Hypothesis: Pentoxifylline is a potential cytokine modulator therapeutic in COVID-19 patients.

We propose a new hypothesis that the established drug pentoxifylline deserves attention as a potential repurposed therapeutic for COVID-19. Pentoxifylline is an immunomodulator with anti-inflammatory properties. It is a nonselective phosphodiesterase inhibitor and through Adenosine A2A Receptor-mediated pathways reduces tumor necrosis factor alpha, interleukin 1, interleukin 6, and interferon gamma and may act to reduce tissue damage during the cytokine storm host response to SARS-CoV-2 infection. This agent has been used clinically for many years and has a favorable profile of safety and tolerability. Pre-clinical data support pentoxifylline as effective in cytokine-driven lung damage. Clinical studies of pentoxifylline in radiation and cytokine-induced lung damage in humans are positive and consistent with anti-inflammatory efficacy. Pentoxifylline is a readily available, off-patent and inexpensive drug, suitable for large-scale use including in resource-limited countries. Current trials of therapeutics are largely focused on the inhibition of viral processes. We advocate urgent randomized trials of pentoxifylline for COVID-19 as a complementary approach to target the host responses.

Severe refractory coeliac disease with response only to parenteral nutrition.

Refractory coeliac disease (RCD) is characterised by recurrent or persistent malabsorptive symptoms and villous atrophy, despite strict adherence to a gluten-free diet for at least 6 months and where other causes of malabsorption including malignancy have been excluded. There is limited evidence and guidance on the effective management of these patients. We describe a case of severe RCD in our hospital, with symptoms controlled effectively only by total parenteral nutrition (TPN). This 68-year-old woman initially presented to the clinic with persistent non-bloody diarrhoea and vomiting. A diagnosis of coeliac disease was confirmed with a positive tissue transglutaminase assay and histology. A strict gluten-free diet was ineffective and she represented 6 months later with 13 kg weight loss (16.7%), ongoing abdominal pain and diarrhoea, with bowels opening 16 times a day. She was oedematous, had an albumin of 12 g/l and required hospital admission. She was treated for pancreatic insufficiency and presumptively for small bowel bacterial overgrowth with no resolution of symptoms. We ruled out infectious causes and investigated for small bowel malignancy; all results were negative. Small bowel enteroscopy showed ulcerative jejunitis. She was given 5 days of TPN, following which her symptoms improved and albumin normalised. This was sustained with symptom resolution and weight gain seen at follow-up. TPN successfully and rapidly induced remission in this case. Thus, a short period of TPN should be considered as a potential component of management in patients with severe RCD.

Blunted increase in serum hepcidin as response to oral iron in HFE-hemochromatosis.

BACKGROUND: HFE hemochromatosis (HFE-H) is the most common and well-defined inherited cause for iron-related morbidity and mortality. Majority of patients with HFE-H are homozygote for C282Y mutation. Recent studies suggest that iron accumulation in most types of hemochromatosis is due to deficiency of hepcidin, a central iron regulator. However, the precise link between hepcidin levels and iron absorption in HFE-H patients has been poorly understood. AIM: To measure hepcidin response to oral iron challenge (200 mg ferrous sulphate), in HFE-H (C282Y/C282Y) patients and compare with healthy controls (HCs). METHODS: Nine patients with C282Y/C282Y HFE-H along with 15 HC were recruited for the study. All HFE-H were iron depleted and studied at a time distant to phlebotomy. Hepcidin was measured using a published immunoassay method after ingestion of 65 mg oral iron challenge. Serum iron, ferritin and transferrin saturation were measured using standard methods. The area under the curve was calculated and compared between the two groups. RESULTS: The basal serum hepcidin levels in patients with HFE-H were significantly low as compared with HC (P=0.0002). Incremental serum hepcidin response seen in HC reached significance at 4 h post iron challenge (P=0.0085) returning to baseline only at 24 h. There was no significant hepcidin response in HFE-H at 4 h (P=0.294). The overall hepcidin response was significantly lower in HFE-H compared with HC (area under the curve: P=0.0127). CONCLUSION: Failure to mount a rapid hepcidin response to an oral iron challenge is the key mechanisms of iron accumulation despite prevailing excess body iron in patients with HFE-H with C282Y/C282Y mutation.

Differences in inflammatory bowel disease phenotype between South Asians and Northern Europeans living in North West London, UK.

