Procoagulant phenotype of virus-infected pericytes is associated with portal thrombosis and intrapulmonary vascular dilations in fatal COVID-19.

BACKGROUND & AIMS: The underlying mechanisms and clinical impact of portal microthrombosis in severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesised that portal microthrombosis is associated with IPVD and fatal respiratory failure in COVID-19. METHODS: Ninety-three patients who died from COVID-19 were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-ß) markers, tissue factor (TF), viral spike protein and nucleoprotein (SP, NP), fibrinogen, and platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy. Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells was assessed upon vWF treatment. RESULTS: IPVD was present in 16/66 patients with COVID-19, with available liver and lung histology, and was associated with younger age (62 vs. 78 years-old), longer illness (25 vs. 14 days), worsening hypoxemia (PaO2/FiO2 from 209 to 89), and an increased requirement for ventilatory support (63% vs. 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, was confirmed by chest CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-ß+/SP+/NP+ pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA+ area, whereas infected SP+/NP+ pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. In vitro SARS-CoV-2 infection of pericytes upregulated TF and induced endothelial cells to overexpress vWF, which expanded human pulmonary microvascular endothelial cell tubules. CONCLUSIONS: SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19. IMPACT AND IMPLICATIONS: Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a procoagulant phenotype of portal venule pericytes, which is induced by SARS-CoV-2 infection of pericytes. Both observations provide a model that may apply, at least in part, to other vascular disorders of the liver, featuring obliterative portal venopathy, similarly characterised at the clinical level by development of hypoxemia and at the histological level by phlebosclerosis and reduced calibre of the portal vein branches in the absence of cirrhosis. Moreover, our findings shed light on an overlooked player in the pathophysiology of thrombosis, i.e. pericytes, which may present a novel therapeutic target.

A Narrative Review on Non-Cirrohotic Portal Hypertension: Not All Portal Hypertensions Mean Cirrhosis.

Non-cirrhotic portal hypertension (NCPH), also known as idiopathic non-cirrhotic portal hypertension (INCPH) and porto-sinusoidal vascular disorder (PSVD), is a rare disease characterized by intrahepatic portal hypertension (IPH) in the absence of cirrhosis. The precise etiopathogenesis of IPH is an area of ongoing research. NCPH diagnosis is challenging, as there are no specific tests available to confirm the disease, and a high-quality liver biopsy, detailed clinical information, and an expert pathologist are necessary for diagnosis. Currently, the treatment of NCPH relies on the prevention of complications related to portal hypertension, following current guidelines of cirrhotic portal hypertension. No treatment has been studied that aimed to modify the natural history of the disease; however, transjugular intrahepatic porto-systemic shunt (TIPS) placement, shunt and liver transplantation are considerable symptomatic options. In this review, we discuss the heterogeneity of NCPH as well as its etiopathogenesis, clinical presentation and management issues. Starting from the assumption that portal hypertension does not always mean cirrhosis, cooperative studies are probably needed to clarify the issues of etiology and the possible genetic background of this rare disease. This knowledge might lead to better treatment and perhaps better prevention.

Noninvasive differentiation of porto-sinusoidal vascular disorder from cirrhosis: a systematic review.

BACKGROUND: Porto-sinusoidal vascular disorder (PSVD) is one of the common causes of portal hypertension and has overlapping features with early cirrhosis. The differentiation of PSVD from cirrhosis requires a liver biopsy, which is invasive and has potential complications. This systematic review aimed at summarizing the current evidence on the performance of noninvasive modalities for differentiating PSVD from cirrhosis. METHODS: A comprehensive search of electronic databases of MEDLINE, Embase, and Scopus was conducted from 2000 to October 2022 for the studies comparing the elastographic and radiological features of PSVD and cirrhosis, using liver biopsy as the gold standard. RESULTS: A total of 12 studies were included in the systematic review. Transient elastography (TE) as a modality was studied in five studies, MR elastography (MRE) in two, contrast CT in two, Contrast CT and MRI in two, and ARFI in only one. Both TE and MRE showed a significantly lower liver stiffness measurement and a higher splenic stiffness measurement with a higher SSM/LSM ratio with PSVD, compared to cirrhosis. Among the radiological features, focal nodular hyperplasia-like lesions, portal vein abnormalities (intrahepatic and extrahepatic), and a larger spleen size favored a diagnosis of PSVD. In contrast, surface nodularity and atrophy of segment IV with a segment I hypertrophy favored a diagnosis of cirrhosis. CONCLUSION: Elastography and cross-sectional imaging can help differentiate PSVD from early cirrhosis with good accuracy. Further studies are required to assess the diagnostic role of a combination of both modalities.

