Clinical spectrum of iron deficiency without anemia is diverse

Esa Soppi, MD, PhD, senior consultant, internal medicine

Key clinical message

The diagnosis of iron deficiency without anemia rests on alerted clinical suspicion, on a history of blood loss and on increased needs or reduced absorption of iron, which needs to be ascertained by determination of the serum or plasma ferritin level. The correct diagnosis is important since failure to detect iron deficiency may lead to wrong treatment(s) and invasive procedures.

Abstract

The symptom spectrum of iron deficiency without anemia is highly variable and the diagnosis may be extremely difficult. The diagnosis rests on alerted clinical suspicion, on a history of blood loss and on increased needs or reduced absorption of iron, which needs to be ascertained by determination of the serum or plasma ferritin level. The correct diagnosis is important since failure to detect iron deficiency may lead to wrong treatment(s) and invasive procedures, and years of delay of the correct diagnosis and entails also high costs to the society. Iron deficiency should always be treated.

Introduction

Iron deficiency without anemia is 2-3 times more common than iron deficiency anemia [1,2]. Since the blood count may be totally normal in iron deficiency without anemia, the diagnosis may be evasive, and the diagnosis will rest on clinical suspicion, i.e., the patients’ symptoms, a history of blood loss, increased iron needs, dietary habits or diminished absorption [2-4]. An additional challenge is the fact that the patient may exhibit highly variable symptoms and there are no pathognomonic signs characterizing this condition [2]. The diagnosis rests ultimately on the serum or plasma level of ferritin, which – if low (< 30 g/L) – is the most specific and sensitive indicator of iron deficiency [3,4]. However, a much higher concentrations of ferritin (up to 100 g/L or even higher) may still indicate iron deficiency [5-7]. In this controversial situation the value of ferritin for diagnosing iron deficiency has not gained wide awareness or acceptance. Thus, even if the results of ferritin determinations are available to the treating physician, conclusions regarding diagnosis may be quite variable [2]. Here, I present four case reports to highlight the diagnostic difficulties.

Cases highlighting the challenge

Case 1

Twelve to nine years before the consultation visit Sjögren’s syndrome was suspected because of xeropthalmia, but all tests for autoimmune reactivity were negative. At the same time, it was noticed that the patient’s platelet count was somewhat increased (513-524×109/L) and that her hemoglobin was 158 g/L. The spleen was sonographically and clinically normal. Bone marrow examination revealed a slight proliferation of megakaryocytes with hyperlobulated nuclei. The other lineages were unaffected, and no stainable iron was detected in the bone marrow. The patient had a V617F mutation of the JAK2 gene.

The patient had increasing arthralgia accompanied with synovitis over the next five to seven years. All tests for autoimmunity were still negative. The patient was HLA-B27 positive. The sedimentation rate was 6 mm/h, the leucocyte count 9.0×10

9/L, the hemoglobin 144 g/L, the mean corpuscular volume (E-MCV) 94 fl, the mean corpuscular hemoglobin (E-MCH) was 30 pg and the platelet count was 586×109/L. A lip biopsy indicated Sjögren’s syndrome and glucocorticosteroid and hydroxychloroquine were started. Later on, a diagnosis of seronegative rheumatoid arthritis was made and a small dose of glucocorticosteroid was continued. She was put on and methotrexate, but this had to be discontinued soon due to elevated liver enzyme values. After this, the leucocyte count was 7.6-7.9×109/L, the hemoglobin 154-160 g/L, the E-MCV 92-94.4 fl and the E-MCH 29.1-30 pg. The platelet count reached a level of 868 – 721 x109/L. Then three phlebotomies were performed after which the blood count was leukocytes 10.2×109/L, hemoglobin 115 g/L, E-MCV 79.3 fl, E-MCH 22.1 pg and platelets 720×109/L. After the phlebotomies the patient became fatigued and experienced joint and muscle pains and dizziness.

The patient was referred to a tertiary level hospital two years before the consultation visit. The spleen was still sonographically normal. Gastroscopy and colonoscopy showed normal results. Bone marrow aspiration and biopsy results were essentially the same as 10 years earlier and revealed some sclerosis and a minor increase in reticulin fibers, no blasts. There was still no stainable iron in the bone marrow. Hydroxyurea was initiated but was soon discontinued as the patient got fever. Thereafter, interferon treatment was initiated and continued occasionally but had ultimately to be discontinued due to adverse effects. Occasional phlebotomies were performed. The symptoms of the patient became worse and included shortness of breath, she had muscle pains in all extremities, restless legs and difficulties to concentrate, brainfog and loss of memory. A CT scan of the brain was normal, and a neurologist did not find any signs of memory impairment or Alzheimer’s disease.

