occurrence of adverse events with grazoprevir/elbasvir combination treatment without ribavirin in post-KT patients with HCV genotype 4 infection. Methods: In this case series, nine therapy-naïve adult post-KT patients with HCV genotype 4 infection were recruited. They had stable graft function and received a fixed dose of grazoprevir/elbasvir (50 mg/100 mg) combination without ribavirin daily for 12 weeks. Patients co-infected with hepatitis B virus, HIV, or with evidence of decompensated liver disease were excluded from the study. Patients were monitored for viral load, laboratory values, and adverse events associated with drug treatment. The response was defined by the sustained virologic response at 12 weeks (SVR12) after the end of treatment. Results: All nine patients completed the treatment period and achieved SVR12 with no treatment failure or relapse. Of them, six patients had HCV genotype 4 infection alone, and three had HCV of mixed genotypes 1 and 4. Two (22%) patients showed a rapid HCV clearance at four weeks. No adverse events or serious adverse events were reported. The patients’ renal function was stable during and after the treatment with no deterioration of graft function, and no adjustments to the immunosuppressive therapy were required. Conclusions: Grazoprevir/elbasvir combination without ribavirin is an effective and safe treatment option for post-KT patients with genotype 4 HCV infection.

Background Several trend analyses on liver transplantation (LT) indications have been published in the U.S. and in other countries, but there are limited data on LT indication trends in Saudi Arabia (SA), especially since the availability of direct-acting antivirals (DAAs) treatment for hepatitis C virus (HCV). This study aimed to analyze trends in the frequency of LT indications among LT recipients in SA over a 19-year period and examine associations between etiologic-specific trends and clinicodemographic characteristics. Methods This retrospective study analyzed clinical and surgical data of adult patients (n = 1009) who underwent LT at the King Faisal Specialist Hospital & Research Center (Riyadh, SA) between 2001 and 2019. Spearman’s rank correlation, Poisson regression, and Joinpoint regression analysis were employed to assess changes in LT etiologic trends. Results In the first period (2001–2010), the main LT indications were HCV (41.9%) and hepatitis B virus (HBV) (21.1%), but nonalcoholic steatohepatitis (NASH) (29.7%) surpassed HCV (23.7%) as the leading LT indication in the second period (2011–2019); and the trends were significant in correlation analyses [incidence rate ratio (IRR) = 1.09 (1.06–1.13) for NASH; IRR = 0.93 (0.91–0.95) for HCV]. In the Joinpoint regression analysis, increases in NASH from 2006 to 2012 (+ 32.1%) were statistically significant, as were the decreases in HCV from 2004 to 2007 (− 19.6%) and from 2010 to 2019 (− 12.1%). Similar patterns were observed in LT etiological comparisons before and after the availability of DAAs and within hepatocellular carcinoma stratifications. Conclusions Trends in the epidemiology of LT indications among LT recipients in SA have changed over a 19-year period. Most notably, NASH has eclipsed HCV in the country due to the effective treatment strategies for HCV. These trends in NASH now need an aggressive public health response to minimize and avert future onset of additional clinical and economic strains on health care systems and LT centers in SA.

Interleukin-37 (IL-37) has recently been recognized as a strong anti-inflammatory cytokine having anti-tumor activity against hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-infected patients. HCC is a typical inflammation-related cancer, and genetic variations within the IL-37 gene may be associated with the risk of HBV infection. Identification of the allelic patterns that genetically have a high disease risk is essential for the development of preventive diagnostics for HBV-mediated liver disease pathogenesis. In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within the IL-37 gene and disease sequelae associated with HBV infection. We genotyped ten IL-37 SNPs in 1274 patients infected with HBV and 599 healthy controls from a Saudi Arabian population. Among the selected SNPs, two SNPs (rs2723175 and rs2708973) were strongly associated with HBV infection, and six SNPs (rs2723176, rs2723175, rs2723186, rs364030, rs28947200, rs4392270) were associated with HBV clearance, comparing healthy controls and HBV infected-patients respectively. A suggestive association of rs4849133 was identified with active HBV surface antigen (HBsAg) carrier and HBV-related liver disease progression. In conclusion, our findings suggest that variations at the IL-37 gene may be useful as genetic predictive risk factors for HBV infection and HBV-mediated liver disease progression in the Saudi Arabian population.

