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.
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Evaluation of Hyperferritinemia in Diabetic Patients
1.
2. Ferritin=24 protein subunits capable of storing up to 4500 iron
atoms.
• Serum glycosylated ferritin: 60–80% (from macrophages)
• Non-glycosylated ferritin: 20–40% (from cell lysis)
3.
4. • 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 controlling established 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.
5.
6. 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
Increased ferritin
synthesis due to iron
overload:
• HFE and other types of
hemochromatosis
• Heritable & acquired
anemias associated with
ineffective erythropoiesis
• Increased iron absorption
from supplemental iron /
traditional beer
• transfusion iron overload
• Aceruloplasminemia
Renal failure
More than 40% of patients with
hyperferritinemia have several
causes simultaneously present.
7. • 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)
8. • Male 22 years old
• BMI=24
• BP= 112/77 mmHg, HR=75
bpm
• Lose 3kg/2 months
• No smoking, no alcohol
abuse.
• Family history : nothing
abnormal
20. 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.“
which 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:
• 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.
21. • 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 .
22. 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)
23. 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.
24. 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)
25. 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.
26. 1. 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.
2. 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.
3. 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.
4. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Kell DB1, Pretorius E.
5. A diagnostic approach to hyperferritinemia with a non-elevated transferrin saturation. Paul C. Adams1, , James C. Barto
6. https://www.resonancehealth.com/products/ferriscan-mri-measurement-of-liver-iron-concentration.html
7. Hyperferritinemia Is Associated with Insulin Resistance and Fatty Liver in Patients without Iron Overload. Robert Brudevold, Torstein Hole,
Jens Hammerstrøm.
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570219/.
9. https://www.em-consulte.com/en/article/1177870
10. 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
