Al-Azhar Assiut Medical Journal

ORIGINAL ARTICLE
Year
: 2017  |  Volume : 15  |  Issue : 3  |  Page : 135--141

Evaluation of serum ferritin level in patients with fever of unknown origin


Raed Hamed Mansour1, Shaban Salah Abd El-moneum1, Tarek Aly Hassan2, Ahmed Abdelalim Abuo Elhassan1, Mohamed Hasan Elnadry1, Wlid Mohamed Elbakrawy3,  
1 Professor, Tropical Medicine Department, Al Azhar University, Cairo, Egypt
2 Professor of Biochemisry, Al Azhar University, Cairo, Egypt
3 Tropical Medicine Specialist, Ministry of Health

Correspondence Address:
Raed Hamed Mansour
Tropical Medicine Department, Alhosin Hospital, Cairo
Egypt

Abstract

Background Diagnosis of the cause of fever of unknown origin (FUO) is a great challenge. Serum ferritin may be a useful index for differentiating between infectious and noninfectious causes of FUO (malignant disease or collagen disease). In this respect, serum ferritin has the advantage of decreasing the number of unnecessary tests and helping to exclude infectious disease. Objective This study aimed to evaluate serum ferritin levels among patients suffering from FUO. Methods A comparison was made between infectious, noninfectious, and undiagnosed cases of FUO as regards serum ferritin level using an in-vitro enzyme-linked immunosorbent assay. Results The most common causes of FUO were infectious diseases (120/300, 40%), followed by noninfectious diseases such as malignant (61/300, 20.4%) and autoimmune causes (49/300, 16.3%). Undiagnosed cases constituted 70/300 (23.3%). The mean serum ferritin level in the infectious group, noninfectious group, and undiagnosed group was 99.25±49.58, 1098.94±284.54, and 112.40±183.23, respectively, with highly significant difference between infectious and noninfectious causes of FUO (P<0.001). However, there were no significant differences between infectious and undiagnosed causes of FUO. The optimal cutoff point was 559.0; the area under the curve was 0.79, with highly significant difference (P<0.001) at 95% confidence interval of 0.71–0.88. Conclusion High serum ferritin level (>559 ng/ml) helps in differentiation between infectious and noninfectious causes of FUO. In undiagnosed cases of FUO we must direct our thinking to infectious diseases.



How to cite this article:
Mansour RH, Abd El-moneum SS, Aly Hassan T, Abuo Elhassan AA, Elnadry MH, Elbakrawy WM. Evaluation of serum ferritin level in patients with fever of unknown origin.Al-Azhar Assiut Med J 2017;15:135-141


How to cite this URL:
Mansour RH, Abd El-moneum SS, Aly Hassan T, Abuo Elhassan AA, Elnadry MH, Elbakrawy WM. Evaluation of serum ferritin level in patients with fever of unknown origin. Al-Azhar Assiut Med J [serial online] 2017 [cited 2018 Nov 18 ];15:135-141
Available from: http://www.azmj.eg.net/text.asp?2017/15/3/135/226051


Full Text



 Introduction



Fever of unknown origin (FUO) was defined in 1961 by Petersdorf and Beeson [1] as a temperature greater than 38.3°C (101°F) on several occasions, of more than 3 weeks’ duration, and failure to reach a diagnosis despite 1 week of inpatient investigation.

The causes of FUO include a wide variety of infectious and noninfectious factors. Acute febrile disorders are not included in the definition and even if it is diagnosed it should not be termed FUOs. Prolonged fevers difficult to diagnose may be due to infection, malignancy, rheumatic diseases, or a variety of other miscellaneous causes [2],[3].

The types of disorders that are associated with prolonged fevers have remained relatively constant over time but the relative proportion of different disease categories has changed over the years. In Petersdorf’s initial description, infectious diseases constituted the largest single category of disorders causing FUO. Decades later, in a re-evaluation of the distribution of FUO causes, Petersdorf noted that malignancies had exceeded infectious diseases as the most important single cause of FUO. Later, in some other series the distribution changed again, which reflects the demographics of the population being studied. The study of FUOs indicates that a majority of patients had unexplained fevers due to noninfectious inflammatory conditions (predominantly rheumatic disorders) [4].

