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Evaluation of Hyperferritinemia in Diabetes Mellitus for Prognosis and Glucose Control

This study examines hyperferritinemia in diabetic patients for prognosis and glucose control. Serum ferritin levels are evaluated alongside various markers to estimate disease severity and progression.

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Evaluation of Hyperferritinemia in Diabetes Mellitus for Prognosis and Glucose Control

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  1. EVALUATION OF HYPERFERRITINEMIA IN DIABETES MELLITUS Nguyễn Thị Hồng Anh, MD Medic Center

  2. Introduction

  3. Introduction • Serum ferritin: body iron stores, erythrocyte morphology. Hyperferritinemia can be a result of inflammation, infection, chronic iron overload, or other uncommon pathologies (hemophagocytic lymphohistiocytosis HLH) →Elevated serum ferritin concentrations are common in clinical practice, marker of cellular damage and inflammation (hydroxyl radical formation, oxidative stress), cell signaling and immune function, positively associated with insulin resistance and the metabolic syndrome, correlated strongly (r=0.49) with QT/QTs interval prolongation (longer than 450 ms). Hereditary hemochromatosis (HH) is the most common genetic iron overload disorder among Caucasians. • 1865: Dr. Armand Trousseau described diabetes with bronze-colored skin. • 1996: Feder et al. identified responsible gene named HFE (chromosomal location: 6p21). • After the discovery of HFE, researchers discovered several other gene mutations that also cause different types of HH. • Symptoms of iron overload: fatigue, bronze-colored skin, abdominal pain, joint pain, irregular menstruation, infertility, impotence, irregular heart rhythm, heart failure, new-onset diabetes, difficulty controllingestablished diabetes, liver enzyme elevation, cirrhosis, hepatocellular carcinoma, neurodegenerative disorders (Alzheimer, Parkinson, and Huntington diseases). • The central regulator of systemic iron homeostasis is hepcidin, a peptide hormone mainly produced by hepatocytes.

  4. Mechanism of hyperferritinemia in selected disorders. Increased apoferritin/L ferritin synthesis/secretion: • Chronic ethanol ingestion • Malignancy (malignant histiocytosis; carcinomas of lung, breast, ovary, kidney lymphoma; liposarcoma) • Gaucher disease • Reactive histiocytosis. • Hereditary hyperferritinemia-cataract syndrome. Increased ferritin release from injured cells: • Hepatic steatosis and steatohepatitis • Metabolic syndrome (obesity, type 2 diabetes, dyslipidemia, hypertension) • Chronic viral hepatitis • Massive liver necrosis due to sepsis/acute hepatitis/ toxic injury/ autoimmune disorders • Acute or chronic infection/inflammation • Acute myocardial infarction • Splenic infarct More than 40% of patients with hyperferritinemia have several causes simultaneously present. Renal failure

  5. Genetic Iron Overload: 6 types: • (1) Type 1 hemochromatosis – HFE hemochromatosis. • (2) Type 2 hemochromatosis – juvenile hemochromatosis: (a) type 2A – mutation in hemojuvelin gene; (b) type 2B – mutation in hepcidin gene. • (3) Type 3 hemochromatosis – transferrin receptor 2 hemochromatosis. • (4) Type 4 hemochromatosis – ferroportin disease: (a) type 4A – with low transferrin saturation; (b) type 4B – with high transferrin saturation. • (5) A(hypo)transferrinemia. • (6) Aceruloplasminemia. • Acquired Iron Overload: • (1) Iatrogenic: (a) multiple blood transfusions; (b) parenteral iron therapy; (c) oral iron therapy. • (2) Chronic liver disease: (a) alcoholic liver disease; (b) hepatitis B and C; (c) porphyria cutanea tarda. • (3) Anemias: (a) thalassemia major; (b) chronic hemolytic anemia; (c) pyruvate kinase deficiency. • (4) Others: dysmetabolic hyperferritinemia

  6. Clinical case

  7. .