Eight months before the consultation visit the patient’s sedimentation was 9 mm/h, the C-reactive protein was 1.3 mg/L, the leucocyte count was 12.0×10

9/L and the differential count showed eosinophilia. The hemoglobin was 113 g/L, the E-MCV 81 fl and the E-MCH 25 pg, the platelets 495×109/L, the soluble transferrin receptor (S-sTfr) 9.4 mg/L and the ferritin 18 g/L. The serum immunoglobulin concentrations, the thyroid and liver function tests and the serum calcium were normal and there was no paraproteinemia. Additional phlebotomies were proposed but the patient refused because she felt that her symptoms were stemming from iron deficiency. A few months before the consultation visit, the patient had started to take 100 mg of elemental iron daily and just before the consultation visit her hemoglobin was 136 g/l, the platelets 482×109/L and the ferritin 13 g/L (Table). She also felt that her general condition had improved somewhat.

The patient came for a consultation to seek a second opinion on the need for phlebotomies and on the use of iron. She was a nonsmoking female (age 66, height 161 cm, weight 61 kg), was clinically healthy, her blood pressure was somewhat elevated at 164/79 mmHg (normal at home measurements) and her pulse rate was 72/min. The spleen was not palpable. She took acetylsalicylic acid 100 mg, rosuvastatin 5 mg and a small dose of glucocorticosteroid daily.

It turned out that she had also donated blood ten times before the treatment of Sjögren’s syndrome. The last blood donation had taken place immediate before start of the hydroxychloroquine treatment. Her history revealed also that she had undergone a hysterectomy and bilateral oophorectomy due to myomas and abundant menstruation 20 years before the consultation visit. She had delivered four children and had had one miscarriage. There was no information available on the amount of blood loss or on blood counts during/after the pregnancies. Obviously, her iron deficiency was caused by abundant menstruations, pregnancies and numerous blood donations.

She was advised to continue the 100 mg daily dose of iron and after two months the hemoglobin was 151 g/l and hematocrit was 44.9% (Table ). The D-vitamin was 102 nmol/L, the active B12 vitamin > 292 pmol/L, the transferrin saturation 22.3% and the serum calcium was normal. She was further advised to continue the oral iron at the same dose. The patient’s symptoms had improved considerably by the follow-up visit and she continued to use 100 mg up to the visit at month 11, when the patient was totally symptom free and the iron therapy was discontinued.

Table. Test results during oral iron therapy

Time point (months)	Oral iron (100 mg)	Leucocytes (x109/L)	Hemoglobin (g/L)	MCV (fl)	MCH (pg)	Platelets (x109/L)	Ferritin (g/L)
- 8	No	12	113	81.0	25.0	495	18.0
Consultation visit	Yes	7.6	136	83.0	26.0	482	13.0
+ 2	Yes	7.4	151	85.4	28.7	467	44.7
+5	Yes	11.1	147	88.0	30.0	402	67.2
+ 8	Yes	7.6	156	91.1	30.4	468	85.9
+ 11	Yes	9.0	159	91.9	30.6	456	164.2

Table. Test results during oral iron therapy

Her hematocrit was never > 49%.

Case 2

The patient (nonsmoking female, age 16) had had intractable tiredness from the age of 10 years, at which age her weight had started to increase without any change in the diet. At that time, she had undergone thoroughly investigations at a tertiary level hospital, but no explanations to her condition was found. Her fatigue persisted and she had difficulties in staying awake during lessons. During the following years her parents had consulted numerous physicians to no avail. During the last 18 months before visit the patient had also had anxiety and she was diagnosed with depression and sertraline 200 mg daily and aripiprazole 5 mg daily were prescribed. The patient slept well but sleep did not produce any relief from tiredness. She had gained another 10 kg weight during the last year.

The patient’s mother had searched the internet and had come to the conclusion that the patient might be iron deficient. She took the initiative to have her daughter’s hemoglobin and ferritin level measured without a physician’s referral.

The patient’s height was 166 cm and her weight 89 kg. A clinical examination was normal. The patient’s menstruation had started three years earlier and had a duration of 7-10 days with very abundant bleeding for 3-4 days. The patient’s hemoglobin was 124 g/L, the E-MCV 82 fl, the E-MCH 25 pg, the serum ferritin 8 g/L, the S-sTfr 2.4 mg/L, the S-TSH 2.5 mU/L and the S-T4v 14 pmol/L. Additional examinations ruled out celiac disease and deficiency of vitamin D and vitamin B12.

The patient was considered iron deficient from birth and was prescribed iron sulphate 100 mg twice daily.

Two months later the patient was feeling somewhat better, but her weight has continued to increase and was now 95 kg. Her hemoglobin was 147 g/L, the E-MCV 85 fl, the E-MCH 28 and the ferritin concentration had increased to 41 g/L.

