Capsule Endoscopy in the Diagnosis, Disease Mapping, and Monitoring of Treatment Response in Gastrointestinal Whipple's Disease.

Whipple's disease is a rare systemic infection causing malabsorption. Affected patients often undergo extensive investigation until final diagnosis with periodic acid-Schiff-positive histology. We present the case of a 73-year-old man diagnosed with Whipple's disease after a prolonged history, with a focus on capsule endoscopy (CE) in both mapping the extent of the pathology and follow-up. We demonstrate pre-treatment and post-treatment CE images, allowing visualization of resolved small bowel pathology, and demonstrate histological resolution. The early use of CE in the investigation of Whipple's disease may expedite diagnosis in patients with more distal bowel pathology and help assess disease severity.

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.

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.

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.

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.

Alcoholic ketoacidosis with multiple complications: a case report.

Alcoholic ketoacidosis is a poorly diagnosed medical emergency usually identified in chronic alcohol misusers following an abrupt cessation or reduction of alcohol consumption. A high index of suspicion should be maintained by acute physicians as response to treatment is rapid with complete resolution of metabolic derangements. Complications are usually the result of not instituting the correct treatment or not addressing associated conditions. We describe a case of alcoholic ketoacidosis with multiple complications at presentation.