Indian National Association for Study of the Liver (INASL) Guidance Paper on Nomenclature, Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease (NAFLD).

Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease globally and in India. The already high burden of NAFLD in India is expected to further increase in the future in parallel with the ongoing epidemics of obesity and type 2 diabetes mellitus. Given the high prevalence of NAFLD in the community, it is crucial to identify those at risk of progressive liver disease to streamline referral and guide proper management. Existing guidelines on NAFLD by various international societies fail to capture the entire landscape of NAFLD in India and are often difficult to incorporate in clinical practice due to fundamental differences in sociocultural aspects and health infrastructure available in India. A lot of progress has been made in the field of NAFLD in the 7 years since the initial position paper by the Indian National Association for the Study of Liver on NAFLD in 2015. Further, the ongoing debate on the nomenclature of NAFLD is creating undue confusion among clinical practitioners. The ensuing comprehensive review provides consensus-based, guidance statements on the nomenclature, diagnosis, and treatment of NAFLD that are practically implementable in the Indian setting.

Maternal and perinatal outcome in pregnancies complicated with portal hypertension: a systematic review and meta-analysis.

BACKGROUND: Portal hypertension is secondary to either cirrhotic or non-cirrhotic causes, and complicating pregnancy poses a challenge to the treating team. A systematic review was performed to determine maternal and perinatal outcomes in women with portal hypertension. Outcomes were compared among those with cirrhotic (CPH) with non-cirrhotic portal hypertension (NCPH) as well as non-cirrhotic portal fibrosis (NCPF) with extra-hepatic portal vein obstruction (EHPVO). METHODS: Medline and EMBASE databases were searched for studies reporting outcomes among pregnant women with portal hypertension. Reference lists from relevant papers and reviews were hand-searched for appropriate citations. Data were extracted to describe maternal complications, obstetric and neonatal outcomes. A random-effects model was used to derive pooled estimates of various outcomes, and final estimates were reported as percentages with a 95% confidence interval (CI). Cumulative, sequential and sensitivity analysis was studied to assess the temporal trends of outcomes over the period. RESULTS: Information on 895 pregnancies among 581 patients with portal hypertension was included from 26 studies. Portal hypertension was diagnosed during pregnancy in 10% (95% CI 4-24%). There were 22 maternal deaths (0%, 95% CI 0-1%), mostly following complications from variceal bleeding or hepatic decompensation. Variceal bleeding complicated in 14% (95% CI 9-20%), and endoscopic interventions were performed in 12% (95% CI 8-17%) during pregnancy. Decompensation of liver function occurred in 7% (95% CI 3-12%). Thrombocytopenia was the most common complication (41%, 95% CI 23-60%). Miscarriages occurred in 14% (95% CI 8-20%), preterm birth in 27% (95% CI 19-37%), and low birth weights in 22% (95% CI 15-30%). Risk of postpartum hemorrhage was higher (RR 5.09, 95% CI 1.84-14.12), and variceal bleeding was lower (RR 0.51, 95% CI 0.30-0.86) among those with CPH compared to NCPH. Risk of various outcomes was comparable between NCPF and EHPVO. CONCLUSION: One in ten pregnancies complicated with portal hypertension is diagnosed during pregnancy, and thrombocytopenia is the most common complication. Hepatic decompensation and variceal bleeding remain the most common cause of maternal deaths, with reduced rates of bleeding and its complications reported following the introduction of endoscopic procedures during pregnancy. CPH increases the risk of postpartum hemorrhage, whereas variceal bleeding is higher among NCPH.

Predictors of in-hospital Outcomes in Patients With Cirrhosis and Coronavirus Disease-2019.

