Before the development of transfusion medicine, severe anaemia was an important cause of morbidity and mortality. The discovery of haematopoietic mechanisms and essential nutrients made it possible to easily treat and prevent this condition. Nevertheless, it is often fatal in patients presenting with extreme anaemia (haemoglobin levels <2 g/dl). We report the rare case of a 54-year-old woman who presented with profound megaloblastic anaemia (haemoglobin of 1.7 g/dl) due to vitamin B12 deficiency, and was successfully treated.
Severe anaemia, vitamin B12, nutritional deficiency
Active blood loss is usually the main concern when extreme anaemia is found: significant acute-onset bleeding without proper management can develop into haemorrhagic shock and death. Other more insidious disorders, such as cancers, infections, malnutrition, and haemopoietic or drug-induced conditions, can also cause severe anaemia. Increased cardiac output, decreased peripheral vascular resistance, and decreased oxygen affinity of red blood cells (RBC) are some of the physiological changes that occur in response to anaemia, and patients will develop dyspnoea, easy fatigue, or tachycardia on exertion, and usually resort to healthcare before haemoglobin levels start to plummet. When a restrictive blood transfusion strategy is implemented, moderate anaemia (haemoglobin (Hb) of 7–10 g/dl) is not associated with increased mortality . In patients without major haemorrhage, chronic anaemia or acute coronary syndrome, the Hb level threshold for RBC transfusion is currently 7 g/dl [2, 3], as morbidity and mortality increases when Hb levels are below 7 g/dl. Carson et al.  retrospectively studied the relationship between the nadir of postoperative Hb levels and mortality, in 300 patients who refused blood transfusions, and showed that the 30-day mortality for Hb of 7–8 g/dl was 0%. However, it increased significantly when values were lower than 5 g/dl: 34% for 4–5 g/dl, 25% for 3–4 g/dl, 54% for 2–3 g/dl, and 100% for 1–2 g/dl (n=7). These outcomes have not been studied for patients with very severe chronic anaemia.
We report the case of a 54-year-old woman admitted at the emergency department with severe fatigue and functional limitation, having been bedridden for the past few months following a 5-year progressive deterioration of general status. In addition to the asthenia, she complained of paraesthesia in all four limbs (without any discernible pattern), episodes of self-limiting lower limb palsy (affecting both legs in an alternating fashion), and frequent falls in the last year which she said were caused by dizziness and lack of balance. She denied any relevant trauma or evident blood loss. Throughout this lengthy period, she had always refused to seek medical attention.
At 49 years of age, she had been diagnosed with gastric cancer (an antral ulcerated lesion with histological features of adenocarcinoma with a solid tubular pattern with isolated signet ring cells, pT3N0R0) and underwent total gastrectomy and chemotherapy (8 cycles, capecitabine plus oxaliplatin), without any complications, but was lost to follow-up at the end of the treatment.
Further information concerning the patient’s history obtained from her family and her electronic medical records revealed she had experienced severe asthenia after the chemotherapy had ended and had since declined any external support or healthcare assistance. They also confirmed the absence of any evident blood loss. The patient only agreed to go to the emergency department due to the persistence of her son, who contacted the national pre-hospital emergency system. The family did not provide any further explanations besides the refusal of the patient to seek any medical attention. On physical examination, we found a prostrated, emaciated and severely malnourished individual, showing severe cutaneous and mucosal pallor and severe peripheral oedema. She was somnolent, but easily awaken by verbal stimuli (Glasgow Coma Scale score of 14 due to confusion). Besides a global decrease in muscle strength due to the evident sarcopenia, she showed no other focal neurological deficits, including sensory or proprioceptive dysfunction. Peripheral oxygen saturation was 83%, although she was eupnoeic: arterial blood gas analysis showed a PaO2 of 93 mmHg but an unmeasurable Hb (pH 7.48, PaCO2 29 mmHg, HCO3- 22 mmol/l, lactate 6.74 mmol/l, glucose 107 mg/dl). She presented with sinus tachycardia ranging from 90 to 120 bpm, an arterial blood pressure of 80/44 mmHg, and a prolonged capillary refill time. There were no other positive findings on examination.
Laboratory studies on admission (Table 1) showed extreme macrocytic anaemia (Hb of 1.7 g/dl, mean corpuscular volume (MCV) of 121.4 fl and haematocrit of 5.1%), signs of haemolysis (high indirect bilirubin of 1.15 mg/dl, remarkably high LDH of 5063 U/l, haptoglobin consumption, and negative Coombs test), thrombocytopenia of 59×109 platelets/l, and a normal leucocyte count. Even though blood samples were scarce, upon suspicion of megaloblastic anaemia, the laboratory managed to broaden the blood analysis: vitamin B12 was not measurable (<84 pg/ml), and folic acid deficiency and HIV infection were excluded (Table 1).
The patient was admitted to the ICU and a slow correction of the anaemia was started with 2 units of packed RBC, parenteral correction of vitamin B12 deficiency (1 mg once daily) and oral supplementation with folic acid (5 mg once daily). Ultrasonography and thoraco-abdominal computed tomography (CT) showed generalized subcutaneous oedema, and mild pleural and pericardial effusions, but no other findings or signs of cancer relapse. A cerebral CT scan excluded intracranial lesions.
