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Journal of
Family Medicine and Disease Prevention
ISSN: 2469-5793
CASE STUDY | VOLUME 3, ISSUE 3 | OPEN ACCESS DOI: 10.23937/2469-5793/1510058

How to Follow up on Unexplained Hyperferritinemia in Primary Care

Basem Abbas Al Ubaidi , and Noora Al Hamadi

Department of Primary Care, Ministry of Health, Arabian Gulf University, Kingdom of Bahrain

*Corresponding author: Basem Abbas Al Ubaidi, Consultant Family Physician, Ministry of Health, Assistant professor in Arabian Gulf University Kingdom of Bahrain, Bahrain, E-mail: bahmed1@health.gov.bh

Received: October 16, 2016 | Accepted: May 30, 2017 | Published: June 01, 2017

Citation: Al Ubaidi BA (2017) How to Follow up on Unexplained Hyperferritinemia in Primary Care. JFam Med Dis Prev 3:058. doi.org/10.23937/2469-5793/1510058

Copyright: © 2017 Al Ubaidi BA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract


50-years-old Bahraini male had an increased level of serum ferritin. The patient showed mildly high alanine aminotransferase and γ-glutamyltransferase and positive chronic hepatitis B.

Introduction


Seventy-five percent of Iron is present in hemoglobin, while 10-20% is stored in the protein ferritin. The remainder 5-15% is found in the iron transport protein transferrin, as well as in myoglobin, cytochromes and as unbound serum iron [1]. Elevated Serum Ferritin (SF) is commonly encountered in primary care. Hyperferritinemia is considered high when the level of ferritin is > 200 mcq/l in a premenopausal women, and the level of > 300 mcq/l in men & postmenopausal women [2]. Worldwide, 90% of detected Hyperferritinemia cases are found related to non-iron overload conditions (e.g. Alcohol related liver disease, hematological disease, renal failure & neoplastic, infection or inflammation and metabolic syndrome), whereas only 10% of cases Hyperferritinemia cases are due to iron overload (Hemochromatosis (HH)) [3-5].

Serum iron displays diurnal variation so the best sample for iron studies is a fasting morning sample [6,7]. 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 > 1000 μg/L requires specialist review to rule out HH with increased risk of hepatic iron overload which lead to hepatic fibrosis and cirrhosis [8].

"Metabolic Hyperferritinemia" must be considered when evaluating patients with elevated SF and associated with hypertriglyceridemia, hypertension and insulin resistance which are more prevalent in the Gulf countries states, reaching up to which reach to 29% to 33% in males, and 38% to 41% in females respectively [9,10].

"Hepatic Hyperferritinemia" is another source of elevated SF, since any injured hepatocytes such as injured will seep ferritin into the serum, so SF deemed be reflected as another type of Liver Function Test (LFT) in liver disease (hepatitis B, hepatitis C, alcoholic liver disease, HH). Consequently, any elevated SF with abnormal LFTs will usually require further investigation in order to rule out hepatic Hyperferritinemia [11].

"Alcohol Hyperferritinemia" is highly associated with alcohol consumption level. Elevated SF, with two or more standard beer drinks causing increases ferritin secretion by the liver [12,13].

"Iatrogenic Hyperferritinemia" is common in patients receiving blood transfusions, especially those with thalassemia major, sickle cell diseases & myelodysplastic syndrome. Moreover, patients on oral iron pills or iron intravenous injection for a long time can develop high serum Hyperferritinemia [14].

"Malignant, Infective and Inflammatory Hyperferritinemia" requires a screening test for SF, C-reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR) and Antinuclear Antibody (ANA) which can help exclude serious disease [15].

Objective


To use up to date evidence-based investigation for interpretation of high serum ferritin in primary care.

