Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency-related cholestasis.

BACKGROUND AND AIMS: The study aimed to describe the clinical course and outcomes, and analyze the genotype-phenotype correlation in patients with tight junction protein 2 (TJP2) deficiency. APPROACH AND RESULTS: Data from all children with chronic cholestasis and either homozygous or compound heterozygous mutations in TJP2 were extracted and analyzed. The patients were categorized into 3 genotypes: TJP2-A (missense mutations on both alleles), TJP2-B (missense mutation on one allele and a predicted protein-truncating mutation [PPTM] on the other), and TJP2-C (PPTMs on both alleles). A total of 278 cases of genetic intrahepatic cholestasis were studied, with TJP2 deficiency accounting for 44 cases (15.8%). Of these, 29 were homozygous and 15 were compound heterozygous variants of TJP2 . TJP2-A genotype was identified in 21 (47.7%), TJP2-B in 7 cases (15.9%), and TJP2-C in 16 cases (36.4%), respectively. Patients with the TJP2-C genotype were more likely to experience early infantile cholestasis (87.5% vs. 53.5%, p =0.033), less likely to clear jaundice (12.5% vs. 52.2%, p =0.037), more likely to develop ascites, and had higher serum bile acids. Patients with the TJP2-C genotype were more likely to die or require liver transplantation (native liver survival: 12.5% vs. 78.6%, p <0.001), with a median age at death/liver transplantation of 2.5 years. Cox regression analysis revealed that TJP2-C mutations ( p =0.003) and failure to resolve jaundice ( p =0.049) were independent predictors of poor outcomes. CONCLUSIONS: Patients with the TJP2-C genotype carrying PPTMs in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely liver transplantation.

Techniques and Outcomes of Transjugular Intrahepatic Portosystemic Shunting in Infants with Budd-Chiari Syndrome.

PURPOSE: To describe the technical aspects, feasibility, and outcomes in children with Budd-Chiari syndrome (BCS) undergoing transjugular intrahepatic portosystemic shunt (TIPS) creation during infancy. MATERIALS AND METHODS: A retrospective review of infants with BCS undergoing TIPS creation between January 2012 and December 2018 was performed. Eight infants (5 males) underwent TIPS creation (7 for refractory ascites and 1 for refractory variceal bleeding) during the study period. The median age at TIPS creation was 10.5 months (range, 8-16 months). The median elapsed time between presentation and TIPS creation was 6.5 months (range, 0-13 months). The median weight and median pediatric end-stage liver disease score of the infants at the time of TIPS creation were 6.7 kg (range, 5.4-10 kg) and 13 kg (range, 8-18 kg), respectively. RESULTS: TIPS creation was successful in all patients. There were no immediate postprocedural complications. An 18-gauge hollow needle was manually curved, through which a 21-gauge Chiba needle was inserted to access the portal vein. All patients received 1 or 2 overlapping bare metal stents. One patient was lost to follow-up after the procedure. The median follow-up duration was 32 months (range, 14-51 months). Four of 7 infants needed reintervention. Two children died during the follow-up period. Two children successfully underwent living donor liver transplant, whereas the remaining 3 children were asymptomatic at the follow-up. CONCLUSIONS: TIPS creation was found to be safe and efficacious in improving portal hypertension and growth in these children, although, with a higher rate of reinterventions, possibly due to the use of small, bare metal stents.

Positional outflow obstruction as a cause of early refractory ascites post-pediatric living donor liver transplantation.

Refractory ascites post-liver transplantation can be a challenging problem. Causes of refractory ascites include venous outflow anastomotic stenosis, vessel kinking by the regenerating liver, pre-existing graft disease, and positional outflow obstruction. We present a case report of a child presenting with high drain output and refractory ascites post-LDLT secondary to a positional kinking. Repeating the Doppler studies with patients both supine and sitting may be helpful.

Preoperative successful thrombectomy and thrombolysis of acute extensive splanchnic venous system and TIPSS thrombosis in a child with Budd-Chiari syndrome-Creating a window to enable living donor liver transplantation.