Haemodynamic stability was achieved without the need for more blood products, and there was sustained haematological improvement with the described strategy. Platelet levels reached a minimum of 28×109/l on day 3 but started to improve on day 4 and were within the normal range on day 5. On the 5th day of hospitalization, haemoglobin (Hb) was 8.5 g/dl, haemolysis markers were steadily decreasing, and the patient’s symptoms were improving, so she was transferred to the medical ward.
She received nutritional and psychiatric evaluation, and the treatment plan was adjusted. Six days later, she was discharged home for outpatient management.
On patient follow-up at 3 and 5 months, she showed normal haematological values, total functional autonomy, and resolution of the peripheral neuropathic symptoms.
Table 1 Laboratory results throughout patient follow-up
hs, high sensitivity; MCH, mean corpuscular haemoglobin; MCV, mean corpuscular volume; RDW-SD, red cell distribution width-standard deviation.
The vast majority of vitamin B12 uptake in the gastrointestinal tract depends on its binding with the intrinsic factor produced by gastric parietal cells and its absorption in the distal ileum. Conditions compromising nutritional intake and diseases causing dysfunction of gastric parietal cells and the associated absence of intrinsic factor, or dysfunction of the distal ileum, will result in B12 deficiency as the body’s stores start to become depleted . Patients may present with a macrocytic anaemia (macrocytic red cells, anisocytosis, macroovalocytes, which were first described in 1855 by Addison ), leukopenia, thrombocytopenia, signs of intravascular haemolysis, elevated levels of homocysteine and methylmalonic acid, and a wide spectrum of neurological symptoms ranging from altered mental status and cognitive defects, to myelopathy and peripheral neuropathy .
The discovery of vitamin B12 and its biochemical role in humans has spanned two centuries of breakthroughs, clinical reports and pivotal studies , leading to two different Nobel Prizes (Medicine in 1934 [7, 8] and Chemistry in 1964). Consequently, vitamin B12 deficiency can now be easily diagnosed and treated . Even though dietary deficiency and pernicious anaemia are frequently found in the general population, and the number of patients surviving gastrointestinal disorders and surgery has increased, extreme insufficiency presenting as life-threatening anaemia, pancytopenia or myelopathy, is far less common than in the past.
In 1947, MacDonald et al. had already recognized the development of a macrocytic anaemia in gastrectomized patients, “if they live long enough”, and its morphological similarity to the “Addisonian anaemia” . In 1966, Williams et al. demonstrated the benefit of permanent vitamin B12 supplementation after gastrectomy, regardless of the presence of haematological signs . Currently, it is standard practice to guarantee lifelong adequate iron, B12 and folate monitoring in this set of patients.
In our patient’s case, the loss to follow-up after her gastrectomy hindered the appropriate follow-up and supplementation. Such an extremely low haemoglobin level only seems possible if there has been a slow and progressive depletion of B12 stores along with physiological and functional adaptation to the progressive anaemia. Active bleeding was excluded as the patient reported no gastrointestinal or genitourinary blood loss, a CT scan showed no signs of internal bleeding or recurrence of oncological disease, and all haematological parameters steadily improved under treatment.
While we are aware of several anecdotal unpublished reports, we only found 23 published reports of patients with similar anaemia (haemoglobin levels <2 g/dl). The lowest value recorded in a patient who survived was 0.4 g/dl. Our case seems to be the third reported of a patient surviving what seems to be extreme chronic anaemia (Appendix Table 1) [11, 12].
In the absence of haemorrhagic shock, the standard therapy in these patients was treatment with a restrictive transfusion strategy, supporting haemodynamic and symptom stability, as transfusion complications such as ischaemic stroke, reversible cerebral vasoconstriction syndrome and hyperhaemolysis can occur. This is similar to the treatment provided to our patient, who recovered without any sequelae or complications.
Reports of patients with extreme anaemia (Hb <2 g/dl) are now very rare after the advent of blood transfusion medicine in the second half of the 20th century, along with wider access to better healthcare, improved management of critical situations and bleeding control, the implementation of enteral and parenteral supplementation with iron, folate and vitamin B12, and active anaemia screening in the general population.
As reported anecdotally in the literature, this type of severe anaemia only seems to be possible if there is slow progressive depletion of vitamin B12 stores in the absence of adequate nutrition. Adherence to treatment and medical advice is essential in patients who will also require life-long follow-up.
Appendix Table 1. Case reports of extreme anaemia (Hb <2 g/dl) in the literature
The only two cases of extreme chronic anaemia are highlighted (in bold). EPO, erythropoietin; F, female; FFP, fresh frozen plasma; Hb, haemoglobin; IVIG, intravenous immunoglobulin; M, male; NB, new-born; PRES, posterior reversible encephalopathy syndrome; RBC, red blood cells; RCVS, reversible cerebral vasoconstriction syndrome; y, years.