OBJECTIVES: The incidence and prevalence of inflammatory bowel disease (IBD) is increasing throughout Asia. Since the 1950s, there has been substantial migration from South Asia (India, Pakistan, and Bangladesh) to the United Kingdom. The aim of this study was to define the clinical phenotype of IBD in UK South Asians living in North West London, and to compare the results with a white Northern European IBD cohort. METHODS: The phenotypic details of 367 South Asian IBD patients (273 ulcerative colitis (UC) and 94 Crohn's disease (CD)), undergoing active follow-up in five North West London hospitals, were compared with those of 403 consecutively collected white Northern European IBD patients (188 UC and 215 CD). RESULTS: The phenotype of IBD differed significantly between the two populations. 63.0% of South Asian UC patients had extensive colitis compared with 42.5% of the Northern European cohort (P < 0.0001). Proctitis was uncommon in South Asian UC patients (9.9 vs. 26.1% in Northern European patients, P<0.0001). In the South Asian CD cohort, disease location was predominantly colonic (46.8%). CD behavior differed significantly between the groups, with less penetrating disease compared with Northern Europeans (P=0.01) and a reduced need for surgery (P=0.003). CONCLUSIONS: The phenotype of IBD in South Asians living in North West London is significantly different from that of a white Northern European IBD cohort. Knowledge of ethnic variations in disease phenotype may help to identify key genetic, environmental, and behavioral factors contributing to the development of IBD.

Unexplained iron deficiency in idiopathic and heritable pulmonary arterial hypertension.

BACKGROUND: Anaemia is common in left heart failure and is associated with a poorer outcome. Many patients with pulmonary arterial hypertension (PAH) are anaemic or iron-deficient. This study was performed to investigate the prevalence of iron deficiency in PAH and to identify possible causes. METHODS: All patients with idiopathic or heritable PAH diagnosed in 1995-2008 were identified. Controls were selected from patients with chronic thromboembolic pulmonary hypertension (CTEPH). Full blood counts were examined and any abnormality was investigated. Patients were excluded if they had a cause for iron deficiency. The prevalence study was based on 85 patients with idiopathic PAH and 120 with CTEPH. A separate group of 20 patients with idiopathic PAH and 24 with CTEPH with matching haemodynamics were prospectively investigated for serum factors affecting iron metabolism. RESULTS: The prevalence study identified a point prevalence of unexplained iron deficiency of 50% in premenopausal women with idiopathic PAH compared with 8% in premenopausal women with CTEPH (p=0.002); 14% in postmenopausal women with idiopathic PAH compared with 6% in postmenopausal women with CTEPH (p=0.16); 28% in men with idiopathic PAH men compared with 2% in men with CTEPH (p=0.002); and 60% in patients with heritable PAH. The serum study showed that patients with idiopathic PAH had lower serum iron and transferrin saturations than those with CTEPH. Interleukin-6 levels correlated with iron levels (r=-0.6, p=0.006) and transferrin saturations (r=-0.68, p=0.001) in idiopathic PAH but not in CTEPH. CONCLUSIONS: The prevalence of unexplained iron deficiency is significantly higher in idiopathic PAH than in CTEPH. This may be linked to interleukin-6.

Case Report: Fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn's disease.

We present the case of a 28 year old lady with refractory Crohn's Disease treated with infliximab throughout her pregnancy. Her baby was born healthy and received a Bacillus Calmette-Guérin (BCG) vaccine aged 3 months. Soon after this the infant became unwell and died aged 4.5 months. At post-mortem the cause of death was attributed to an unusual complication of the BCG vaccine, known as disseminated BCG. BCG vaccination is contraindicated in individuals who are receiving immunosuppressive drugs. We recommend physicians should exercise caution before such vaccines are used in infants born to mothers taking anti-TNF therapies or other potentially immunosuppressive IgG1 antibodies.

Hepcidin levels in hereditary hyperferritinemia: Insights into the iron-sensing mechanism in hepatocytes.