Ferritin is a protein consisting of 24 subunits that is present in every cell type (Theile, 1987 [5]). It stores iron and releases it in a controlled manner. The amount of ferritin stored reflects the amount of iron stored. Ferritin serves to store iron in a nontoxic form to deposit it in a safe form and to transport it to areas where it is required [6]. It is an acute-phase protein whose plasma concentrations increase in response to inflammation [7].

 Aim



The aim of this study was to evaluate the serum ferritin level in patients with FUO.

 Patients and methods



A cross-sectional study carried out in cooperation between the Tropical Medicine Department, Al-Azhar University, Cairo, and Menof Fever GIT Hospital was held between October 2014 and April 2016. The study was carried out on 300 patients who were admitted to the FUO Department at Menof Fever, Liver and GIT Hospital. Patients with fever of greater than 3 weeks’ duration for which no causes were identified, who were above 18 years old, and who agreed to participate were enrolled in the study. Patients with long-standing fever before the study, patients on iron therapy, patients with hemolytic anemia, and patients with comorbid diseases were excluded from the study. All patients who participated in the study were subjected to careful history taking, clinical examination, routine laboratory investigations including complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fetal bovine serum, liver and renal function tests, Widal agglutination test, monospot test, Brucella agglutination test, and blood and urine culture in suspected cases. Also, malarial blood film test in suspected cases (performed by a clinical pathology specialist in the laboratory), immunological tests such as rheumatoid factor, antinuclear antibodies, anti-streptomycin O titre (ASOT), anti-double-strand DNA, and evaluation of tumor markers such as α-fetoprotein, carcinoembryonic antigen, prostate specific antigen, and CA19-9 were carried out in suspected cases. Tuberculin test and estimation of serum ferritin level by enzyme-linked immunosorbent assay were performed. Chest radiography, echocardiography, abdominal ultrasonography, computed tomography, and MRI were carried out. Invasive procedures such as bone marrow biopsy, lymph node biopsy, and lower gastrointestinal endoscopy were carried out in some selected cases. The enrolled patients were classified into three groups: group I included 120 (40%) patients with infectious causes of FUO; group II included 110 (36.6%) patients with noninfectious causes of FUO; group III included 70 (23.4%) patients in whom the cause could not be diagnosed.

 Results



The demographic characteristics showed no statistically significant difference among the studied groups with respect to age and sex. Chills, fatigue, and arthralgia were common presenting symptoms with no significant differences among the studied groups, but weight loss was a presenting symptom in 30% of patients in group II compared with 17.5 and 12.9% in groups I and III, respectively (P=0.01). There was significant difference between the studied groups as regards splenomegaly, lymphadenopathy, arthritis, and cardiac murmur, but there was no significant difference regarding hepatomegaly and skin rash. Regarding the clinical finding among the studied groups, splenomegaly, lymphadenopathy, arthritis, and cardiac murmur were the most common signs presenting in the noninfectious group with high statistical difference compared with infectious and undiagnosed groups, whereas no significant difference was present between the studied groups as regards hepatomegaly and skin rash.

[Table 1] shows that the most common cause of FUO is infection, followed by malignant and autoimmune causes.{Table 1}

Brucella agglutination test helped in the diagnosis of 11.1% of the total number of cases of FUO, whereas the Widal test, blood culture, and stool culture helped in the diagnosis of 6.6% of the total number of cases of FUO. The most common malignant cause of FUO was hepatocellular carcinoma (HCC) (34, 55.6%), followed by Hodgkin’s lymphoma (7, 11.5%) and pancreatic carcinoma (5, 8.2%).