Four months later the patient was feeling much better and the doses of both sertraline and aripiprazole had been reduced. Her hemoglobin was now 157 g/L, the E-MCV 91 fl, the E-MCH 31 pg and the ferritin was 53 g/L. Her weight was 102 kg.

Four months later both sertraline and aripiprazole were discontinued, and the patient was feeling increasingly better and was thriving through the school hours easily. Her hemoglobin was now 161 g/L, the E-MCV 91 fl, the E-MCH 30 pg and the ferritin was 99 g/L. In the meantime, the patient was examined in a tertiary level hospital because of the weight gain, then 108 kg, but no specific reasons for the weight gain were identified and the weight gain as well as the improvement of the patient’s condition remained elusive. The only statement was that neither the symptoms nor the improvement was related neither to the iron deficiency nor to iron supplementation and that ferritin measurements were useless and were to be considered merely as a fashionable phenomenon.

The mother did not agree the conclusions and iron supplementation was continued at the same dose and the next consultation visit was scheduled after three months.

Case 3

A nonsmoking female (age 43) requested a consultation because she had experienced fatigue, exhaustion, shortness of breath and severe muscle cramps of the back as well as tenderness and a burning sensation of the tongue. The symptoms had persisted for the last seven years, during which time she had visited tens of physicians of different specialties including dentists.

The patient’s height was 174 cm and weight 72 kg. There were no abnormalities on physical examination, including the oral cavity. Her blood pressure was 153/90 mmHg (normotensive by home measurements). She was able to work in spite of her symptoms.

Her medical history revealed that at the time of symptom debut she had lost some weight and had had mild diarrhea. A whole-body CT scan raised a suspicion of Crohn’s disease and mesalazine 1 g twice daily had been prescribed which she was still using. She was considered depressed at that time. She had continuously and strongly insisted that her symptoms were caused by some somatic disease which would need to be identified and duly treated. Then she was considered psychotic and numerous antidepressants and antipsychotic drugs were prescribed and electroconvulsive therapy was administered. Despite these efforts, she felt that her symptoms persisted unchanged and she decided to keep her thoughts to herself but continued to seek help from numerous physicians.

Her history revealed further that she had made five blood donations at the age of about 20 years and she had delivered three children. The hemoglobin had been normal during the pregnancies and there had not been any major bleeding at deliveries. The last delivery was two years before symptom debut. Concomitantly with the start of symptoms her menstruation had become abundant with 3-6 bleeding days, including profuse clots during the first days.

Two years prior to the consultation visit her hemoglobin had been 117-120 g/L and her E-MCH 26 pg. Thereafter she had used liquid iron preparations up to 40 mg daily, but she had difficulties in tolerating them. A cyst in her left ovary was discovered and hormonal contraception was terminated. Six months before the consultation visit the patient’s hemoglobin had been 143 g/L, the E-MCV 91 fl, the E-MCH 30 pg, the platelet count 286×109/L, the ferritin 8 g/L and the sedimentation rate 2 mm/h. Thyroid, liver and kidneys function tests and tests for celiac disease and calprotectin (42 g/g) were normal.

At the time of the consultation visit her ferritin value was 6.3 g/L, the vitamin D concentration 49.4 nmol/l and the vitamin D dose was increased from 20 to 100 g daily. Active B12 was 74.5 pmol/l and she was prescribed three 1mg injections of cobalamin. She was advised to try oral iron at a maximum daily dose of 200 mg.

Case 4

A nonsmoking female (age 18) sought help with her mother because of a diagnosis of chronic fatigue syndrome (CFS), a diagnosis the parents did not accept.

The syndrome was diagnosed in a university hospital 15 months prior to the consultation visit and supportive psychotherapy was prescribed since several antidepressants had proved ineffective. Two years before the CFS diagnosis the patient had begun to have extreme tiredness, brainfog and inability to concentrate, which prevented her from thriving in school. She had to remain at home since she was not able to walk and had to crawl to move around at home. At the beginning of the symptoms he had also had almost daily migraine for 4 months, she had hair loss and did not recover well from physical activity.

Before the diagnosis of CFS a brain MRI was performed with normal results. Numerous laboratory examinations had been normal, including thyroid tests, serum calcium and gastroscopy. Her hemoglobin had been 130 g/L, the E-MCV 83 fl and the E-MCH 27 pg. Vitamin D had been 96 nmol/L and the serum ferritin 4 g/L. She had her menarche at age 13 years and had 5 bleeding days 3-4 days of which were very abundant.

The parents made some internet searched and suspected that the patient might have iron deficiency. They had provided the patient with several iron preparations during the previous year, but the patient could tolerate any.