AIM: To study the role of hepcidin in hereditary hyperferritinemia cataract syndrome (HHCS). METHODS: Six patients from two families with HHCS, confirmed by genetic analysis showing A to G mutation at position +40 in the L-ferritin gene, were recruited to undergo serum hepcidin and prohepcidin measurements using radioimmunoassay and enzyme linked immunoassay, respectively, and measurements were compared with levels in serum from 25 healthy volunteers (14 females), mean age 36 +/- 11.9 years. RESULTS: The serum hepcidin and prohepcidin levels in patients with HHCS were 19.1 +/- 18.6 and 187 +/- 120.9 ng/mL, respectively. Serum ferritin was 1716.3 +/- 376 microg/L. Liver biopsy in one patient did not show any evidence of iron overload. Serum hepcidin and prohepcidin values in healthy controls (HCs) were 15.30 +/- 15.71 and 236.88 +/- 83.68 ng/mL, respectively, while serum ferritin was 110 +/- 128.08 microg/L. There was no statistical difference in serum hepcidin level between the two cohorts (19.1 +/- 18.6 ng/mL vs 15.30 +/- 15.71 ng/mL, P = 0.612) using two-tailed t-test. CONCLUSION: Serum hepcidin levels in HHCS patients is similar to that in HCs. Our study suggests that circulating ferritin is not a factor influencing hepcidin synthesis and does not have a role in the iron-sensing mechanism in hepatocytes.

Presence of hepcidin-25 in biological fluids: bile, ascitic and pleural fluids.

AIM: To examine body fluids such as ascitic fluid (AF), saliva, bile and pleural effusions for the presence of hepcidin using a novel radioimmunoassay (RIA). METHODS: Serum samples were collected from 25 healthy volunteers (mean age: 36 +/- 11.9 years, 11 males, 14 females). In addition bile was obtained from 12 patients undergoing endoscopic retrograde cholangiopancreatography (mean age: 66.9 +/- 16.7 years, M:F = 5:7). Saliva was collected from 17 healthy volunteers (mean age: 35 +/- 9.9 years, M:F = 8:9). Pleural and AF were collected from 11 and 16 patients [(mean age: 72 +/- 20.5 years, M:F = 7:4) and (mean age: 67.32 +/- 15.2 years, M:F = 12:4)], respectively. All biological fluid samples (serum, exudative and transudative fluids) were tested for the presence of hepcidin-25 molecule using RIA. RESULTS: Hepcidin-25 was detected in all biological fluids tested. The mean +/- SD hepcidin-25 in serum was 15.68 +/- 15.7 ng/mL, bile 7.37 +/- 7.4 ng/mL, saliva 3.4 +/- 2.8 ng/mL, exudative fluid 65.64 +/- 96.82 ng/mL and transudative fluid 14.1 +/- 17.8 ng/mL. CONCLUSION: We provide clear evidence that hepcidin-25 is present in bile, saliva, pleural and ascitic fluids. Hepcidin is likely to play a role here in innate immunity.

Hepcidin and inflammatory bowel disease: dual role in host defence and iron homoeostasis.

OBJECTIVE: Hepcidin is an endogenous antimicrobial peptide with a key role in iron homoeostasis. Hepcidin is similar to defensin, the deficiency of which is associated with Crohn's disease. To date there has been no validated method to reliably assay serum hepcidin. We studied iron indices in inflammatory bowel disease (IBD) including hepcidin. DESIGN: We assessed serum hepcidin concentrations (using a newly developed competitive radioimmunoassay) and ferritin in patients with IBD. Haematinics including serum soluble transferrin receptor, serum iron, serum vitamin B12 and red cell folate levels were also measured. The hepcidin results were compared with a control group of healthy volunteers from the local community. SETTING: This study was based in a hospital. PATIENTS: Sixty-one patients with IBD (51 patients with ulcerative colitis and 10 with Crohn's disease). Their mean hepcidin results were compared with 25 healthy controls. MAIN OUTCOME MEASURE: hepcidin concentration in serum samples in IBD patients compared with normal volunteers. RESULTS: We found significantly low serum hepcidin levels in patients with IBD. The hepcidin levels were low in IBD patients without iron deficiency anaemia as evidenced by normal ferritin and serum iron levels (n=41, mean hepcidin 6.81 ng/ml, SEM 1.2) and in IBD patients with iron deficiency anaemia (n=18, mean hepcidin 4.14 ng/ml, SEM 0.72) compared with healthy controls (n=25, mean hepcidin 15.3 ng/ml, SEM 3.14) (P=0.0045 and P=0.0050 on unpaired t-tests, respectively). We also measured IL-6 (enzyme-linked immunosorbent assay method, Abcam plc) in 21 of the 61 patients with IBD and compared the results with samples from 10 healthy volunteers. The IL-6 level was significantly higher (P=0.0222 on unpaired t-tests) in this group of IBD patients (n=21, IL-6 mean 2.94 pg/ml, SEM 0.64) compared with controls (n=10, IL-6 mean 0.663 pg/ml SEM 0.14). A significant positive correlation (Pearson's correlation coefficient r=0.6331) was present between hepcidin and IL-6, but not between hepcidin and serum soluble transferrin receptor (r=-0.235). CONCLUSION: The low hepcidin results in IBD patients may reflect a causal or perpetuator effect on intestinal inflammation.