Khalid Alswat,1 Faisal M Sanai,2 Waleed Al-hamoudi,1 Mona Ismail,3 Yaser Dahlan,2 Hamdan Saleh AlGhamdi,4,5 Ibrahim Altraif,4,5 Abduljaleel Alalwan,4,5 Mohamed MA Babatin,6 Saleh A Alqahtani7,8 1Liver Disease Research Center, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 2Gastroenterology Unit, Department of Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia; 3Division of Gastroenterology, Department of Internal Medicine, King Fahd Hospital of the University, College of Medicine, Imam Abdulrahman Bin Faisal University, Al-Khobar, Saudi Arabia; 4King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia; 5Hepatology Division, Department of Hepatobiliary Sciences and Organs Transplant Center, King Abdulaziz Medical City of National Guard, Riyadh, Saudi Arabia; 6Gastroenterology Unit, Department of Medicine, King Fahad Hospital, Jeddah, Saudi Arabia; 7Liver Transplant Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; 8Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USACorrespondence: Khalid AlswatLiver Disease Research Center, Department of Medicine, College of Medicine, King Saud University, P.O. Box 2925(59), Riyadh, 11461, Saudi ArabiaTel +966114670810Fax +966114672403Email kalswat@ksu.edu.saBackground and Aims: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing in Saudi Arabia (SA), but descriptions of the clinical and metabolic characteristics of these patients are limited. The present study aims to fill this gap.Methods: Demographic, clinical, and laboratory data of all NAFLD patients from 2009 to 2019 were retrieved from the Systematic Observatory Liver Disease Registry (SOLID) [n=832 (337 males; 495 females); mean (± standard deviation, SD) age was 42.6± 13.6 years; mean body mass index (BMI) was 35.0± 9.3kg/m2]. Non-invasive surrogate scores of fibrosis (eg AST to Platelet Ratio Index (APRI), Fibrosis-4 (FIB-4), and NAFLD fibrosis (NFS) scores) were calculated and analyzed. In addition, data from NAFLD patients with normal and high alanine aminotransferase (ALT) were compared using two different methods: the standard laboratory reference range which defines normal as ALT< 61 IU/L, and the range proposed by a recent national study which sets upper limits of normal ALT at 33 IU/l for men and 22 IU/l for women.Results: Hyperlipidemia was the most common comorbidity (41.7%), followed by type 2 diabetes mellitus (T2DM) (35.3%) and hypertension (28.4%). Prevalence of advanced fibrosis varied widely across definitions [FIB-4, N=19 (2.5%); APRI, N=21 (2.8%); NFS, N=62 (8.6%)] and exhibited sexual dimorphism with males having worse metabolic characteristics. NAFLD patients with normal ALT were more likely to be older, female, have a lower BMI, and have a higher prevalence of cirrhosis, DM, hypertension, hyperlipidemia, and renal dysfunction.Conclusion: Patients with NAFLD have metabolic characteristics associated with several comorbidities, including NAFLD patients with normal ALT. Mechanistic studies are needed to examine and analyze complex, interactive effects between sex, age, and other factors that may accelerate NAFLD disease progression.Keywords: non-alcoholic fatty liver disease, non-invasive biomarkers of fibrosis, Systematic Observatory Liver Disease Registry, Saudi Arabia

The 69th World Health Assembly endorsed the Global Health Sector Strategy for Viral Hepatitis, embracing a goal to eliminate hepatitis infection as a public health threat by 2030. This was followed by the World Health Organization's (WHO) global targets for the care and management of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These announcements and targets were important in raising awareness and calling for action; however, tracking countries’ progress towards these elimination goals has provided insights to the limitations of these targets. The existing targets compare a country's progress relative to its 2015 values, penalizing countries who started their programmes prior to 2015, countries with a young population, or countries with a low prevalence. We recommend that (1) WHO simplify the hepatitis elimination targets, (2) change to absolute targets and (3) allow countries to achieve these disease targets with their own service coverage initiatives that will have the maximum impact. The recommended targets are as follows: reduce HCV new chronic cases to ≤5 per 100000, reduce HBV prevalence among 1-year-olds to ≤0.1%, reduce HBV and HCV mortality to ≤5 per 100000, and demonstrate HBV and HCV year-to-year decrease in new HCV- and HBV-related HCC cases. The objective of our recommendations is not to lower expectations or diminish the hepatitis elimination standards, but to provide clearer targets that recognize the past and current elimination efforts by countries, help measure progress towards true elimination, and motivate other countries to follow suit.