Background: Coronavirus disease-2019 (COVID-19) cases continue to increase globally. Poor outcomes in patients with COVID-19 and cirrhosis have been reported; predictors of outcome are unclear. The existing data is from the early part of the pandemic when variants of concern (VOC) were not reported. Aims: We aimed to assess the outcomes and predictors in patients with cirrhosis and COVID-19. We also compared the differences in outcomes between the first wave of pandemic and the second wave. Methods: In this retrospective analysis of a prospectively maintained database, data on consecutive cirrhosis patients (n = 221) admitted to the COVID-19 care facility of a tertiary care center in India were evaluated for presentation, the severity of liver disease, the severity of COVID-19, and outcomes. Results: The clinical presentation included: 18 (8.1%) patients had compensated cirrhosis, 139 (62.9%) acute decompensation (AD), and 64 (29.0%) had an acute-on-chronic liver failure (ACLF). Patients with ACLF had more severe COVID-19 infection than those with compensated cirrhosis and AD (54.7% vs. 16.5% and 33.3%, P < 0.001). The overall mortality was 90 (40.7%), the highest among ACLF (72.0%). On multivariate analysis, independent predictors of mortality were high leukocyte count, alkaline phosphatase, creatinine, child class, model for end-stage liver disease (MELD) score, and COVID-19 severity. The second wave had more cases of severe COVID-19 as compared to the first wave, with a similar MELD score and Child score. The overall mortality was similar between the two waves. Conclusion: Patients with COVID-19 and cirrhosis have high mortality (40%), particularly those with ACLF (72%). A higher leukocyte count, creatinine, alkaline phosphatase, Child class, and MELD score are predictors of mortality.

Pediatric non-cirrhotic portal hypertension: Endoscopic outcome and perspectives from developing nations.

Non-cirrhotic portal hypertension (NCPH) forms an important subset of portal hypertension in children. Variceal bleed and splenomegaly are their predominant presentation. Laboratory features show cytopenias (hypersplenism) and preserved hepatic synthetic functions. Repeated sessions of endoscopic variceal ligation or endoscopic sclerotherapy eradicate esophageal varices in almost all cases. After variceal eradication, there is an increased risk of other complications like secondary gastric varices, cholangiopathy, colopathy, growth failure, especially in extra-hepatic portal vein obstruction (EHPVO). Massive splenomegaly-related pain and early satiety cause poor quality of life (QoL). Meso-Rex bypass is the definitive therapy when the procedure is anatomically feasible in EHPVO. Other portosystemic shunt surgeries with splenectomy are indicated when patients present late and spleen-related issues predominate. Shunt surgeries prevent rebleed, improve growth and QoL. Non-cirrhotic portal fibrosis (NCPF) is a less common cause of portal hypertension in children in developing nations. Presentation in the second decade, massive splenomegaly and patent portal vein are discriminating features of NCPF. Shunt surgery is required in severe cases when endotherapy is insufficient for the varices. Congenital hepatic fibrosis (CHF) presents with firm palpable liver and splenomegaly. Ductal plate malformation forms the histological hallmark of CHF. CHF is commonly associated with Caroli's disease, renal cysts, and syndromes associated with neurological defects. Isolated CHF has a favourable prognosis requiring endotherapy. Liver transplantation is required when there is decompensation or recurrent cholangitis, especially in Caroli's syndrome. Combined liver-kidney transplantation is indicated when both liver and renal issues are present.

Histological analyses of trucut liver biopsies from patients with noncirrhotic portal fibrosis and extra-hepatic portal vein obstruction.