Prohepcidin levels in refractory anaemia caused by lead poisoning.

Recent research evidence suggests a central role for hepcidin in iron homeostasis. Hepcidin is a hormone synthesized in the liver. Hepcidin is also thought to play a vital role in the pathogenic mechanism of anaemia in patients with inflammation or chronic disease. A 38-year-old female who presented with recurrent abdominal pain was found to have raised urinary porphyrins and a blood lead level of 779 µg/l. Her haemoglobin level was 8.3 g/dl. Her MCV was normal. Serum ferritin, B12 and folate were normal. Her serum prohepcidin level was 2,489 ng/ml (normal <450 ng/ml). To our knowledge, this is the first report of raised prohepcidin levels in a patient with anaemia of chronic disease resulting from lead poisoning.

Acute Appendagitis Presenting with Features of Appendicitis: Value of Abdominal CT Evaluation.

We report a case of acute appendagitis in a patient who presented initially with typical features of acute appendicitis. The diagnosis of acute appendagitis was made on pathognomonic signs on computed tomography (CT) scan. Abdominal pain is a common surgical emergency. CT is not always done if there are clear features of acute appendicitis. The rare but important differential diagnosis of acute appendagitis must be borne in mind when dealing with patients with suspected acute appendicitis. A CT scan of the abdomen may avoid unnecessary surgery in these patients.

Defective release of Hepcidin not defective synthesis is the primary pathogenic mechanism in HFE-Haemochromatosis.

Recent findings indicate a principal role for Hepcidin in iron homeostasis. Hepcidin is also thought to play a vital role in the pathogenic mechanism of anaemia in patients with inflammation or chronic disease. Under normal conditions influx and efflux of iron from duodenal enterocytes is regulated by Ferroportin. Ferroportin is a Hepcidin binding protein expressed in duodenal enterocytes. Hepcidin is a peptide synthesised in the liver and is the main regulator of iron homeostasis. It is a defensin like protein and exhibits anti-microbial and anti-fungal activity. The Hepcidin gene is principally expressed in hepatocytes but to a lesser extent in neutrophils and macrophages. Hereditary Haemochromatosis is caused by disruption of iron homeostasis due to mutations in the HFE gene (C282Y or H63D). Unrestricted uptake of iron by duodenal enterocytes causes iron overload which is the hallmark of the disease. Current thinking is that defective Hepcidin synthesis or defective iron-sensing mechanisms leading to Hepcidin deficiency is the cause of iron overload in HFE-Haemochromatosis. Thus HFE-Haemochromatosis has been described as an endocrine disease. Basal levels of Hepcidin appear to be normal in HFE-Haemochromatosis patients. This contradicts current theories of defective Hepcidin synthesis as the cause of Hereditary HFE-Haemochromatosis. We propose that the defect in HFE-Haemochromatosis is the loss of Hepcidin surge in response to intake of dietary iron and is not as a result of reduced synthesis.

Why does laparoscopic common bile duct exploration fail?

Laparoscopic common bile duct exploration (LCBDE) for choledocholithiasis carries an overall ductal clearance rate of between 85% and 95%. We present our single institute experience with LCBDE. Between July 1999 and July 2003, 60 patients (42 females, 18 males; median age, 59.5 years) with proven choledocholithiasis underwent LCBDE for common bile duct (CBD) clearance. The method failed to clear the CBD in six patients, resulting in a 90% overall success rate. Conversion to a conventional open approach (n = 1), hand-assisted LCBDE (n = 1), T-tube placement followed by multiple postoperative endoscopic retrograde cholangiopancreatography (ERCP; n = 2), and endobiliary stent placement followed by single successful postoperative ERCP in each case (n = 2) were chosen as treatment options when the laparoscopic method failed to clear the CBD. LCBDE is a feasible and safe method of managing CBD stones. Impacted stones at the lower end of the CBD or in the ampulla of Vater represent the most likely factors leading to failure of LCBDE. Laparoscopic endobiliary stent placement followed by postoperative ERCP represents the most attractive alternative in these difficult cases of impacted stones.