Background Once daily tacrolimus regimen was found to exhibits similar bioavailability, safety and efficacy properties compared to twice-daily tacrolimus in kidney transplantation patients. Aim To compare the efficacy and safety of once-daily prolonged release tacrolimus compared to twice-daily tacrolimus in liver transplantation patients. Methods MEDLINE, EMBASE, CENTRAL databases were searched for clinical trials until December 2020. Efficacy outcome measured as the rate of treatment failure indicated by biopsy-proven acute rejection, Serum creatinine, graft loss, or death. Two reviewers independently selected studies, collected data and assessed risk of bias. The results are reported as risk ratio with 95% confidence interval (CI) for dichotomous data. Results Seven studies included with 965 patients. All the included studies were of moderate quality according to the risk of bias assessment using Cochrane Risk of Bias tool. Biopsy-proven acute rejection was reported in four studies, and pooled analysis of those studies indicated similar rejections in both twice daily and once daily tacrolimus groups (risk ratio: 1.06, 95%CI: 0.84-1.34, n = 758, I 2 = 0%) and also we found no significant difference between both groups for renal outcome (serum creatinine; mean difference, 0.001 mg/dL, 95%CI: -0.042 to 0.043, n = 846, I 2 = 18.6%). Similarly, there was similar number of adverse events such as hypertension, headache, back pain, blood related disorders, infections and nausea observed in both groups. Conclusion The analysis findings confirm that both once daily and twice daily tacrolimus formulations are comparable in terms of efficacy and safety outcomes.

Background and aims The Middle East (ME) has a high prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), driven by obesity and type-2 diabetes mellitus (T2DM). Studies in Saudi Arabia (KSA) and United Arab Emirates (UAE) predict an escalating impact of NAFLD/NASH, particularly advanced fibrosis due to NASH (AF-NASH), increasing cases of cirrhosis, liver cancer and death. The scale of this burden in other ME countries is unknown with no reports of NAFLD/NASH healthcare resource utilization (HCRU) or costs. We estimated the clinical and economic burden of NAFLD/NASH in KSA, UAE and Kuwait. Methods Markov models populated with country-specific obesity and T2DM prevalence data estimated numbers and progression of NAFLD/NASH patients from 2018 to 2030. Model inputs, assumptions and outputs were collected from literature, national statistics, and expert consensus. Results Over 13 years, the KSA model estimated cases increasing as follows: patients with fibrosis F0–3 doubled to 2.5 m, compensated and decompensated cirrhosis and hepatocellular carcinoma trebled to 212,000; liver failure or transplant patients increased four-fold to 4,086 and liver-related death escalated from 200,000. Similar trends occurred in UAE and Kuwait. Discounted lifetime costs of NASH standard-care increased totaling USD40.41 bn, 1.59 bn and 6.36 bn in KSA, UAE (Emiratis only) and Kuwait, respectively. NASH-related costs in 2019 comprised, respectively, 5.83%, 5.80% and 7.66% of national healthcare spending. Conclusions NASH, especially AF-NASH, should be considered a higher priority in ME Public Health policy. Our analyses should inform health policy makers to mitigate the enormity of this escalating regional burden.