Serum ferritin was highly statistically elevated in group II compared with groups I and III, whereas there was no statistically significant difference between group I and group III as regards serum ferritin ([Table 2]).{Table 2}

The highest mean serum ferritin among infectious causes of FUO was observed in osteomyelitis (160 cases), followed by HIV (129 cases), whereas the lowest mean serum ferritin was in dental abscess cases ([Table 3]) [8].{Table 3}

The highest mean serum ferritin among malignant causes of FUO was observed in bronchogenic carcinoma (1362 cases), followed by HCC (1350 cases), whereas the lowest mean serum ferritin was in colorectal carcinoma (1146 cases) ([Table 4]).{Table 4}

The highest mean serum ferritin among autoimmune causes of FUO was observed in rheumatic fever (847.5 cases), whereas the lowest was in systemic lupus erythematosus (SLE) (751 cases) ([Table 5]).{Table 5}

Autoimmune causes of FUO had highly statistically elevated serum ferritin level when compared with malignant causes of FUO ([Table 6]).{Table 6}

[Table 7] shows that the optimal cutoff point of serum ferritin as a differentiation test between infectious and noninfectious causes of FUO was 559 ([Figure 1]).{Table 7}{Figure 1}

 Discussion



FUO constitutes one of the greatest challenges of clinical practice. It is one of the most common symptoms indicative of a disease. It has been categorized into four variants: classic, neutropenic, HIV associated, and nosocomial [9].

The classic type is defined as febrile disease of more than 3 weeks’ duration with fever above 38.3°C on several occasions that remains undiagnosed after 3 days of investigations in the hospital or after three outpatient visits [8].

In previous studies, the causes of FUO have been classified as infectious diseases, malignancies, collagen diseases, and others [10].

Although the serum ferritin level is related to body iron content under normal circumstances, extreme serum ferritin elevation (hyperferritinemia) is a nonspecific indicator of iron disorder [11].

Serum ferritin may be increased in patients with fever but such an increase might become a factor in differential diagnosis of FUO rather than an acute-phase reactant, considering that the diagnostic criterion for FUO is a fever lasting longer than 3 weeks [12].

Interest in the utilization of serum ferritin as a clinical tool for diagnosis of human diseases has increased. As patients with hematologic malignancies such as Hodgkin’s disease and acute leukemia have reduced cellular immunity level and increased serum ferritin levels, serum ferritin is thought to be associated with immunity [13].

In addition, serum ferritin is related to inflammation and may be increased in the presence of chronic inflammation such as chronic kidney disease, rheumatoid arthritis, or other autoimmune diseases. During chronic inflammation, such as hematologic malignancy or autoimmune diseases, the body produces hepcidin in the liver as a defense mechanism so that neither pathogens nor tumor cells can utilize serum iron by suppressing intestinal absorption and sequestration of iron in the macrophage, producing a relatively iron-deficient state, which is reflected by an increase in serum ferritin [14].

Therefore, these data suggest that serum ferritin may be a useful index to differentiate between infectious and noninfectious causes of FUO (malignant disease or collagen disease). In this respect, serum ferritin has the advantage of decreasing the number of unnecessary tests and helping to exclude infectious disease [12].

The age and sex distribution in our study shows no significant difference between the studied groups. The results agreed with those of Yu et al. [15] and Efstathiou et al. [16], who reported that there was no significant difference between infectious and noninfectious causes of FUO as regards age and sex distribution.

In the current study, there was no significant difference between the studied groups as regards fever, chills, fatigue, and arthralgia, whereas weight loss was a presenting symptom in 30% of patients in group II compared with 17.5 and 12.9% in groups I and III, respectively (P=0.01). This is because cachexia and weight loss are usually associated with malignancy.

Efstathiou et al. [16] reported that there was a significant difference between infectious and noninfectious causes of FUO as regards the presence of weight loss, with no significant difference in other symptoms as chills, fatigue, and arthralgia. Our results also agree with those of Kim et al. [12], who found that there was no significant difference between infectious and noninfectious causes of FUO as regards fever, chills, fatigue, and arthralgia.

