Gastroparesis in patients with inactive Crohn's disease: a case series

BACKGROUND: Few studies have described patients with foregut dysmotility in inflammatory bowel disease. The aim of this case series was to evaluate clinical characteristics of 5 patients with inflammatory bowel disease and symptoms and signs of upper gut dysmotility. CASE PRESENTATIONS: We describe a series of four patients with Crohn's disease and one with indeterminate colitis who presented with severe symptoms and signs of gastroparesis. We reviewed medical records of all cases. Gastric emptying of a solid meal was assessed by scintigraphy. Small bowel enteroclysis, gastroduodenoscopy and colonoscopy with biopsies were performed to estimate the activity of the disease and to exclude organic obstruction. None of the patients had any signs of active inflammation or stricture. All of the patients had markedly delayed gastric emptying with a mean t 1/2 of 234 minutes (range 110–380 minutes; normal values 54–94 minutes). CONCLUSION: Clinicians should consider impaired gastric emptying when evaluating patients with Crohn's disease and severe symptoms of upper gut dysmotility, which cannot be attributed to active inflammation or organic obstruction of the digestive tract. Symptoms in these patients are refractory to various therapeutic interventions including tube feeding and gastric surgery

Rare liver tumour - epithelioid haemangioendothelioma: a case report

Publisher Copyright: © 2022 Sniedze Laivacuma et al., published by Sciendo.Epithelioid haemangioendothelioma (EHE) is a rare vascular soft tissue malignant tumour with unknown etiology; the estimated prevalence of EHE is less than one in 1 million. A 56-year-old man was admitted in our department due to pain in the right side of the abdomen lasting for two years and weight loss up to 10 kg. Since 2012, the patient underwent lung and abdominal CT scanning as well as biopsy, however the diagnosis was challenging. In 2015, repeated abdominal CT scanning and a liver core biopsy was performed. The epithelioid haemangioendothelioma was diagnosed based by histopathological examination with subsequent radiological and clinical correlation. Therefore, accurate histopathological examination with radiological and clinical correlation is essential in the diagnosis of epithelioid haemangioendothelioma.publishersversionPeer reviewe

Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia.

We identified a homozygous missense mutation in the gene encoding NAD synthesizing enzyme NMNAT2 in two siblings with childhood onset polyneuropathy with erythromelalgia. No additional homozygotes for this rare allele, which leads to amino acid substitution T94M, were present among the unaffected relatives tested or in the 60,000 exomes of the ExAC database. For axons to survive, axonal NMNAT2 activity has to be maintained above a threshold level but the T94M mutation confers a partial loss of function both in the ability of NMNAT2 to support axon survival and in its enzymatic properties. Electrophysiological tests and histological analysis of sural nerve biopsies in the patients were consistent with loss of distal sensory and motor axons. Thus, it is likely that NMNAT2 mutation causes this pain and axon loss phenotype making this the first disorder associated with mutation of a key regulator of Wallerian-like axon degeneration in humans. This supports indications from numerous animal studies that the Wallerian degeneration pathway is important in human disease and raises important questions about which other human phenotypes could be linked to this gene

Everolimus and long acting octreotide as a volume reducing treatment of polycystic livers (ELATE): study protocol for a randomized controlled trial

Contains fulltext : 97893.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Polycystic liver disease (PLD) is defined as having more than 20 liver cysts and can present as a severe and disabling condition. Most symptoms are caused by the mass effect of the liver size and include abdominal pain and distension. The somatostatin analogues octreotide and lanreotide have proven to reduce polycystic liver volume. mTOR inhibitors such as everolimus inhibit cell proliferation and might thereby reduce growth of liver cysts. This trial aims to assess the benefit of combination therapy of everolimus and octreotide compared to octreotide monotherapy. In this study we present the structure of the trial and the characteristics of the included patients. METHODS/DESIGN: This is a randomized open-label clinical trial comparing the effect of 12 months of everolimus and octreotide to octreotide monotherapy in PLD patients. Primary outcome is change in liver volume determined by CT-volumetry. Secondary outcomes are changes in abdominal symptoms and quality of life. Moreover, safety and tolerability of the drugs will be assessed. DISCUSSION: This trial will compare the relative efficacy of combination therapy with octreotide and everolimus to octreotide monotherapy. Since they apply to different pathways of cystogenesis we expect that combining octreotide and everolimus will result in a cumulative reduction of polycystic liver volume. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT01157858

Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of NaV1.7

<p>Abstract</p> <p>Background</p> <p>Sodium channel Na_V1.7 is preferentially expressed within dorsal root ganglia (DRG), trigeminal ganglia and sympathetic ganglion neurons and their fine-diamter axons, where it acts as a threshold channel, amplifying stimuli such as generator potentials in nociceptors. Gain-of-function mutations and variants (single amino acid substitutions) of Na_V1.7 have been linked to three pain syndromes: Inherited Erythromelalgia (IEM), Paroxysmal Extreme Pain Disorder (PEPD), and Small Fiber Neuropathy (SFN). IEM is characterized clinically by burning pain and redness that is usually focused on the distal extremities, precipitated by mild warmth and relieved by cooling, and is caused by mutations that hyperpolarize activation, slow deactivation, and enhance the channel ramp response. PEPD is characterized by perirectal, periocular or perimandibular pain, often triggered by defecation or lower body stimulation, and is caused by mutations that severely impair fast-inactivation. SFN presents a clinical picture dominated by neuropathic pain and autonomic symptoms; gain-of-function variants have been reported to be present in approximately 30% of patients with biopsy-confirmed idiopathic SFN, and functional testing has shown altered fast-inactivation, slow-inactivation or resurgent current. In this paper we describe three patients who house the Na_V1.7/I228M variant.</p> <p>Methods</p> <p>We have used clinical assessment of patients, quantitative sensory testing and skin biopsy to study these patients, including two siblings in one family, in whom genomic screening demonstrated the I228M Na_V1.7 variant. Electrophysiology (voltage-clamp and current-clamp) was used to test functional effects of the variant channel.</p> <p>Results</p> <p>We report three different clinical presentations of the I228M Na_V1.7 variant: presentation with severe facial pain, presentation with distal (feet, hands) pain, and presentation with scalp discomfort in three patients housing this Na_V1.7 variant, two of which are from a single family. We also demonstrate that the Na_V1.7/I228M variant impairs slow-inactivation, and produces hyperexcitability in both trigeminal ganglion and DRG neurons.</p> <p>Conclusion</p> <p>Our results demonstrate intra- and interfamily phenotypic diversity in pain syndromes produced by a gain-of-function variant of Na_V1.7.</p

