Current and emerging pharmacological therapy for nonalcoholic fatty liver disease

The main treatment of patients with non-alcoholic fatty liver disease(NAFLD) is life style modification including weight reduction and dietary regimen.Majority of patients are safely treated with this management and pharmacologic interventions are not recommended. However, a subgroup of NAFLD patients with non-alcoholic steatohepatitis(NASH) who cannot achieve goals of life style modification may need pharmacological therapy. One major obstacle is measurement of histological outcome by liver biopsy which is an invasive method and is not recommended routinely in these patients. Several medications, mainly targeting baseline mechanism of NAFLD, have been investigated in clinical trials for treatment of NASH with promising results. At present, only pioglitazone acting as insulin sensitizing agent and vitamin E as an antioxidant have been recommended for treatment of NASH by international guidelines. Lipid lowering agents including statins and fibrates, pentoxifylline, angiotensin receptor blockers, ursodeoxycholic acid, probiotics and synbiotics are current agents with beneficial effects for treatment of NASH but have not been approved yet. Several emerging medications are in development for treatment of NASH. Obeticholic acid, liraglutide, elafibranor, cenicriviroc and aramchol have been tested in clinical trials or are completing trials. Here in, current and upcoming medications with promising results in clinical trial for treatment of NAFLD were reviewed.

Comparison of different diagnostic methods in infants with Cholestasis

AIM: To evaluate different methods in differentiating idiopathic neonatal hepatitis from biliary atresia. METHODS: Sixty-five infants with cholestatic jaundice and final diagnosis of idiopathic neonatal hepatitis and biliary atresia were studied prospectively from September 2003 to March 2006. A thorough history and physical examination were undertaken and the liver enzymes were examined. All cases underwent abdominal ultrasonography, hepatobiliary scintigraphy, and percutaneous liver biopsy. The accuracy, sensitivity, specificity and predictive values of these various methods were compared. RESULTS: There were 34 girls and 31 boys, among them 46 subjects had idiopathic neonatal hepatitis (age, 61 ± 17 d) and 19 had biliary atresia (age, 64 ± 18 d). The mean age at onset of jaundice was significantly lower in cases of biliary atresia when compared to idiopathic neonatal hepatitis cases (9 ± 13 d vs 20 ± 21 d; P = 0.032). The diagnostic accuracy of different methods was as follows: liver biopsy, 96.9%; clinical evaluation, 70.8%; ultrasonography, 69.2%; hepatobiliary scintigraphy, 58.5%; and liver enzymes, 50.8%.CONCLUSION: Our results indicate that clinical evaluation by an experienced pediatric hepatologist and a biopsy of the liver are considered as the most reliable methods to differentiate idiopathic neonatal hepatitis and biliary atresia.

Post-transplant lymphoproliferative disorder after liver transplantation: Incidence, long-term survival and impact of serum tacrolimus level

To investigate incidence and survival of post-transplant lymphoproliferative disorder (PTLD) patients after liver transplantation.METHODSA cross-sectional survey was conducted among patients who underwent liver transplantation at Shiraz Transplant Center (Shiraz, Iran) between August 2004 and March 2015. Clinical and laboratory data of patients were collected using a data gathering form.RESULTSThere were 40 cases of PTLD in the pediatric age group and 13 cases in the adult group. The incidence of PTLD was 6.25% in pediatric patients and 1.18% in adult liver transplant recipients. The post-PTLD survival of patients at 6 mo was 75.1% ± 6%, at 1 year was 68.9% ± 6.5% and at 5 years was 39.2% ± 14.2%. Higher serum tacrolimus level was associated with lower post-PTLD survival in pediatric patients (OR = 1.07, 95%CI: 1.006-1.15, P = 0.032). A serum tacrolimus level over 11.1 ng/mL was predictive of post PTLD survival (sensitivity = 90%, specificity = 52%, area under the curve = 0.738, P = 0.035).CONCLUSIONIncidence of PTLD in our liver transplant patients is comparable to other centers. Transplant physicians may consider adjustment of tacrolimus dose to maintain its serum level below this cutoff point.