BACKGROUND: Both noncirrhotic portal fibrosis (NCPF) and extrahepatic portal venous obstruction (EHPVO) are important causes of noncirrhotic portal hypertension (PH) in the Asian region. In this study, we analyzed the histopathological changes of liver needle-core biopsies from patients with NCPF and EHPVO. PATIENTS AND METHODS: The patients were diagnosed as per the Asia Pacific Association for the Study of Liver (APASL) criteria. Minimum adequacy criteria for liver core biopsies were defined, and finally, 69 liver biopsies from patients with NCPF and 100 liver biopsies from patients with EHPVO were analyzed. All histological parameters were predefined, and three experienced pathologists analyzed the biopsies after reaching consensus. Institute ethics committee clearance was taken. RESULTS: Although some histological features were overlapping, phlebosclerosis of intra-hepatic branches of the portal vein (PV), periportal aberrant vascular channels, remnant portal tracts, and hepatic fibrosis beyond the portal tracts without the formation of complete hepatic nodules (P < 0.001 for all) were common histological characteristics of NCPF on core-needle liver biopsies; while maintained lobular architecture, nonspecific dilatation of PV branches, absence of intra-hepatic PV phlebosclerosis, aberrant vascular channels, and significant fibrosis were characteristics of EHPVO. CONCLUSIONS: Despite the considerable histological overlap between NCPF and EHPVO, careful histological evaluation, supplemented by clinical features, radiological and biochemical findings can help in making a conclusive diagnosis. Patients with NCPF and EHPVO with clinical jaundice show transaminitis, high serum alkaline phosphatase level, more variceal bleed, and histological evidences of nodular regenerative hyperplasia.

Celiac Disease and Portal Hypertension: A Causal Association or Just a Coincidence?

INTRODUCTION: Celiac disease (CD) has been linked to portal hypertension (PHT) of varied etiology, but the causality association has never been proved. We aim to study the prevalence of CD in patients of PHT of different etiology. METHODS: A prospective observational study was conducted from June 2017 to December 2018 involving all the cases of PHT of varied etiology. Consecutive patients of PHT with chronic liver disease (CLD) of defined etiology like ethanol, viral hepatitis (B or C), Budd-Chiari syndrome (BCS), autoimmune-related cirrhosis, and cryptogenic CLD (cCLD) (group A) and those with noncirrhotic PHT (NCPHT), which included noncirrhotic portal fibrosis (NCPF) and extrahepatic portal vein obstruction (EHPVO) (group B), were screened for CD by IgA anti-tTG antibody followed by duodenal biopsy in serology-positive patients. RESULTS: Out of a total of 464 patients, group A constituted 382 patients, CLD related to ethanol (155), cCLD (147), hepatitis B (42), hepatitis C (21), autoimmune (10), and BCS (7), whereas 82 patients were in group B with NCPF (64) and EHPVO (18). Total 29 patients were diagnosed with CD in both groups, 17 in group A (4.5%) and 12 in group B (14.6%). In group A, 13 patients with cCLD, two with HBV-related CLD, one with BCS, and one with autoimmune-related CLD were concomitantly diagnosed as CD. In group B, CD was diagnosed in 12 patients of NCPF (11) and EHPVO (1). Liver histology showed chronic hepatitis in two patients and was normal in three patients. CONCLUSION: CD is common in PHT of different etiology, especially in cCLD, NCPH and autoimmune hepatitis; however, the etiological basis for this association is still to be defined. The likelihood of CD is higher in liver disease than the general population, and these patients should be screened for CD.

Maternal-fetal outcome in pregnancies complicated with non-cirrhotic portal hypertension: experience from a Tertiary Centre in South India.

OBJECTIVE: To assess the maternal and perinatal outcomes of pregnant women with non-cirrhotic portal hypertension (NCPH). METHODS: This was an observational study done by retrieving the records of pregnant women with non-cirrhotic portal hypertension admitted to a tertiary hospital in South India, over a 9-year study period. Data regarding the clinical course, complications during pregnancy, labor, and delivery details were reviewed. We also compared the outcomes among women with non-cirrhotic portal fibrosis (NCPF) with extrahepatic portal vein obstruction (EHPVO). RESULTS: During the study period, portal hypertension was noted in 0.07%(n = 108) of the pregnancies and 74.1% of them had NCPH. The diagnosis was made for the first time in 54.7% of them when presented with pancytopenia or splenomegaly. Variceal bleeding complicated 25% of the pregnancies in women with NCPH pregnancies, with three among them having a massive bleed. Eighteen among them underwent endoscopy following bleeding; variceal banding procedure was performed in nine of them without any complications. Preterm birth was the most common (20.6%) obstetric complication. There was one maternal death from severe sepsis, acute kidney injury, and disseminated intravascular coagulation, following a massive variceal bleed. Obstetric outcomes and medical complications were similar in women with NCPF and EHPVO. Perinatal loss was comparable in both the groups (14.3% vs. 9.6%, p = 0.417) CONCLUSION: Multidisciplinary team approach, with optimal and timely intervention with intensive monitoring, can reduce the morbidity and help achieve an optimal maternal-perinatal outcome in pregnancies complicated with portal hypertension.