Ibrahim G Alghamdi,1 Majid Almadi,2,3 Fahad Alsohaibani,4 Mahmoud Mosli,5 Edward B De Vol,6 Faisal Abaalkhail,7,8 Faisal A AlSaif,9 Waleed K Al-hamoudi,10 Nasser Al-Sanea,11– 13 Mazen Hassanain,9,14 Saleh A Alqahtani6,15,16 1Public Health Department, College of Applied Medical Sciences, University of Al-Baha, Al-Baha, Saudi Arabia; 2Division of Gastroenterology, Department of Medicine, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia; 3Division of Gastroenterology, McGill University Health Center, Montreal General Hospital, McGill University, Montreal, Canada; 4Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; 5Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 6Biostatistics, Epidemiology, and Scientific Computing Department, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; 7Gastroenterology Section, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 8College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; 9Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 10Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 11Health Affairs, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia; 12Department of Surgery, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; 13Department of Surgery, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; 14Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; 15Liver Transplant Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; 16Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USACorrespondence: Saleh A AlqahtaniLiver Transplant Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi ArabiaEmail salalqahtani@kfshrc.edu.saPurpose: Over the last decades, the incidence of pancreatic cancer has increased, particularly in countries with a higher socioeconomic status. The present work aimed to provide detailed epidemiological data on the incidence of pancreatic cancer in Saudi Arabia.Patients and Methods: In this retrospective descriptive study, the epidemiological data on pancreatic cancer cases diagnosed in 13 administrative regions of Saudi Arabia between January 2004 and December 2015 were extracted from the Saudi Cancer Registry. The frequency, the crude incidence rate (CIR), and the age-standardized incidence rate (ASIR), stratified by geographical region, gender, and the year of diagnosis, were analyzed.Results: From January 2004 to December 2015, a total of 2338 cases of pancreatic cancer were registered, including 1443 males and 895 females. The overall CIR was 1.28/100,000 among males and 0.80/100,000 in females, with an overall ASIR of 2.26 and 1.41/100,000 for males and females, respectively. Higher ASIR and CIR were observed among males than females (ratio 1.6). In both genders, the ASIR of pancreatic cancer increased with increasing age, with the highest incidence in patients aged 70 years or more. The ASIR in the Eastern Region (3.2/100,000) and the regions of Riyadh (3.0/100,000) and Tabuk (2.6/100,000) proved to be significantly higher than in the other regions of the country. Among women, the ASIR was significantly higher in Riyadh (2.3/100,000), the northern region (2.2/100,000), and Tabuk (2.0/100,000).Conclusion: This study revealed a slight increase of the CIR and ASIR of pancreatic cancer among males and females of the Saudi population. Eastern region, Riyadh, and Tabuk had the highest overall ASIRs of pancreatic cancer among males, Riyadh, Northern region, and Tabuk among Saudi females. The area least affected by pancreatic cancer was observed in Jazan among male and female Saudis. The rates of pancreatic cancer in Saudi Arabia were significantly higher among males compared with female Saudis. Further analytical studies are needed to identify the potential risk factors for pancreatic cancer among the Saudi population.Keywords: pancreatic cancer, epidemiology, Saudi Arabia, incidence, Middle-East

Introduction Hepatic steatosis (HS) negatively impacts transplant outcomes in living liver donors. To date, liver biopsy is preferred for HS evaluation. This study aims to evaluate the measurement of controlled attenuation parameter (CAP) as a diagnostic tool of HS in living liver donors. Methods Candidates recruited to this study, conducted from April 2016 to February 2020, were potential donors who had undergone transient elastography using Fibroscan® and CAP measurements at liver segments VI and VII, followed by liver biopsy. The HS grades from liver biopsy were classified as S0 (66%). For CAP, they were S0 (≤218dB/m), S1 (218-249dB/m)), S2 (250-305dB/m)), and S3 (>305dB/m)). The CAP measurements were compared with the liver biopsy results. Results Of the 150 potential donors [male, 73.3%; mean age, 30.0±7.0 years; body mass index (BMI), 24.7±3.5kg/m2], 92 (61.3%) had no or mild HS, while 58 (38.7%) and 10% had moderate to severe HS based on CAP and liver biopsy, respectively. Subjects with moderate to severe HS per CAP were mostly males (0.014), and had higher BMI (p = .006), alanine aminotransferase (ALT) (.001), gamma-glutamyl transferase (.026), and high-density lipoprotein (.008). On multivariate analysis, high ALT (OR, 1.051; 95% CI, 1.016–1.087; p = .004) was a predictor of significant HS. The sensitivity, specificity, positive and negative predictive values of CAP to detect significant HS were 93.3%, 67.4, 24.1%, and 98.9%, respectively. Conclusion The high sensitivity and negative predictive values of CAP make it a good screening test to exclude significant HS in potential living liver donors which, in turn, can help avoid unnecessary liver biopsies.