Preoperative extensive PV thrombosis can pose a technical challenge during liver transplantation surgery. Several strategies adopted to mitigate this problem include creation of a superior mesenteric vein-PV jump graft, use of a polytetrafluoroethylene graft, renoportal anastomosis, or cavoportal hemitransposition. Extensive and diffuse thrombosis of the splanchnic venous system may even necessitate multivisceral transplantation. We describe the case of a pediatric patient with Budd-Chiari syndrome and decompensated cirrhosis, who developed extensive thrombosis of the porto-spleno-mesenteric venous system prior to liver transplantation. We used a combination technique of thrombus aspiration by a novel trans-TIPPS approach followed by thrombolysis. Complete preoperative resolution of the extensive thrombosis was achieved. This allowed the creation of a brief window to enable planned LDLT. In prudently selected patients, performing an early mechanical and chemical thrombolysis of an extensive acute splanchnic venous thrombosis can thus help expedite a planned LDLT.

Therapeutic coil embolization of dominant shunt in hepatopulmonary syndrome enhances post-liver transplant respiratory recovery.

Coil embolization of the atypical enlarged pulmonary artery/arteriole with visible shunting may improve hypoxemia in patients with hepatopulmonary syndrome (HPS). When used selectively in cases with large shunts, either pre- or post-liver transplantation (LT), it can aid an early recovery and reduce morbidity. We present a case where a large intrapulmonary shunt was embolized preoperatively to improve hypoxemia associated with HPS and enhance post-operative recovery.

Presenting signs and patient co-variables in Gaucher disease: outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative.

BACKGROUND: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. AIM: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify 'at-risk' patients who may benefit from diagnostic testing. METHODS: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. RESULTS: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. CONCLUSION: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.

Prevalence of non A to E hepatitis in Mumbai, India.

INTRODUCTION: Acute viral hepatitis is a common problem in India. World wide data shows that 5 to 20 percent of this is caused by non A-E hepatitis. There is no data in India regarding non A-E hepatitis. We carried out this study to evaluate the epidemiology, clinical features, risk factors and outcome of non A-E hepatitis. MATERIAL AND METHODS: In this single centre study, we evaluated all patients admitted with features of acute viral hepatitis at our hospital between the period of February to July 2015. A detailed history about the epidemiology, risk factors and clinical features was done. Patients were evaluated with bilirubin, transaminases and prothrombin time. Each patient was investigated for IgM HAV, IgM HEV, HBsAg and Antibody against hepatitis C. Patients turning out negative were investigated for presence of autoimmune hepatitis or Wilson's disease. All viral markers were repeated a week later to confirm non A-E status. RESULTS: A total 265 patients were included of which 41 (15.4%) patients were non A-E hepatitis. They had higher age (28.55 vs 34.99, p<0.05) but similar gender and sub urban location. Median SEC classification was A2 in hepatitis A/E group as compared to A3 in non A-E group. The duration of symptoms and clinical features between the two groups were similar with Anorexia, Malasie, Nausea/vomiting being most common. The risk factors between the two groups were similar. The bilirubin and transaminases were non significantly lower than hepatitis A/E patients while albumin levels were significantly lower. The outcomes of both groups were similar with no mortality or fulminant hepatitis. CONCLUSION: Non A-E hepatitis patients tends to be older, lower SEC class and had lower albumin levels as compared to hepatitis A/E.

Herb-induced Liver Injury-A Guide to Approach. Lessons from the Tinospora cordifolia (Giloy) Case Series Story.

Background: Tinospora cordifolia (TC) is being increasingly consumed in India for its health and suggested immune-enhancing benefits in preventing and countering COVID-19. We previously published our experience of hepatotoxicity with self-medication of TC in six individuals. Since herb-induced liver injury (HILI) has been described with Tinospora crispa (TCR) consumption, it was contested that our patients may have mistakenly self-medicated with TCR which is similar in appearance to TC. Methods: We collected the four plant samples and two commercial preparations that were consumed by our patients for further analysis. The six samples underwent high performance thin layer chromatography phytochemical analysis and DNA barcoding studies for the confirmation of the genus and species. The four plant part samples which included stems and leaves were also analysed by a botanist for the characteristic morphological and microscopic features. Results: Based on morphological, microscopic, phytochemical and DNA studies, the four plant part samples were identified as TC. The two commercial preparations could not be analysed on phytochemical analysis or DNA barcoding studies due to other ingredients that most likely interfered with the analysis. The herb consumed by our study subjects was confirmed to be Tinospora cordifolia. Conclusion: We have highlighted the key morphological and phytochemical differences between these two species. We propose an algorithmic approach to accurately identify the implicated herb in cases of HILI. Future studies on causality need to focus on the serological/histopathological identification of active herb/metabolites in human tissues.