Splenectomy with endotherapy in non-cirrhotic portal fibrosis related portal hypertension: Can it be an alternative to proximal spleno-renal shunt?

BACKGROUNDS/AIMS: Proximal splenorenal shunt (PSRS) is usually done in symptomatic non-cirrhotic portal fibrosis (NCPF). The outcomes of splenectomy with endotherapy in non-bleeder NCPF patients has not been well studied. We here by aimed to study the post-surgical outcomes on short and long-term basis between PSRS and splenectomy among non-bleeder NCPF patients. METHODS: The consecutive non-bleeder NCPF patients whom underwent either splenectomy or PSRS from 2008 to 2016 were enrolled. The patients were followed up post-surgery clinically and biochemical investigations, Doppler ultrasound and upper gastrointestinal endoscopy were done as required. The peri-operative parameters compared were operative time, blood loss, hospital stay and morbidity. The long-term outcome measures compared were incidence of portal hypertension (PHTN) related bleed, change in grade of varices, shunt patency, shunt complications and thrombosis of spleno-portal axis. RESULTS: Among 40 patients with non-bleeder status, 24 underwent splenectomy and 16 underwent PSRS. The baseline characteristics including indication of surgery, biochemical investigations and grade of varices were comparable between PSRS and splenectomy. The peri-operative morbidity was not significantly different between two groups. The median follow up duration was 42 months (12-72 months), the decrement in grade of varices was significantly higher in PSRS group (p=0.03), symptomatic PHTN related UGIB was non-significant between PSRS and splenectomy (p=0.5). In PSRS group, 3 (18.3%) patients had shunt thrombosis (n=1) & encephalopathy (n=2) while in splenectomy group two patients developed thrombosis of splenoportal axis. CONCLUSIONS: Splenectomy with endotherapy is alternative to PSRS in non-bleeder NCPF patients with indications for surgery.

The histological assessment of liver fibrosis in grafts from extended criteria donors predicts the outcome after liver transplantation: A retrospective study.

BACKGROUND: The use of extended criteria donors (ECD) in liver transplantation is increasing due to the organ shortage. Histological evaluation of the liver graft in the context of procurement is an important tool for extending the donor pool without affecting the quality of the transplanted organs. Macrovesicular steatosis is widely accepted as predictor of early allograft dysfunction (EAD), while other features, such as portal fibrosis, are poorly studied. AIM: To identify morphological features, other than macrovesicular steatosis, that may affect recipients' outcome. METHODS: Between 2014 and 2016, 132 donors with extended criteria underwent pre-transplant liver biopsy during procurement. Histological variables of the graft, donors'/recipients' clinical data, EAD and patient/graft survival were registered. RESULTS: The recipients who received a graft with histological-proven portal fibrosis had a significant lower patient and graft survival in comparison to patients without fibrosis (P = 0.044 and P = 0.039, respectively). Donors' dyslipidemia was significantly associated with the occurrence of EAD (P = 0.021). When dyslipidemia was combined with histological liver fibrosis a 54.5% incidence of EAD was observed (P = 0.012). CONCLUSIONS: The histological assessment of liver fibrosis in pre-transplant biopsy of ECD grafts, together with donor's clinical data, provides important information on recipients' outcome.

Idiopathic noncirrhotic portal hypertension.

Cirrhosis is the most common cause of portal hypertension but there are many causes of noncirrhotic portal hypertension. Many of these etiologies may be diagnosed by liver biopsy. Idiopathic noncirrhotic portal hypertension is being increasingly diagnosed and has varied histopathological findings as well as overlapping definitions. Many of these histological changes can be subtle, thus making it a challenging diagnosis for the pathologist to make. This review summarizes the clinical aspects of idiopathic noncirrhotic portal hypertension and outlines the different definitions and histological features of the entity. In addition, pearls and pitfalls for the pathologist in making this diagnosis are included.