Glycogen hepatopathy (GH) is a rare complication of type 1 diabetes mellitus that leads to an abnormal accumulation of glycogen in the hepatocytes. The exact mechanism of GH remains unknown, but fluctuations in blood glucose and insulin levels play important roles in promoting glycogen accumulation. We report a case of a 16-year-old female diagnosed with poorly controlled type 1 diabetes mellitus with hepatomegaly and elevated liver enzymes. The patient experienced multiple admissions for diabetic ketoacidosis, and she also had celiac disease diagnosed 2 years previously based on serology and a duodenal biopsy. The laboratory analyses results were compatible with acute hepatitis, and the celiac serology was positive. Other investigations ruled out viral hepatitis and autoimmune and metabolic liver diseases. Ultrasound and computerized tomography (CT) scans of the abdomen revealed liver enlargement with diffuse fatty infiltration. A liver biopsy revealed the presence of abundant glycogen in the cytoplasm of the hepatocytes. PAS staining was strongly positive, which confirmed the diagnosis of GH. There were no features of autoimmune hepatitis or significant fibrosis. Duodenal biopsy results were consistent with celiac disease. Despite our efforts, which are supported by a multidisciplinary team approach that included a hepatologist, a diabetic educator, a dietitian, and an endocrinologist, we have encountered difficulties in controlling the patient’s diabetes, and she persistently maintains symptomatic hepatomegaly and abnormal liver biochemistry. Given the patient’s age, we assumed that these abnormalities were related to patient noncompliance. In conclusion, GH remains an under-recognized complication of type 1 DM that is potentially reversible with adequate glycemic control. The awareness of GH should prevent diagnostic delay and its implications for management and the outcome.

Objectives Liver retransplant is considered the only hope for patients with irreversible graft failure after primary transplant. In most Western centers, retransplantis done mainly from deceased donors; so far, only few published studies have reported on outcomes of liver retransplant with living donors. In this study, our aim was to analyze the outcomes of living-donor liver retransplant. Materials and methods Patients who underwent liver retransplant between February 2011 and February 2019 were included in the study. Preoperative, operative, and postoperative data were analyzed. Results from 2 patient groups were compared: liver retransplant with living donors and liver retransplant with deceased donors. Results Thirty-two patients underwent liver retransplant (21 adult and 11 pediatric patients). The most common indications for liver retransplant were hepatic artery thrombosis (28.5%) and primary graft nonfunction (23.8%) in adults and hepatic artery thrombosis (45.5%) and chronic rejection (36.4%) in pediatric patients. Seventeen retransplant patients (53.1%) required early retransplant (within 1 mo), mainly due to hepatic artery thrombosis (52.9%) and primary graft nonfunction (35.3%). Late retransplant was mainly due to chronic rejection (40%) and recurrence of primary disease (26.7%). Seventeen patients (53.1%) underwent living-donor retransplant, and 5 donors underwent robotic right hepatectomy. Graft and patient survival rates at 1, 3, and 5 years were 81.3% for living-donor and 51.4% for deceased-donor liver retransplant recipients (P = .08). On multivariate analyses, we observed significant differences between both groups in pretransplant Model for End-Stage Liver Disease and Pediatric End-Stage Liver Disease scores (P = .05), preoperative international normalized ratio (P = .012), and cold ischemia time (P = .046). Conclusions The use of living donors for liver retransplant, despite its technical demand, was shown to be a safe and feasible option, especially when there is scarcity of deceased donors.

Summary Limited clinical trial data has shown high efficacy of co-formulated ledipasvir/sofosbuvir (LDV/SOF) in the treatment of hepatitis C virus (HCV) genotype (GT)-4 infected cirrhotic patients. We assessed real-world safety and efficacy of LDV/SOF with or without ribavirin (RBV) in GT4-infected patients with compensated and decompensated cirrhosis. Patients & Methods This observational cohort (n = 213) included GT4 treatment-naive (59.6%) and -experienced (40.4%) patients with advanced fibrosis (F3, Metavir; n = 30), compensated (F4, n = 135) and decompensated cirrhosis (n = 48) treated for 12 (n = 202) or 24 weeks (n = 11) with LDV/SOF. RBV was dosed by physician discretion between 600–1200 mg daily. Patients with prior DAA failure were excluded from the analysis. The primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12) on an intention-to-treat analysis, and occurrence of serious adverse events (SAEs). Results The mean age of the overall cohort was 59.6 ± 12.1 years and 125 (58.7) were female. Overall, 197 (92.5%) of the patients achieved SVR12, including 93.3% of F3 fibrosis, 93.3% of compensated cirrhotics and 89.6% of the decompensated cirrhotics ( P = 0.686). Addition of RBV (68.5%) did not enhance efficacy (91.8% vs. 94.0% without RBV, P = 0.563), including in F3 fibrosis, compensated and decompensated cirrhosis ( P > 0.05, for all). There was no difference in SVR12 rates with 24 and 12 weeks therapy (90.9% and 92.6%, respectively; P = 0.586). Treatment failure (n = 16) was mostly related to relapse (n = 11), while on-treatment death (n = 3) and breakthrough (n = 2) comprised a minority. SAEs occurred in 9 (4.2%) patients requiring early treatment discontinuation in 4 (3 on-treatment deaths and 1 pregnancy). Conclusion LDV/SOF therapy yielded high SVR12 rates in both compensated and decompensated cirrhotic GT4 patients. The addition of RBV to this regimen did not improve efficacy. The safety profile of this regimen was comparable with that reported for other HCV genotypes.