Polymorphisms in gene encoding TRPV1-receptor involved in pain perception are unrelated to chronic pancreatitis

Contains fulltext : 79505.pdf (publisher's version ) (Open Access

A TGFβ-ECM-Integrin signalling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

: The formation of multiple cysts in the liver occurs in a number of isolated monogenic diseases or multisystemic syndromes, during which bile ducts develop into fluid-filled biliary cysts. For patients with polycystic liver disease (PCLD), nonsurgical treatments are limited, and managing life-long abdominal swelling, pain, and increasing risk of cyst rupture and infection is common. We demonstrate here that loss of the primary cilium on postnatal biliary epithelial cells (via the deletion of the cilia gene Wdr35) drives ongoing pathological remodeling of the biliary tree, resulting in progressive cyst formation and growth. The development of cystic tissue requires the activation of transforming growth factor-β (TGFβ) signaling, which promotes the expression of a procystic, fibronectin-rich extracellular matrix and which itself is perceived by a changing profile of integrin receptors on the cystic epithelium. This signaling axis is conserved in liver cysts from patients with either autosomal dominant polycystic kidney disease or autosomal dominant polycystic liver disease, indicating that there are common cellular mechanisms for liver cyst growth regardless of the underlying genetic cause. Cyst number and size can be reduced by inhibiting TGFβ signaling or integrin signaling in vivo. We suggest that our findings represent a therapeutic route for patients with polycystic liver disease, most of whom would not be amenable to surgery

Rationale and design of the RESOLVE trial: lanreotide as a volume reducing treatment for polycystic livers in patients with autosomal dominant polycystic kidney disease

Contains fulltext : 109282.pdf (publisher's version ) (Open Access)BACKGROUND: A large proportion of patients with autosomal dominant polycystic kidney disease (ADPKD) suffers from polycystic liver disease. Symptoms arise when liver volume increases. The somatostatin analogue lanreotide has proven to reduce liver volume in patients with polycystic liver disease. However, this study also included patients with isolated polycystic liver disease (PCLD). The RESOLVE trial aims to assess the efficacy of lanreotide treatment in ADPKD patients with symptomatic polycystic livers. In this study we present the design of the RESOLVE trial. METHODS/DESIGN: This open-label clinical trial evaluates the effect of 6 months of lanreotide in ADPKD patients with symptomatic polycystic livers. Primary outcome is change in liver volume determined by computerised tomography-volumetry. Secondary outcomes are changes in total kidney volume, kidney intermediate volume and renal function. Furthermore, urinary (NGAL, alpha1-microglobulin, KIM-1, H-FABP, MCP-1) and serum (fibroblast growth factor 23) biomarkers associated with ADPKD disease severity are assessed to investigate whether these biomarkers predict treatment responses to lanreotide. Moreover, safety and tolerability of the drug in ADPKD patients will be assessed. DISCUSSION: We anticipate that lanreotide is an effective therapeutic option for ADPKD patients with symptomatic polycystic livers and that this trial aids in the identification of patient related factors that predict treatment response. TRIAL REGISTRATION NUMBER: Clinical trials.gov NCT01354405

Prevalence of genetic polymorphisms in the promoter region of the alpha-1 antitrypsin (SERPINA1) gene in chronic liver disease: a case control study

Contains fulltext : 89639.pdf (publisher's version ) (Open Access)BACKGROUND: Alpha-1 antitrypsin (A1AT) deficiency, caused by the Z allele (p.E342K) and S allele (p.E264V) in the SERPINA1 gene, can induce liver and pulmonary disease. Different mechanisms appear to be responsible for the pathogenesis of these divergent disease expressions. The c.-1973T >C polymorphism located in the SERPINA1 promoter region is found more frequent in A1AT deficiency patients with liver disease compared to patients with pulmonary disease, but data are lacking regarding contribution to the development of liver diseases caused by other aetiologies. AIM: To study the prevalence of c.-1973T >C, Z allele and S allele in a cohort of patients with liver disease of various aetiologies compared with healthy controls and to evaluate its effect on disease progression. METHODS: A total of 297 patients with liver disease from various aetiologies and 297 age and gender matched healthy controls were included. The c.-1973T >C polymorphism and Z and S alleles of the SERPINA1 gene were analyzed by real-time PCR. RESULTS: c.-1973T >C was similarly distributed between patients with liver disease of various origins and healthy controls. Furthermore, the distribution of c.-1973T >C was independent from aetiology subgroup. In patients with liver disease mean ages at of onset of liver disease were 44.4, 42.3 and 40.7 years for the c.-1973 T/T, T/C and C/C genotype respectively (NS). S allele heterozygosity was increased in patients with drug induced liver injury (DILI), (OR 4.3; 95%CI 1.1-17.2). CONCLUSION: In our study, c.-1973T >C polymorphism was not a risk factor for liver disease of various aetiologies. In addition, S allele heterozygosity might contribute to the development of DILI