Journey of Women in Gastroenterology in South Asian Countries: From Training to Leadership.

Women in gastroenterology are underrepresented all over the world and in South Asia, the numbers are even fewer. Women doctors in South Asia have their unique set of problems that they have to deal with. They are trained well and are keen to publish but are not considered good enough. They do not get the same opportunities as their male colleagues. There is more expectation from women doctors to look after their families and children. We can correct this discrepancy by giving more opportunities, arranging flexible training, deserving promotions, leadership roles, equal pay, and research mentors for women doctors in gastroenterology in South Asia, and educating our society to treat women doctors, at par with men. How to cite this article: Kedia D, Kamani L, Begum MR, et al. Journey of Women in Gastroenterology in South Asian Countries: From Training to Leadership. Euroasian J Hepato-Gastroenterol 2023;13(1):41-43.

Genomic Variations in ATP7B Gene in Indian Patients with Wilson Disease.

OBJECTIVE: To report genotype data of the patients with Wilson disease (WD) hailing from across several parts of India to add to the available spectrum of causative variants in ATP7B gene (ATPase copper transporting beta polypeptide gene) and associated phenotypes in the Indian population. METHODS: The entire ATP7B gene was sequenced in 58 patients with WD and additional testing was also done by MLPA to look for intragenic deletions duplications and exome sequencing to rule out genetic variations with similar phenotypic overlap. RESULTS: Of all patients, 37 patients had a total of 33 distinct pathogenic variations, including 29 in the exonic regions and 4 at intronic splice sites. Of the variations identified, six were novel. The underlying genomic variations could be identified in nearly two-thirds of the patients by sequencing the entire gene. CONCLUSIONS: This study reports the genotype-phenotype data to add to the available spectrum of causative variants in ATP7B gene. The inability to detect a pathogenic variation in some patients and the existence of phenotypic variations in individuals with the same variation suggest that additional factors or genes may play a role in causation of the disease. Further, a marked genetic heterogeneity was found in the study patients, indicating ethnic diversity of the Indian population.

Transjugular Intrahepatic Portosystemic Shunt for Refractory Ascites in Gaucher Disease.

Gaucher disease is rare, inherited lysosomal storage disorder that leads to the excessive accumulation of certain lipids, especially within the bone marrow, liver, and spleen. We present a case of a 30-year-old man with Gaucher disease who underwent a splenectomy at the age of eight for severe cytopenia. His subsequent history was notable for recurrent avascular osteonecrosis and his liver disease progressed to portal hypertension, variceal bleeding, and refractory ascites. Upon evaluation of his candidacy for liver transplantation, he was sarcopenic, with tense, high serum-ascites albumin gradient (SAAG) ascites and florid venous collaterals on his anterior abdominal wall. His hepatic venous pressure gradient (HVPG) was 22 mmHg. He underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure, following which his HVPG was reduced to 2 mmHg and striking reversal of ascites as well as improvement of his nutritional state. TIPS was not complicated by hepatic encephalopathy. The successful outcome of TIPS in Gaucher disease with advanced hepatic disease underscores its utility as a bridge to liver transplantation with continuing enzyme replacement therapy.

Decompensation of Cirrhosis: An Unusual Cause.

We describe a case of a 69-year-old woman, a known case of compensated Hepatitis C cirrhosis, presenting with recurrent urinary tract infection (UTI) secondary to Salmonella Paratyphi B. She had recently tested positive for Salmonella Paratyphi bacteremia associated with UTI, managed with antibiotics. Two weeks later, she presented with fever and burning micturition with signs of abdominal distension and pedal edema suggestive of decompensation of cirrhosis. She had repeat positive urine cultures for Salmonella and was managed with broad-spectrum antibiotics, surgical stone removal, and supportive measures leading to resolution of symptoms and ascites. She was administered a prolonged antibiotic course on discharge for chronic shedding of Salmonella in the urine. UTIs are a common cause of decompensation in immunosuppressed states like liver cirrhosis, and rare infections like salmonella need to be identified and managed appropriately with sensitive antibiotics and the right duration of treatment.

Cutaneous mucormycosis: an unusual cause of decompensation in a patient with ethanol-related cirrhosis with COVID-19 exposure.