Cyclic vomiting syndrome in children: Experience with 181 cases from southern Iran

AIM： To evaluate the clinical presentation, response to prophylactic therapy and outcome of children with cyclic vomiting syndrome （CVS） in Shiraz, Iran. METHODS： During a period of 11 years （March 1994 to March 2005）, 181 consecutive children with a final diagnosis of CVS were evaluated, treated and followed in our center. Patients were randomized to receive either amitriptyline or propranolol as prophylactic treatments. RESULTS： There were 88 boys and 93 girls with mean age of onset of symptoms of 4.9 ± 3.3 years （range, neonatal period to 14 years）, the mean age at final diagnosis was 6.9 years （range, 1.5 to 14）, and the mean duration between the onset of the first attack and the final diagnosis of CVS was 2 ± 1.81 years （range, 1/6 to 8）. The mean duration of each attack was 4.26 days （range, from few hours to 10 d） and the mean interval between the attacks was 1.8 mo （range, 1 wk to 12 too）. The time of onset of the attacks was midnight to early morning in about 70% of cases. Amitriptyline was effective in 46 out of 81 （56%） patients （P 〈 0.001）. Propranolol appeared to have a superior action and was effective in 74 out of 83 （92%） patients （P 〈 0.0001）. CONCLUSION： There is a significant lag time between the onset of clinical symptoms and the final diagnosis of CVS in our area. In patients with typical clinical presentations of CVS, who are examined by an experienced physician, invasive workup is not necessary. Propranolol appears more effective than arnitriptyline for prophylactic use in children with CVS.

Risk factors of gastroesophageal reflux disease in Shiraz,southern Iran

AIM: To determine the prevalence and symptoms of gastroesophageal reflux disease (GERD) in a healthy general population in relation to demographic,lifestyle and health-seeking behaviors in Shiraz,southern Iran. METHODS: A total of 1978 subjects aged > 35 years who referred to Gastroenterohepatology Research Center and who completed a questionnaire consisting of 27 questions for GERD in relation to demographic,lifestyle and health-seeking behaviors were included in this study for a period of five months. The validity and reliability of the questionnaire were determined. RESULTS: The prevalence of GERD was 15.4%,which was higher in females (17.3%),in rural areas (19.8%),and in illiterate subjects (21.5%) and those with a mean age of 50.25 years. The prevalence was significantly lower in subjects having fried food (14.8%),and fruit and vegetables (14.6%). More symptoms were noticed in subjects consuming pickles (22.1%),taking aspirin (21%) and in subjects with psychological distresses (27.2%) and headaches (22%). The correlation was statistically significant between GERD and halitosis (18.3%),dyspepsia (30.6%),anxiety (19.5%),nightmares (23.9%) and restlessness (18.5%). Their health seeking behavior showed that there was a significant restriction of diet (20%),consumption of herbal medicine (19%),using over-the-counter drugs (29.9%) and consulting with physicians (24.8%). Presence of GERD symptoms was also significantly related to a previous family history of the disease (22.3%).CONCLUSION: GERD is more common in females,rural and illiterate subjects and correlated with consumption of pickles,occurrence of headache,psychological distress,dyspepsia,halitosis,anxiety,nightmare and restlessness,and a family history of GERD and aspirin intake,but the correlation was negative with consumption of fat and fiber intake.