  8. Materials and method • Objectives: evaluate serum Ferritin in diabetic patients to estimate prognosis, glucose control ability • Methods: Descriptive cross-section statistics • Test: CBC, FBS, HbA1C, LDLC-C, TG, AST, ALT, GGT, eGFR, Urinalysis, microalbuminuria, uric acid, HBsAg, AntiHBs, AntiHBctotal, AntiHCV, FT4, TSH, Ferritin, serum iron, Transferin saturation, hsCRP, serum ionogram, Antinuclear Antibody (ANA) • Assessbody mass index, blood pressure, liver steatosis(CAP: dB/m), liver fibrosis (Elastography: kPa) (Fibroscan 502TOUCHE F60084), B mode transabdominal US (Operators: Bùi Hồng Lĩnh et al.). • Inclusive criteria: • DM patients > 17 yrs and euthyroid. • Exclusive criteria • Haematologic diseases: thalassemia, chronic hemolytic anemia, sickle cell diseases & myelodysplastic syndrome . • Consumption beer / alcohol >20g/day • HBV, HCV • Malignancy. • Drug induced hepatitis • Autoimmune hepatitis • Pregnancy, breast-feeding period. • Iron supplement.

  9. Staging liver steatosis and fibrosis • Steatosisseverity: CAP: dB/m • S0 = no steatosis • S1 =normal steatosis • S2 = mild steatosis • S3 = moderate steatosis • S4 = severe steatosis • Stages of liver fibrosis: kPa • F0 = no fibrosis • F1 = mild fibrosis • F2 = moderate fibrosis • F3 = much fibrosis • F4 = severe fibrosis

  10. Results

  11. Liver fibrosis & steatosis

  12. ESTIMATE OF HYPERFERRITINEMIA

  13. Results • Sept 2018 - April 2019. • 268 type 2 diabetic patients (119 M, 149F). • Age=17 - 87 years . • Duration of acquired DM= first onset - 23years. • 21 obese patients (7.82%) + 92 overweight patients (34.32%) = 42.14% • Hypertension: 152 patients (56,71%). • Kidney disease: 87 patients (32.46%).. • Dyslipidemia: 247 patients (92,16%). • Liver steatosis: 150 patients (55.97%) • Significant liver fibrosis (≥ F2: 35.45%)

  14. Hyperferritinemia: 133 patients (49,62%), no significant difference between liver fibrosis degree. • Young onset <40y: 38 patients (10.1%): 19 patients had hyperferritinemia (50%) →No difference in frequency of hyperferritinemia between ages. • Male hyperferritinemia:73 patients (73/119=61.3% male), Female hyperferritinemia: 60 patients (60/149=40.2% female) →Male is more likely to be hyperferrinemia than female (61.3% vs 40.2%) • Moderate & severe liver steatosis link to higher rate of hyperferritinemia (59% vs 41%). • Hepatitis: 177 patients (66%); 101 hyperferritinemia hepatitic patients (57.06%) No hepatitis: 91 patients (33.95%); 22 hyperferrtinemia patients (24.17%) → Hepatitis link to higher rate of hyperferritinemia (57% vs 24.17%). • Severe hyperferritinemia (Ferritinemia > 1000ng/mL: 18 cases)+ extreme hyperferritnemia (Ferritinemia > 2000ng/mL: 4cases): 16.54% of hyperferritinemia

  15. Hyperferritinemia: -90% non-iron overload -10%: iron overload

  16. Discussion • Dysmetabolic hyperferritinemia, being more prevalent especially in the presence of metabolic syndrome, should be considered as the most likely disorder in such scenarios of high ferritin with normal transferrin saturation. • There are many types of hyperferritinemia presented in primary care.“Metabolic Hyperferritinemia” must be considered when evaluating patients with elevated SF and associated with hypertriglyceridemia, hypertension and insulin resistancewhich are more prevalent in the Gulf countries states, reaching up Arab 29% to 33% in males, and 38% to 41% in females respectively. • This study: 61.3% male patients and 40.2% female patients are hyperferritinemia • Mild elevations of SF < 1000 μg/L are tolerable levels in the absence of HH; the risk of hepatic iron overload is exceedingly low, whereas high elevation of SF > 1000μg/L requires specialist review to rule out HH with an increased risk of hepatic iron overload, which leads to hepatic fibrosis and cirrhosis.