We describe a case of cutaneous mucormycosis in a middle-aged man with ethanol-related chronic liver disease. He presented with symptoms of fever, breathlessness for 10 days and altered mental status for 2 days. On admission, he was in septic shock and had acute respiratory distress syndrome (ARDS). He was noted to have ruptured blisters in his left axilla. Although he repeatedly had negative COVID-19 Reverse Transcription-PCR results, he had positive IgG antibodies for COVID-19. He was managed with broad-spectrum antibiotics, steroids, vasopressors and ventilation for ARDS. Over the course of his hospitalisation, the axillary lesion progressed to a necrotising ulcer with deep tissue invasion. Debridement and culture of the axillary ulcer revealed mucor species, and he was started on amphotericin and posaconazole for mucormycosis. Unfortunately, he continued to deteriorate despite aggressive management and died after a prolonged hospital stay of 40 days.

Migratory Panniculitis with Autoimmune Cholangitis and Pancreatitis (IgG4- Related Disease): A Rare Presentation.

A 30-year-old woman presented with an acute-onset high-grade fever (103°F), multiple episodes of throbbing abdominal pain in the right quadrant, and pustular red lesions on the left leg. The radiological findings were suggestive of autoimmune cholangitis and pancreatitis. The skin lesions recurred on different portions of the body, and histopathological findings showed lobular and septal lymphohistiocytic infiltrate without vasculitis. The epidermis had focal ulcerations, and the dermis showed the presence of subcutaneous fat and an infiltrate of lymphocytes, histiocytes, and neutrophils (described as lobular and septal panniculitis without vasculitis). Based on the clinical and histopathological features, a diagnosis of migratory panniculitis was made. The patient was managed with analgesics, antibiotics, and a long course of steroids; the patient responded well to these medications. To the best of our knowledge, this is one of the first case reports of migratory panniculitis associated with IgG4-related disease. Patients with migratory panniculitis should be investigated for the presence of IgG4-related autoimmune disease. However, steroids remain the drug of choice when these conditions occur together.

Quality of Life of Patients with Wilson's Disease and Their Families.

Objectives: Wilson's disease (WD) is a chronic disease caused by altered copper metabolism requiring lifelong therapy. Its long-term and debilitating nature has the potential to affect the quality of life (Qol) of patients as well as their families. Our study aims to assess this impact of the disease on patients and their families. Methods: We conducted a prospective, observational study over 2 years on 73 patients and 73 age-matched controls with 33 children and 40 adults in each group. The Qol of cases and controls was assessed using the PedsQL Generic Core Scales and World Health Organisation Quality of Life BREF (WHOQOL-BREF) for children and adults, respectively. Families of child and adult patients were interviewed using PedsQL Family Impact Module and Family Attitude Scale (FAS), respectively. The data were statistically analyzed. Results: Mean age of the cases was 22.04 ± 11.8 years. Qol scores for both adults and children were worse in cases with neuropsychiatric disease than in those with hepatic disease. For children, the mean scores of overall psychological functioning were lower in cases compared with controls (P = 0.0001). Qol of parents of the patients was significantly lower than those of parents of the controls as was the family functioning (P = 0.0001 and P = 0.016). Family Attitude Scale scores for adults did not differ significantly between cases and controls. Conclusion: The Qol of patients with neuro-WD is worse than that of hepatic disease. The disease impacts the psychological functioning of the children and the Qol of their families, which improves with the duration of the disease. What is known: WD is a long-term, debilitating disease. Patients have to take lifelong treatment with frequent medical visits and often multiple hospitalizations. What is new: WD affects the Qol of not only the patients but also their families. Qol of patients with neuro-WD is worse than that of patients with hepatic disease.

Gender Differences in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) has currently emerged as the most common liver disorder in both developed and developing countries. It has been observed that NAFLD exhibits sexual dimorphism, and there is limited understanding on the sex differences in adults with NAFLD. Nonalcoholic fatty liver disease shows marked differences in prevalence and severity with regards to gender. There are considerable biological disparities between males and females attributed to differences in the chromosomal makeup and sex hormone levels, distinct from the gender differences resulting from the sociocultural influences that lead to differences in lifestyle, which have a significant impact on the pathogenesis of this complex disorder. A multitude of factors contributes to the gender disparities seen and need to be researched in-depth to better understand the mechanisms behind them and the therapeutic measures that can be taken. In this article, we will review the gender disparities seen in NAFLD, as well as recent studies highlighting certain gender-specific factors contributing to its varying prevalence and severity. How to cite this article: Nagral A, Bangar M, Menezes S, et al. Gender Differences in Nonalcoholic Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2022;12(Suppl 1):S19-S25.