Regarding liver size among the studied groups, hepatomegaly was present in three (2.5%) patients in group I, in seven (6.4%) patients in group II, and in two (2.9%) patients in group III, with no significant difference between groups II and III. Therefore, hepatomegaly cannot be used to differentiate between causes of FUO as it is presented in our study in infectious and noninfectious cases without a statistically significant difference between them. The results agree with those of Efstathiou et al. [16], who reported that there was no significant difference between infectious and noninfectious causes of FUO as regards the presence of hepatomegaly.

In the current study, splenomegaly was present in 25 (20.8%) patients in group I compared with 33 (30%) patients in group II and in two (2.9%) patients in group III due to infectious causes of FUO as typhoid fever. The results matched those of Efstathiou et al. [16], who reported that there was a significant difference between infectious and noninfectious causes of FUO as regards the presence of splenomegaly. However, the findings do not agree with those of Kim et al. [12], who found that there was no significant difference between infectious and noninfectious causes of FUO as regards splenomegaly.

In this study, there was significant difference between the studied groups as regards lymphadenopathy and arthritis and no significant difference as regards the presence of skin rash.

These findings agree with those of Efstathiou et al. [16], who reported that there was a significant difference between infectious and noninfectious causes of FUO as regards the presence of cardiac murmur, arthritis, and lymphadenopathy. However, there was no significant difference between infectious and noninfectious causes of FUO as regards the presence of skin rash.

Our findings do not agree with the findings of Kim et al. [12], who found that there was no significant difference between infectious and noninfectious causes of FUO as regards lymphadenopathy and arthritis.

In our study, there was no significant difference between the studied groups as regards hemoglobin (Hb), white blood cells (WBCs), or platelets. These results agree with Kim et al. [12] and Efstathiou et al. [8], who found that there was no significant difference between infectious and noninfectious causes of FUO as regards the same laboratory parameters, but they do not agree with the results of Abdelbaky et al. [17], who reported that there was a highly significant difference between infectious and noninfectious causes of FUO as regards WBCs, with no significant difference in Hb or platelets. Our findings do not agree with Wang et al. [13] either, who said that there was significant difference between infectious and noninfectious causes of FUO as regards Hb and WBCs.

In the present study, we found highly significant difference between the studied groups as regards ESR and CRP. This agrees with the results of Kim et al. [12] and Abdelbaky et al. [17], who found that there was a highly significant difference between infectious and noninfectious causes of FUO as regards ESR and CRP. Further, Kucukardali et al. [18] reported that there was a significant difference between infectious and noninfectious causes of FUO regarding these parameters. In contrast, our results do not concur with those of Efstathiou et al. [16] and Abdelbaky et al. [17], who reported significant difference regarding these two parameters between infectious and noninfectious causes of FUO.

In the current study, there was significant difference between group 1 and group 2 as regard liver function tests and renal function tests, which can be attributed to the most common noninfectious cause of FUO which is HCC.

This does not agree with the findings of Kim et al. [12] and Efstathiou et al. [16], who found no significant difference between infectious and noninfectious causes of FUO as regards liver function tests and renal function tests.

In the present study, we found that infectious diseases were represented by 40% of all patients suffering from FUO. Malignant diseases were the second cause of FUO, represented by 20.4%, followed by autoimmune diseases (16.3%). This agrees with the finding of Baicus et al. [19], who reported that infectious diseases were represented by 45.1% of all patients. Malignant diseases were the second cause of FUO, represented by 25.6%, followed by collagen diseases (18.9%). Further, Yamanishi et al. [11] reported that infectious diseases were represented by 32.7% of patients, followed by malignant diseases (18.3%), and collagen diseases (14.3%).

However, the results do not agree with Liu et al. [20], who reported that infectious diseases were represented by 33.9% of cases with FUO, collagen diseases by 25.1%, neoplasms by 21.1%, and unidentified causes by 19.8%. That is, collagen diseases were ranked the second cause of FUO, followed by malignancy.

In the present study, we found that brucellosis was the common infectious disease that caused FUO, represented by 28.3% of all infectious causes of FUO. The higher incidence of brucellosis was due to the location of our study, which was held at Menoufia governorate where many farmers live.

Zheng et al. [21] also found that brucellosis was the most common infectious cause of FUO.