Background/Aim: Due to epidemic levels of obesity and type 2 diabetes mellitus (DM), nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) will be driving factors in liver disease burden in the coming years in Saudi Arabia and United Arab Emirates (UAE). Materials and Methods: Models were used to estimate NAFLD and NASH disease progression, primarily based on changes in adult prevalence rates of adult obesity and DM. The published estimates and expert interviews were used to build and validate the model projections. Results: In both countries, the prevalence of NAFLD increased through 2030 parallel to projected increases in the prevalence of obesity and DM. By 2030, there were an estimated 12,534,000 NAFLD cases in Saudi Arabia and 372,000 cases in UAE. Increases in NASH cases were relatively greater than the NAFLD cases due to aging of the population and disease progression. Likewise, prevalent cases of compensated cirrhosis and advanced liver disease are projected to at least double by 2030, while annual incident liver deaths increase in both countries to 4800 deaths in Saudi Arabia and 140 deaths in UAE. Conclusions: Continued high rates of adult obesity and DM, in combination with aging populations, suggest that advanced liver disease and mortality attributable to NAFLD/NASH will increase across both countries. Reducing the growth of the NAFLD population, along with potential therapeutic options, will be needed to reduce liver disease burden.

Transmission of congenital clotting factor deficiencies following orthotopic liver transplantation is rare. There has been one reported case of donor-to-recipient transmission of factor XII deficiency in a transplant, and we report the second case.

The aim of this study was to evaluate the association of 10 SNPs in different microRNAs (miRNAs) with susceptibility to hepatitis B virus (HBV) infection, HBV clearance, persistence of chronic HBV infection, and progression to liver cirrhosis and hepatocellular carcinoma (HCC). Patients were categorized into the following groups: inactive HBV carrier, active HBV carrier, HBV-cleared subject and cirrhosis+HCC. Samples were analysed for 10 SNPs in microRNAs using either PCR-based genotyping or the TaqMan assay. We found that rs1358379 was associated with susceptibility to HBV infection, HBV clearance, persistent chronic HBV infection and liver cirrhosis+HCC. In addition, we found that rs2292832 and rs11614913 were associated with risk of HBV infection, viral clearance and cirrhosis+HCC, whereas rs2910164 was associated with proneness to HBV infection, and ability to clear the virus. There was evidence of associations between rs6505162 and HBV clearance and the development of liver disease, whereas a single association was found between rs2289030 and HBV clearance. Similarly, rs7372209 and rs4919510 were specifically associated with the development of HBV-induced liver complications. SNPs in miRNAs affect the susceptibility, clearance and progression of HBV infection in Saudi Arabian patients. We found, using Gene Ontology or pathway analyses, that these genes may contribute to the pathophysiology of HBV infection and related liver complications. However, differences in the association of examined SNPs with various clinical stages indicate variations in the respective functional roles of these polymorphisms and their miRNAs, and thus, further investigation to fully explore their therapeutic potential is warranted.

Peripheral blood mononuclear cells (PBMCs) play a critical role in clearing hepatitis C virus (HCV). PBMC defects have been linked with HCV infection; however, the underlying mechanisms remain obscure. We hypothesized that PBMCs of HCV-infected patients are more susceptible to programmed cell death (PCD), and are therefore unable to clear HCV. We compared spontaneous PBMC PCD and cytokine [interleukin (IL)-1, -6, -8, -10, and -12] secretion between untreated (naive) HCV+ and treated [sustained responder (SR)] patients with HCV, and HCV− healthy controls. Spontaneous PBMC PCD was assessed by annexin-V fluorescein isothiocyanate/propidium iodide staining, and cytokine levels were measured by cytometric bead array. Differences between groups were analyzed through paired and nonpaired t tests and Mann–Whitney U test. The rate of spontaneous PCD was higher in PBMCs of naive HCV+ patients (p