  17. FerriScan recommended in multiple clinical patient management guidelines • International regulatory clearance and approvals (USA, Europe, Australia) • The technique is robust, there is no shift in accuracy or precision across different MRI scanners, between MRI centres and models of scanner. • FerriScan is unaffected by inflammation, fibrosis, cirrhosis or chelation therapy. • FerriScan requires no breath-hold and may therefore be used for paediatric patients, patients of all ages. • Non-invasive, no contrast agents and has a scan time of approximately 10 minutes. • FerriScan provides an high sensitivity and specificity, accurate-validated MRI-based measurement of liver iron concentration (LIC), over the entire range encountered in clinical practice. • Results are accurate, reliable and reproducible over time .

  18. Guideline in Clinical Assessment of Hyperferritinemia in Primary Care 1. It is mandatory to ask about alcohol and iron over load in each hyperferritinemia presentation. 2. Check the body mass index, blood pressure, blood sugar and blood lipid , if suspecting metabolic syndrome. 3. Check the blood count and inflammatory markers (Creactive protein or erythrocyte sedimentation rate) in order to detect occult inflammatory disorders. 4. Check serum creatinine and electrolytes for renal function 5. Check liver function tests: Abnormal results should prompt consideration of viral hepatitis screening and abdominal ultrasonography. 6. Check the transferrin saturation: the level of transferrin saturation > 45% has a sensitivity of 94% and a positive predictive value of 6% for hereditary hemochromatosis (check for C282 Y homozygotes/H63D)

  19. 7. Refer the patient to Hematology and Hepatology if: a. The patient has a confirmed iron overload with ferritin level of > 1000 μg/L or abnormal liver function, regardless of the cause. b. The patient has a positive HFE mutation results. c. The patient has a high ferritin level need for frequent venesection (Phlebotomy) or iron chelation; the aim is to lower the serum ferritin concentrations to a level < 50 μg/L. d. Check for genetic and iron overload in siblings of the hemochromatosis patient. e. Refer the patient for direct assessment of liver iron stores, for instance Magnetic Resonance Imaging (MRI) or liver biopsy. f. Refer the patient to Hepatology if viral hepatitis or inflammatory disorder are suspected.

  20. 8. Consider interventions in patient with metabolic Hyperferritinemia (SF range 300-1000 μg/L), in whom iron overload is unlikely (transferrin saturation ≤ 45) by reducing SF (alcohol abstinence, improved glycemic control, weight reduction, and lowering triglyceride concentrations)

  21. CONCLUSION Hyperferritinemia with normal transferrin saturation, with or without iron overload is often found in patients with hepatic steatosis and/or hepatitis. The metabolic hyperferritinaemia (disorder of iron and glucose and/or lipid metabolism) may occur with the incidence up to 49% in type 2 diabetes mellitus.

  22. REFERENCES • https://link.springer.com/article/10.1007/s12185-017-2365-3.Gajendra Singh Dhakad, Ashish Kumar Sharma, Gulab Kanwar, Ajay Kumar Singh4, Shrikant Sharma. Evaluation of iron profile in type 2 diabetes mellitus patients of tertiary care center of central India. • International Journal of Clinical Biochemistry and Research, January-March, 2019;6(1):15-19.The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis. • Dysmetabolic Hyperferritinemia: All Iron Overload Is Not Hemochromatosis. Jasbir Makker,a,b,* Ahmad Hanif,b Bharat Bajantri,b and Sridhar Chilimuria,b Metallomics. 2014 Apr;6(4):748-73. doi: 10.1039/c3mt00347g. • Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Kell DB1, Pretorius E. • A diagnostic approach to hyperferritinemia with a non-elevated transferrin saturation. Paul C. Adams1, , James C. Barto • https://www.resonancehealth.com/products/ferriscan-mri-measurement-of-liver-iron-concentration.html • Hyperferritinemia Is Associated with Insulin Resistance and Fatty Liver in Patients without Iron Overload. Robert Brudevold, Torstein Hole, Jens Hammerstrøm. • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570219/. • https://www.em-consulte.com/en/article/1177870 • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807778/. The relationship between serum ferritin levels and electrocardiogram characteristics in acutely ill patients.Krzysztof Laudanski, MD MA, Huma Ali, MD, Andrew Himmel, MD, Kasia Godula, MD, Mary Stettmeier, MD, and Lisa Calvocoressi, PhD

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