Oral manifestation in inflammatory bowel disease:A review

Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis, not only affect the intestinal tract but also have an extraintestinal involvement within the oral cavity. These oral manifestations may assist in the diagnosis and the monitoring of disease activity, whilst ignoring them may lead to an inaccurate diagnosis and useless and expensive workups. Indurated tag-like lesions, cobblestoning, and mucogingivitis are the most common specific oral findings encountered in CD cases. Aphthous stomatitis and pyostomatitis vegetans are among non-specific oral manifestations of IBD. In differential diagnosis, side effects of drugs, infections, nutritional deficiencies, and other inflammatory conditions should also be considered. Treatment usually involves managing the underlying intestinal disease. In severe cases with local symptoms, topical and/or systemic steroids and immunosuppressive drugs might be used.

Solitary rectal ulcer syndrome in children:A literature review

Solitary rectal ulcer syndrome(SRUS) is a benign and chronic disorder well known in young adults and less in children.It is often related to prolonged excessive straining or abnormal defecation and clinically presents as rectal bleeding,copious mucus discharge,feeling of incomplete defecation,and rarely rectal prolapse.SRUS is diagnosed based on clinical symptoms and endoscopic and histological findings.The current treatments are suboptimal,and despite correct diagnosis,outcomes can be unsatisfactory.Some treatment protocols for SRUS include conservative management such as family reassurance,regulation of toilet habits,avoidance of straining,encouragement of a high-fiber diet,topical treatments with salicylate,sulfasalazine,steroids and sucralfate,and surgery.In children,SRUS is relatively uncommon but troublesome and easily misdiagnosed with other common diseases,however,it is being reported more than in the past.This condition in children is benign;however,morbidity is an important problem as reflected by persistence of symptoms,especially rectal bleeding.In this review,we discuss current diagnosis and treatment for SRUS.

COVID-19 infection and liver injury:Clinical features,biomarkers,potential mechanisms,treatment,and management challenges

It is hypothesized that liver impairment caused by coronavirus disease 2019(COVID-19)infection might play a central role in severe clinical presentations.Liver injury is closely associated with severe disease and,even with antiviral drugs,have a poor prognosis in COVID-19 patients.In addition to the common hepatobiliary disorders caused by COVID-19,patients with pre-existing liver diseases demand special considerations during the current pandemic.Thus,it is vital that upon clinical presentation,patients with concurrent pre-existing liver disease associated with metabolic dysfunction and COVID-19 be managed properly to prevent liver failure.Careful monitoring and early detection of liver damage through biomarkers after hospitalization for COVID-19 is underscored in all cases,particularly in those with pre-existing metabolic liver injury.The purpose of this study was to determine most recent evidence regarding causality,potential risk factors,and challenges,therapeutic options,and management of COVID-19 infection in vulnerable patients with pre-existing liver injury.This review aims to highlight the current frontier of COVID-19 infection and liver injury and the direction of liver injury in these patients.

Review on immunosuppression in liver transplantation

The optimal level of immunosuppression in solid organ transplantation,in particular for the liver,is a delicate balance between the benefit of preventing rejection and the adverse side effects of immunosuppression. There is uncertainty about when this level is achieved in any individual recipient. Immunosuppression regimens vary between individual centers and changes with time asnew agents and data are available. Presently concerns about the adverse side effects of calcineurin inhibitor,the main class of immunosuppressive agents used in liver transplantation(LT),has led to consideration of the use of antibody induction therapies for patients at higher risk of developing adverse side effects. The longevity of the transplanted organ is potentially improved by better management of rejection episodes and special consideration for tailoring of immunosuppression to the individual with viral hepatitis C,hepatocellular carcinoma or pregnancy. This review provides an overview of the current strategies for post LT immunosuppression and discusses modifications to consider for special patient populations.