Non-alcoholic fatty liver disease (NAFLD) is a major national and international health burden. It is one of the most common liver diseases worldwide and the most common cause of abnormal liver enzymes in many developed countries. Non-alcoholic fatty liver disease is also known as an important cause of cryptogenic cirrhosis and second leading cause for liver transplantation. It is commonly associated with metabolic syndrome. Non-alcoholic steatohepatitis (NASH) is the progressive phenotype of NAFLD. In spite of promising performance of non-invasive tools, liver biopsy remains the gold standard test for NASH diagnosis. Over decades, many drugs have been investigated in phase 2 and 3; however, no approved therapy to date. Despite the alarming global rates of NAFLD, there are no local community-based studies on the prevalence of NAFLD or local practice guidelines on its management; this expert review aims to fill this gap.

Background and Aim. This is an open label prospective cohort study conducted at a tertiary care hospital. The primary endpoint is SVR12 in patients treated with sofosbuvir-based therapy in post-liver transplant patients with genotype 4 HCV recurrence.Methodology. Thirty-six treatment-experienced liver transplant patients with HCV recurrence received sofosbuvir and ribavirin ± peginterferon.Results. We report here safety and efficacy data on 36 patients who completed the follow-up period. Mean age was 56 years, and the cohort included 24 males and one patient had cirrhosis. Mean baseline HCV RNA was 6.2 log10 IU/mL. The majority of patients had ≥ stage 2 fibrosis. Twenty-eight patients were treated with pegylated interferon plus ribavirin in addition to sofosbuvir for 12 weeks and the remaining were treated with sofosbuvir plus ribavirin only for 24 weeks. By week 4, only four (11.1%) patients had detectable HCV RNA. Of the 36 patients, 2 (5.5%) relapsed and one died (2.75%).Conclusion. Our results suggest that sofosbuvir + ribavirin ± pegylated interferon can be utilized successfully to treat liver transplant patients with HCV recurrence.

Background/Aims: Hepatitis B virus (HBV) continues to be one of the most important viral pathogens in humans. Surface (S) protein is the major HBV antigen that mediates virus attachment and entry and determines the virus subtype. Mutations in S gene, particularly in the “a” determinant, can influence virus detection by ELISA and may generate escape mutants. Since no records have documented the S gene mutations in HBV strains circulating in Saudi Arabia, the current study was designed to study sequence variation of S gene in strains circulating in Saudi Arabia and its correlation with clinical and risk factors. Patients and Methods: A total of 123 HBV-infected patients were recruited for this study. Clinical and biochemical parameters, serological markers, and viral load were determined in all patients. The entire S gene sequence of samples with viral load exceeding 2000 IU/mL was retrieved and exploited in sequence and phylogenetic analysis. Patients and Methods: A total of 123 HBV-infected patients were recruited for this study. Clinical and biochemical parameters, serological markers, and viral load were determined in all patients. The entire S gene sequence of samples with viral load exceeding 2000 IU/mL was retrieved and exploited in sequence and phylogenetic analysis. Results: A total of 48 mutations (21 unique) were recorded in viral strains in Saudi Arabia, among which 24 (11 unique) changed their respective amino acids. Two amino acid changes were recorded in “a” determinant, including F130L and S135F with no evidence of the vaccine escape mutant G145R in any of the samples. No specific relationship was recognized between the mutation/amino acid change record of HBsAg in strains in Saudi Arabia and clinical or laboratory data. Phylogenetic analysis categorized HBV viral strains in Saudi Arabia as members of subgenotypes D1 and D3. Conclusion: The present report is the first that describes mutation analysis of HBsAg in strains in Saudi Arabia on both nucleotide and amino acid levels. Different substitutions, particularly in major hydrophilic region, may have a potential influence on disease diagnosis, vaccination strategy, and antiviral chemotherapy.

End-stage liver disease secondary to hepatitis C virus (HCV) infection is the major indication for orthotopic liver transplantation (OLT) worldwide. The percentage of HCV patients infected with genotype 4 (G4) among recipients of OLT varies depending on geographic location. In the Middle East, including Saudi Arabia, G4 infection is the most common genotype among transplant recipients. Due to the low prevalence of HCV-G4 in Europe and the United States, this genotype has not been adequately studied in prospective trials evaluating treatment outcomes and remains the least studied variant. The aim of this review is to summarize the natural history and treatment outcome of HCV-G4 following liver transplantation, with particular attention to new HCV therapies. This review incorporates all published studies and abstracts including HCV-G4 patients.