What makes non-cirrhotic portal hypertension a common disease in India? Analysis for environmental factors.

In India, an unexplained enteropathy is present in a majority of non-cirrhotic intrahepatic portal hypertension (NCIPH) patients. Small intestinal bacterial contamination and tropical enteropathy could trigger inflammatory stimuli and activate the endothelium in the portal venous system. Groundwater contaminated with arsenic is an environmental factor of epidemic proportions in large areas of India which has similar consequences. Von Willebrand factor (a sticky protein) expressed by activated endothelium may promote formation of platelet microthrombi and occlusion of intrahepatic portal vein branches leading to NCIPH. Environmental factors linked to suboptimal hygiene and sanitation, which enter through the gastrointestinal (GI) tract, predispose to platelet plugging onto activated endothelium in portal microcirculation. Thus, NCIPH, an example of poverty linked thrombophilia, is a disease mainly affecting the lower socio-economic strata of Indian population. Public health measures to improve sanitation, provide clean drinking water and eliminate arsenic contamination of drinking water are urgently needed. Till such time as these environmental factors are addressed, NCIPH is likely to remain 'an Indian disease'.

Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features.

Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent.

Spectrum of histopathological changes in patients with non-cirrhotic portal fibrosis.

BACKGROUND AND AIMS: Non-cirrhotic portal fibrosis (NCPF) is a clinical disorder characterized by features of portal hypertension in the absence of significant fibrosis. It is one of the commonest causes of portal hypertension in India. This study aimed to analyze histomorphological spectrum of NCPF in detail. METHODS AND RESULTS: There were 67 specimens from 66 patients which included 43 (65.2%) male and 23 (34.8%) female patients with a mean age of 31 years (range: 7-61 years). The liver function tests showed only a mild derangement. The average length of biopsy was 1.4 cm (median: 1.2 cm, range: 0.8-3.4 cm) and the mean number of portal tracts per biopsy was 11.1 (median: 10, range: 5-30). Most cases showed a combination of histological features; the mean number of histological features per biopsy was 7.4 (median: 7, range: 3-12). Obliterative portal venopathy was seen in 47.8% cases. Portal angiomatosis (61.2%), paraportal shunt vessels (61.2%), portal vein dilatation (74.6%), hypoplastic portal tracts (56.7%), megasinusoids (64.1%), and abnormally dilated central veins (64.1%) were other prevalent features. Portal/periportal fibrosis and perisinusoidal fibrosis were seen in 77.6% and 61.2% cases; none showed bridging fibrosis or cirrhosis. The median hepatic venous pressure gradient (HVPG) and liver stiffness (LS) values were 8 mm of Hg (range: 5-20 mm of Hg) and 9.2 kPa (range: 4.4-26.3 kPa). There was no correlation of HVPG or LS with either portal/periportal fibrosis or perisinusoidal fibrosis. CONCLUSION: Due to relatively non-specific and non-pathognomonic nature, a combination of different histological features in the absence of significant fibrosis and appropriate clinico-radiological background is needed for diagnosing NCPF.

Transient Elastography (Fibroscan) in Patients with Non-cirrhotic Portal Fibrosis.

BACKGROUND: Non-cirrhotic portal hypertension (NCPH) is a common cause of variceal bleed in developing countries. Transient elastography (TE) using Fibroscan is a useful technique for evaluation of fibrosis in patients with liver disease. There is a paucity of studies evaluating TE in patients with Non-cirrhotic portal fibrosis (NCPF) and none in Asian population. Aim of this study was to evaluate role of TE in NCPF. METHODS: Retrospective data of consecutive patients of NCPF as per Asian pacific association for the study of liver (APASL) guidelines were noted. All patients had liver biopsy, TE, computed tomography of abdomen and hepatic venous pressure gradient (HVPG). Twenty age and gender matched healthy subjects and forty age matched patients with cirrhosis with Child's A were taken as controls. RESULTS: A total of 20 patients with age [median 29.5 (13-50) years], Male:Female = 11:9 with a diagnosis of NCPF were enrolled from January 2011 to December 2015. Of 20 patients 18 patients had variceal bleed and required endoscopic band ligation. There was no difference in haemoglobin and platelet count between patients with cirrhosis and NCPF, but total leucocyte count was significantly lower in patients with NCPF compared to patients with cirrhosis (3.2 vs 6.7 × 103/cumm, P = 0.01). TE (Fibroscan) was high in patients with NCPF compared to healthy controls (6.8 vs 4.7 kPa, P = 0.001) but it was significantly low compared to cirrhotic patients (6.8 vs 52.3 kPa, P = 0.001). HVPG is significant low in patients with NCPF compared to patients with cirrhosis (5.0 vs 16.0 mmHg, P = 0.001). CONCLUSION: Transient elastography (Fibroscan) is significantly low in patients with NCPF compared to patients with cirrhosis. It is a very useful non-invasive technique to differentiate between Child's A cirrhosis and non-cirrhotic portal fibrosis.