Antimicrobial susceptibility of Helicobacter pylori strains isolated from patients in Shiraz, Southern Iran

AIM: To improve our understanding of Iranian regional variation in Helicobacter pylori (H. pylori ) antibiotic resistance rates to find the best antibiotic therapy for eradication of H. pylori infections.METHODS: A total of 266 patients undergoing endoscopy in Shiraz, Southern Iran, were included in this study. H. pylori strains were isolated from antral biopsies by culture and confirmed by the rapid urease-test and gram staining. Antibiotic susceptibility of H. pylori isolates was determined by E-test.RESULTS: A total of 121 H. pylori strains were isolated, 50 from male and 71 from female patients. Data showed that 44% (n = 53), 20% (n = 24), 5% (n = 6), and 3% (n = 4) of all strains were resistant to the antibiotics metronidazole, amoxicillin, clarithromycin, and tetracycline, respectively. When the antibiotics were considered together we found 11 sensitivity patterns for the strains. Resistance to metronidazole was significantly higher in female than in male patients (P < 0.05). In about 71% of the metronidazole-resistant isolates, the minimum inhibitory concentrations (MICs) exceeded 256 μg/mL.CONCLUSION: We found a moderate rate of primary resistance to metronidazole. However, a high MIC (> 256 mg/L) which was found in 71% of the isolates is considerable. In the case of amoxicillin, an increased resistance rate of 20% is worrying. Resistance to clarithromycin and tetracycline is also emerging among the H. pylori strains in our region.

Prevalence and risk factors of gastroesophageal reflux disease in Qashqai migrating nomads, southern Iran

AIM： To investigate the prevalence and risk factors of gastroesophageal reflux disease （GERD） symptoms in Qashqai migrating nomads with a different life style in Fars province, southern Iran. METHODS： In summer 2006, 748 Qashqai migrating nomads aged 25 years or more were enrolled using a multiple-stage stratified cluster random sampling method. A questionnaire consisting of demographic characteristics, lifestyle and GERD symptoms （heartburn, regurgitation, chest pain, dysphagia, hoarseness and cough） as completed for each subject. RESULTS： The questionnaire was completed in 717 subjects. The prevalence rate of GERD, defined as reflux occurring at least one time per week in the preceding year, was 33% （237 subjects）. The prevalence was higher in older individuals （36.0% vs 28.9%, P 〈 0.05） and in those with other gastrointestinal complaints （51.0% vs 27.8%, P 〈 0.001）, but not different in obese and non-obese subjects. It was also higher in those consuming fruits and vegetables more than once a week （36.2% vs 17.3%, P 〈 0.001）. GERD had a positive correlation with smoking （42.1% vs 27.8%, P 〈 0.001）, but a negative relation with non-alcoholic beverages. The association between GERD and non-steroidal antiinflammatory drugs （NSAIDs） consumption was also significant （40.2% vs 25.4%, P 〈 0.001）. CONCLUSION： The prevalence of GERD （33%） is very high in Qashqai migrating nomads which may be due to a lower socioeconomic and educational level of these people and difference in the life style. Older age, frequent consumption of fruits and vegetables, smoking and NSAIDs are risk factors for GERD in this population.

Cholangiocarcinoma and liver transplantation:What we know so far?

Cholangiocarcinoma(CCA)is a type of cancer with increasing prevalence around the world that originates from cholangiocytes,the epithelial cells of the bile duct.The tumor begins insidiously and is distinguished by high grade neoplasm,poor outcome,and high risk for recurrence.Liver transplantation has become broadly accepted as a treatment option for CCA.Liver transplantation is expected to play a crucial role as palliative and curative therapy for unresectable hilar CCA and intrahepatic CCA.The purpose of this study was to determine which cases with CCA should be subjected to liver transplantation instead of resection,although reported post-transplant recurrence rate averages approximately 20%.This review also aims to highlight the molecular current frontiers of CCA and directions of liver transplantation for CCA.