Case Study


50-years-old Bahraini male came to the local health center to follow up in a chronic disease clinic for his medical issues. He is a known case of good controlled DM type 2 {FBS 6.4 (3.6-5.6 mmol/l)}, HBA1c 48 FBS mmol/L (20-39 mmol/mol) on oral hypoglycemic treatment [Glucophage 500 mg twice daily], and dyslipidemia mainly elevated triglyceridemia {Total cholesterol 4.9 mmol/L; mean HDL cholesterol 1 mmol/L (0.83-1.86 mmol/l); mean LDL cholesterol 2.85 mmol/L (1.68-3.367 mmol/l); mean Triglycerides 2.3 mmol/L (0.2-1.8 mmol/l)} on fibrates [Bezalip 400 mg daily]. Incidentally, the patient was found to have high serum ferritin level. His mean serum ferritin was 561 mcq/l {S. ferritin range from 502 to 600 mcq/l. (normal range in males is 12-300 mcq/l)}. The patient's investigation showed abnormal liver function test {alanine aminotransferase 53 IU/L (normal range is 10-40 IU/L) and γ-glutamyltransferase 66 IU/L (normal range 0-37 IU/L). Patient's CBC, ESR and renal function tests were normal. He was otherwise obese, his weight was 104 kg, and height 175 cm (BMI = 33.9), and waist circumferences was 110 cm in diameter, blood pressure was 160/100 mmHg.

Patient's family's history was negative for the familial liver disease or iron overload. It was also showed negative personal history of iron overload, ineffective erythropoiesis, hereditary hemochromatosis, and porphoria cutanea tarda. The patient denied any alcohol intake, liver disease; renal disease, previous infection or inflammation and malignancies.

While patient's examination showed that his abdomen was soft and lax, with no tenderness; the liver was palpable 2 cm; below the costal margin (notch was not palpable). Other examination (chest and cardiovascular examination) were unremarkable. Eye examination showed no eye redness, abnormal pigmentation or cataract.

The next investigation was iron studies with results being all normal. The concomitant Hepatitis B virus was shown (Core IgG positive; HBSAG negative; Anti-HBS negative; positive PCR), while the hepatitis C virus was negative. Hemoglobin Pattern by HPLC showed normal pattern (no hemoglobinopathy), Anti-nuclear antibody was negative, whereas plasma fibrinogen was normal 377 mg/dL (fibrinogen: 150-400 mg/dL).

Liver ultrasound shows mild hepatomegaly with moderate to severe fatty changes, and mild splenomegaly.

Case Discussion


Generally, the patient had high serum ferritin with metabolic syndrome without iron overload (obesity, type 2 diabetes mellitus, hypertriglyceridemia and hypertension) [1,16,17].

The patient also had moderate to severe Nonalcoholic Steatohepatitis (NASH), with liver parenchymal inflammation due to "fatty liver" combined with positive hepatitis B [18,19].

The chronic viral hepatitis combined with metabolic NASH was believed to be the cause of the hyperferritinaemia. There was no evidence of iron overload. Lifestyle modifications and Hepatology referral were recommended.

There are two main causes for increased serum ferritin:

1. Raised serum ferritin without iron overload (90% of cases) (Table 1) [18-20] .

Table 1: Causes of raised serum ferritin without iron overload [19]. View Table 1

2. Raised serum ferritin with iron overload (10% of cases) (Table 2) [18-20] .

Table 2: Causes of raised serum ferritin with iron overload [19]. View Table 2

Guideline in Clinical Assessment of Hyperferritinemia Primary Care [4,18,21-24]


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 (C reactive 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).

7. Refer the patient to Hematology and Hepatology if:

a. The patient has confirmed iron overload with ferritin level > 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.

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) [24].

Conclusion


Mostly, an increased ferritin with normal transferrin saturation is often found in patients with hepatic steatosis. The simultaneous disorder of iron and glucose and/or lipid metabolism may occur in metabolic hyperferritinaemia. Patients present with positive hepatitis profile indicate combined infective and metabolic hyperferritinaemia.

Recommendation


• Elevated S.F is usually due to acute/chronic inflammation, heavy alcohol ingestion, acute/chronic liver, kidney, metabolic syndrome and rarely malignancy.

• Initial tests are full CBC, liver/renal function and inflammatory markers.

• Normal fasting serum transferrin saturation will exclude iron overload.

• Unexplained very high levels of SF ≥ 1000 μg/L warrant specialist referral.

• Consider HFE gene study, if hereditary hemochromatosis is considered (SF ≥ 1000 μg/L and raised serum transferrin saturation is ≥ 45%).

References


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