Arvind Sangwaiya

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 Crohns 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 Crohns 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 (Pearsons 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.

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.

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

Introduction Majority of patients with HFE hemochromatosis (HFE-H) are homozygote for C282Y mutation. Studies suggest iron accumulation in most types of hemochromatosis is due to hepcidin deficiency. The precise link between hepcidin levels and iron absorption in HFE-H patients has been poorly understood. We measured hepcidin response to oral iron challenge (200 mg ferrous sulphate), in HFE-H (C282Y/C282Y) patients and compare to healthy controls (HC). 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. Serum iron, ferritin and transferrin saturation (%TSAT) were measured using standard methods. The area under the curve (AUC) was calculated and compared between the two groups. Results The basal serum hepcidin levels in patients with HFE-H were significantly low as compared to HC (p=0.0002) (table 1). Incremental serum hepcidin response seen in HC reached significance at 4 h post iron challenge (p=0.0085). There was no significant hepcidin response in HFE-H at 4 h (p=0.294) (figure 1). The overall hepcidin response was significantly lower in HFE-H as compared to HC (AUC: p=0.0127). Figure 1 OC-113 Table 1 OC-113 Data represents basal time-points pre-iron load Healthy Controls (n=15) C282Y/C282Y (n=9) p Mean age, (±SD) 28.4 (±4.1) 53.8 (±13.4) Hepcidin (ng/ml) 32.9 (24.8–43.7) 13.1 (7.2–23.9) <0.0001* Iron (μmol/l) 14.6 (12.7–16.8) 27.9 (20.2–38.6) 0.0002* Ferritin (μg/l) 51.2 (34.7–75.5) 50.9 (39–66.6) 0.53 %TSAT 25.3 (21.5–29.8) 52.3 (37.1–73.8) 0.0001* Hepcidin: ferritin ratio 1.1 (0.8–1.5) 0.3 (0.1–0.5) 0.0044* Data are presented as GM (95%CI) by unpaired t test (*p<0.05 considered significant) Conclusion Failure to mount a rapid hepcidin response to an oral iron challenge is one of the key mechanisms of iron accumulation in spite of prevailing excess body iron in HFE-H patients with C282Y/C282Y mutation.

Amyloid light-chain amyloidosis, myeloma and autonomic neuropathy

Systemic amyloidosis secondary to myeloma is an uncommon condition that often has an insidious onset and poses as a diagnostic challenge due to the lack of typical presenting symptoms and signs. Prompt diagnosis of amyloidosis and appropriate referral have the potential to improve outcome for these patients. Here, we report the unusual case of a man whose primary presenting complaint was of long-standing orthostatic hypotension.

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.