Advances in liver transplantation allocation systems

With the growing number of patients in need of liver transplantation, there is a need for adopting new and modifying existing allocation policies that prioritize patients for liver transplantation. Policy should ensure fair allocation that is reproducible and strongly predictive of best pre and post transplant outcomes while taking into account the natural history of the potential recipients liver disease and its complications. There is wide acceptance for allocation policies based on urgency in which the sickest patients on the waiting list with the highest risk of mortality receive priority. Model for end-stage liver disease and Child-Turcotte-Pugh scoring system, the two most universally applicable systems are used in urgencybased prioritization. However, other factors must be considered to achieve optimal allocation. Factors affecting pre-transplant patient survival and the quality of the donor organ also affect outcome. The optimal system should have allocation prioritization that accounts for both urgency and transplant outcome. We reviewed past and current liver allocation systems with the aim of generating further discussion about improvement of current policies.

Effects of anestrus dog serum on superovulation in rats and mice

Objective:To study the effects of anestrus dog serum in rodents (contains high amount of FSH) compared with two common superovulatory programs.Methods: Rats (n=30) at diestrus phase were evenly divided into pregnant mare serum gonadotrophins (PMSG) group (administrated with 30 IU PMSG, and 48 h later following by 25 IU hCG), recombinant follicle stimulating hormone (rFSH) group (reducing dose every 12 h from 5 to 1 IU, then following by 25 IU hCG) and anestrus dog serum group (reducing dose every 12 h from 0.6 to 0.1 mL, then following by 25 IU of hCG). Mice (n=30) were also evenly divided into PMSG group (5 IU PMSG used at 13 pm, and 48 h later following by 5 IU of hCG), rFSH group (from 13 pm, reducing dose every 12 h from 2.5 to 0.5 IU, then following by 5 IU hCG) and anestrous dog serum group (from 13 pm, reducing dose every 12 h from 0.100 to 0.025 mL, then following by 5 IU hCG). Mice and rats placed with males for 24 h after last injection. Histology samples of ovaries were prepared and the numbers of corpus lutea were counted on day 14 after mating. Results: In mice, the differences among mean number of corpus lutea in all groups (P=0.01) and between FSH and dog serum group were significant (P=0.0007). But no significant differences were found between the mean number of corpus lutea in dog serum and PMSG, or between FSH and PMSG groups. In rats, mean number of corpus lutea were significant differences among three groups (P=0.01), and between PMSG and dog serum groups (P=0.02). Conclusions: Superovulatory response in anestrus dog serum group is similar to PMSG group in mice, which is relatively similar to FSH in rats.

Solitary rectal ulcer syndrome:Is it really a rare condition in children?

AIM:To evaluate the clinicopathologic characteristics of the children with solitary rectal ulcer.METHODS:Fifty-five children with a confirmed diagnosis of solitary rectal ulcer were studied in a period of11 years from March 2003 to March 2014.All data were collected from the patients,their parents and medical records in the hospital.RESULTS:From 55 studied patients,41 were male(74.5%) and 14 female(25.5%).The mean age of the patients was 10.4 ± 3.7 years and the average time period from the beginning of symptoms to diagnosis of solitary rectal ulcer was 15.5 ± 11.2 mo.The most common clinical symptoms in our patients were rectal bleeding(n=54,98.2%) and straining during defecation or forceful defecation(n = 50,90.9%).Other symptoms were as follows respectively:Sense of incomplete evacuation(n = 34,61.8%),mucorrhea(n=29,52.7%),constipation(n=14,25.4%),tenesmus and cramping(n =10,18.2%),diarrhea(n= 9,16.4%),and rectal pain(n= 5,9.1%).The colonoscopic examination revealed 67.3%ulcer,12.7%polypoid lesions,10.9%erythema,7.3%both polypoid lesions and ulcer,and 1.8%normal.Most of the lesions were in the rectosigmoid area at a distance of 4-6 cm from the anal margin.Finally,69.8%of the patients recovered successfully with conservative,medical and surgical management.CONCLUSION:The study revealed that solitary rectal ulcer is not so uncommon despite what was seen in previous studies.As the most common symptom was rectal bleeding,clinicians and pathologists should be familiar with this disorder and common symptoms in order to prevent its complications with early diagnosis.