At the consultation visit the patient’s height was 156 cm and the weight 74 kg. The patient’s symptoms had not changed but she was able to walk. The physical examination was uneventful. Her blood pressure was 100/70 mmHg and pulse of 70/min. Her hemoglobin was 134 g/L, the E-MCV 87 fl and the E-MCH 29 pg. The ferritin concentration was 20 g/L and the transferrin saturation 11%.

Based on the discussion with the mother and the patient it was concluded that the patient had indeed have deficiency which was further provoked by the abundant menstruation. She might have been iron deficient from, birth since her younger sister had had iron deficiency anemia before menarche although the mother had not been anemic during the pregnancies.

Because the patient did tolerate oral iron at all, ferric carboxymaltose (500 mg) was infused three months after the first visit when the ferritin concentration was 39 g/L. Seven weeks after the infusion the ferritin concentration was 167 g/L and the patient was totally free of symptoms.

Discussion

In case 1, the diagnosis of essential thrombocytosis was made and substantiated by the bone marrow examination and the JAK2 mutation [8]. The JAK2 V617F somatic mutation is very rare in the general population and, when present, supports the diagnosis [9]. At the same time the patient had, however, been iron deficient, which introduces uncertainty as to the true platelet count, since iron deficiency often causes thrombocytosis, occasionally thrombocytopenia [4]. Because the patient had a rather high hemoglobin (158 g/L) but no stainable iron in the bone marrow, polycythemia vera was suspected and several phlebotomies were performed which induced iron deficiency anemia and the patient became symptomatic due to iron deficiency [2,4].

Later, oral iron therapy increased the patient’s hemoglobin to around 150 g/L. The leucocyte count was close to the upper limit of the reference range, but the patient was taking a small dose of glucocorticosteroid which may have increased the leucocyte count. As a whole, the diagnosis of polycythemia vera was highly improbable and phlebotomies should not have been performed. During iron replacement the platelet count remained close to the upper end of the reference range, which may indicate that the previous thrombocytosis may have been due to iron deficiency [4], but the late effects of drug treatment of essential thrombocytosis cannot be ruled out.

in Case 2, the patient had continuous weight gain and mental symptoms and was diagnosed with depression and treated accordingly. However, she had a blood count taken on her own initiative which showed normal hemoglobin but microcytosis and hypochromia; her ferritin was low and thus iron deficiency was diagnosed [3,4]. Her medical history indicated that she had been iron deficient from birth which may have had long-term effects on her well-being [4]. Depressive and other cognitive symptoms as well as weight gain are common signs of iron deficiency (without anemia) [2,10,11], probably because iron constitutes an essential part of numerous of enzyme molecules in our body, including enzymes active in the brain. The activity of these enzymes is reduced by iron deficiency and they function properly only if iron is available for extended periods [2,4,12-14].

Continuous weight gain during iron therapy may indicate that the restoration of iron-containing enzyme systems takes much more time than restoration of hemoglobin and iron stores.

In case 3, depression and even psychosis were diagnosed, and electroconvulsive therapy was administered although the patient was convinced that she had some somatic disease. It is apparent this somatic disease had been iron deficiency (without anemia) [2].

In case 4, chronic fatigue syndrome (CFS) was diagnosed in spite of the very low ferritin (4 g/L). Recently, Komaroff (2019) [15] reviewed the multitude of biological changes associated with the CFS and highlights the time of disease onset when many standard laboratory test results are normal; at this stage, many clinicians tell the patients that “there is nothing wrong.” Komaroff [15] wisely brought up an alternative explanation: that the standard laboratory tests might not be the right tests to identify the underlying abnormalities, which was the case for patient 4. Since iron has a multitude of functions in the body [2,4,12-14], it is no surprise that the clinical findings related to CFS patients [15] are compatible with those in iron deficiency without anemia [2 Soppi 2019). Iron deficiency should always be considered in all patients with CFS and, if present, treated accordingly. The patient recovered totally after intravenous iron but needs extended follow-up and, possibly, another infusion [16].

Conclusion

The clinical spectrum of iron deficiency without anemia can be diverse [2] and the diagnosis may be extremely difficult. The diagnosis rests on alerted clinical suspicion and a careful medical history and is established by a low ferritin serum ferritin concentration. Especially pregnant women in early pregnancy, teens after puberty, patients with atypical depression and patients with CFS should be actively examined for iron deficiency. The correct diagnosis is important, since failure to detect iron deficiency may lead to inappropriate and even dangerous medications and invasive procedures. There may be years of delay of the correct diagnosis which entails also high costs to the society.

Based on my long clinical experience I am convinced that significant delay, especially if the

patient has been iron deficient from birth, may result in permanent damage and the patient will not recover [17]. Once detected, iron deficiency should always be treated [14,16]. Iron deficiency without anemia should be considered a chronic disease, especially if it has lasted for years before the diagnosis.

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