This study does not concur with the findings of Baicus et al. [19], who reported that tuberculosis was the most common infectious cause of FUO. The higher incidence of tuberculosis in that study was due to alcohol abuse and high medical facilities in Romania. This study does not concur with the findings of Abdelbaky et al. [17] either, who found tuberculosis to be the most common infectious cause of FUO.

Zheng et al. [21] also found that tuberculosis was the most common infectious cause of FUO. He reported that the relatively high incidence of tuberculosis was due to overcrowded population, alcohol abuse, and HIV infection.

In the present study, we found that HCC was the most common malignant disease causing FUO, represented by 55.6% of all malignant causes of FUO. The higher incidence of HCC in this study was due to the high percentage of hepatitis C virus among the Egyptian people, which leads to liver cirrhosis and HCC. However, this finding does not agree with Liu et al. [20], who found that lymphoma, including non-Hodgkin’s lymphoma and Hodgkin’s lymphoma, is the most common malignant cause of FUO.

It does not agree with Chien et al. [22] either, who found that acute leukemia was the most common malignant cause of FUO, followed by lymphoma.

In the present study, we found that rheumatic fever was the most common autoimmune disease behind FUO, represented by 44.9% of all autoimmune causes of FUO. These results disagree with Liu et al. [20], who found that adult-onset Still disease is the most common collagen cause of FUO. Our finding does not agree with that of Chien et al. [22] either, who found that juvenile rheumatoid arthritis is the most common collagen cause of FUO.

In the current study, we found that there was a highly significant difference between infectious and noninfectious causes of FUO as regards serum ferritin levels and no significant difference between infectious and undiagnosed causes of FUO. These results agree with Kim et al. [12] and Liu et al. [20], who reported that there were significant differences between infectious and noninfectious causes of FUO as regards serum ferritin.

In the current study, we found that there was highly significant difference between autoimmune and malignant causes of FUO as regards serum ferritin levels. This agrees with Moore et al. [23], who stated that serum ferritin is higher in malignant diseases than in autoimmune diseases, with high statistically significant difference between them. We found that the optimal cutoff point of serum ferritin in discriminating between infectious and noninfectious causes of FUO was 559, which is similar to the rate cited by Kim et al. [12] − namely, 561 ng/ml. Further, Cunha [2] found that the optimal cutoff point of serum ferritin in discriminating between infectious and noninfectious causes of FUO was 500 ng/ml.

Efstathiou et al. [16] suggested that low ferritin concentrations (<500 ng/ml) were associated with infectious diseases.

Cunha and Petelin [24] found that highly elevated ferritin levels suggest FUOs attributable to malignancy.

Although serum ferritin may be increased in patients with fever, such an increase might become a factor in differential diagnosis of FUO rather than an acute-phase reactant, considering that the diagnostic criterion for FUO is a fever lasting longer than 3 weeks. Interest in the utilization of serum ferritin as a clinical tool for the diagnosis of human diseases has increased [20] and [24]. As patients with hematologic malignancies such as Hodgkin’s disease and acute leukemia have a reduced cellular immunity level and increased serum ferritin levels, serum ferritin is thought to be associated with immunity [21]. In addition, serum ferritin is related to inflammation and may be increased in the presence of chronic inflammation, such as chronic kidney disease, rheumatoid arthritis, or other autoimmune diseases. During chronic inflammation or autoimmune diseases, the body produces hepcidin in the liver as a defense mechanism so that neither pathogens nor tumor cells can utilize serum iron by suppressing intestinal absorption and sequestration of iron in the macrophage, producing a relatively iron-deficient state, which is reflected by an increase in serum ferritin [22].

 Conclusion



High serum ferritin level (>559 ng/ml) helps in differentiation between infectious and noninfectious causes of FUO. In undiagnosed cases of FUO, we must direct our thinking to infectious diseases as there was no significant difference between infectious and undiagnosed cases of FUO as regards serum ferritin level, whereas there was significant difference between undiagnosed and noninfectious cases of FUO.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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