ADAMTS13 missense variants associated with defective activity and secretion of ADAMTS13 in a patient with non-cirrhotic portal hypertension.

BACKGROUND: Non-cirrhotic intrahepatic portal hypertension (NCIPH) is characterized by thrombotic microangiopathy of the portal venous system, low ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs-13), and high vWF (von Willebrand factor) levels. This study aimed to screen for ADAMTS13 mutations, focusing on the CUB domain, in these patients. METHODS: Prospectively recruited NCIPH patients and healthy volunteers underwent tests for plasma vWF-ADAMTS13 balance. Sanger sequencing of the CUB domain of ADAMTS13 was done in a subset of the NCIPH patients, and the detected mutation was screened for in all the study participants. Next-generation sequencing of clinically relevant exome and liver immunostaining for ADAMTS13 was done in patients with detected ADAMTS13 mutation. RESULTS: Plasma vWF-ADAMTS13 balance was significantly altered in 24 NCIPH patients (Child's class A:23, B:1) as compared to 22 controls. On initial sequencing of the CUB domain (17 cases and 3 controls), one NCIPH patient showed a rare missense variant (SNV) at position c.3829C >T resulting in p.R1277W (rs14045669). Subsequent RFLP analysis targeted to the R1277W variant did not detect this in any other NCIPH patient, nor in any of the 22 controls. The NCIPH patient with the R1277W variant had severe ADAMTS13 deficiency, consistently high vWF, other missense SNVs in ADAMTS13, vWF, and complement genes. Immunostaining of his liver biopsy revealed globules of ADAMTS13 within stellate cells. CONCLUSIONS: We report missense variants in ADAMTS13, vWF, and complement genes in a patient with NCIPH who had decreased secretion and activity of ADAMTS13 protein. Further studies are needed in NCIPH patients in this regard.

The burden, pattern and factors that contribute to periportal fibrosis in HIV-infected patients in an S. mansoni endemic rural Uganda.

INTRODUCTION: Both Human Immunodeficiency Virus (HIV) and S.mansoni infections are common in Uganda and can cause liver disease. No study has determined co-infection significance in Uganda. We carried out a study on the burden, pattern and factors that contribute to peri-portal fibrosis (PPF) in HIV infected patients attending a Primary healthcare setting at Pakwach. METHODOLOGY: We conducted a cross-sectional study in the HIV clinic at Pakwach health centre IV. Data on demographics, contact with the Nile, CD4+ cell count, ART and alcohol use were collected. Urinary Circulating Cathodic Antigen (CCA), was done for S. Mansoni detection. Liver scan was done for presence and pattern of PPF. HBsAg testing was performed on all participants. Data was analyzed using Stata Version 10. RESULTS: We enrolled 299 patients, median age 39 years (IQR 16), most were female, 210 (73%). Overall, 206 (68.9%) had PPF, majority 191 (92.7%) had pattern c, either alone (63 participants) or in combination with pattern d (128 participants). Age of 30-50 years was significantly associated with PPF (OR 2.28 p-value-0.003). CONCLUSION: We found high prevalence of S. mansoni and PPF in the HIV infected population and age was a significant factor for PPF. We recommend all HIV infected patients be examined routinely for S. mansoni infection for early anti-schistosomal treatment.