Iron-deficiency anemia (IDA) is the commonest cause of anemia globally. IDA patients typically experience many systemic symptoms like weakness, pallor, fatigue, palpitations, exertional dyspnea, light-headedness, postural hypotension, neuropathy, and tachycardia. Oral symptoms may include mucosal atrophy, atrophic glossitis, angular cheilitis, dysgeusia, anemic stomatitis burning sensation that is peculiar to the oral mucosa, recurrent aphthous ulcers, lingual varicosities, and oral candidiasis.
Oral candidiasis is a commonest fungal infection and esophageal candidiasis (EC) is the commonest cause of infectious esophagitis. The patients may experience anorexia, dysgeusia, weight loss, and dysphagia, resulting in nutritional deficiency. Candida is a yeast that colonizes the epithelial surface of the urogenital system and alimentary canal of healthy humans as normal flora. Candida overgrowth occurs during an impairment of the systemic or local immune system, resulting in candida infection. Mucosal candida infections, such as those involving the esophagus, oropharynx, and vagina, are prevalent in the general population. EC occurs more commonly among HIV patients. This is because over 10%–15% of patients infected with HIV will develop EC during their lifetime, while 85%–90% of people with HIV will develop oropharyngeal candidiasis. Other risk factors include unregulated application of antibiotics and hormones, an endocrine disorder, physiological weakness, chemotherapy, nutritional factors, radiotherapy, and the presence of malignant conditions may play a role in the occurrence of this disease.
We report a case of severe IDA in a female patient with hemoglobin of 2.9 g/dL without any other risk factor for IDA except EC. As per our literature review, normally EC cannot cause IDA especially of this magnitude and other causes can be identified on extensive medical work up. There is limited literature on this association between severe IDA and EC. Our case highlights the need for further studies.
2. Case presentation
We report the case of a 38-year-old previously healthy female patient who was referred to our emergency unit from a primary health center. The patient presented with pain, swelling, and tenderness on both lower limbs (ankles and feet) for the last 2 months with the symptoms worsening over the last 10 days. The patient complained that the swelling increases with standing up and during walking while she experiences relief when lying flat. Patient also admitted to having black tarry stool with constipation for the last few weeks. She reported generalized body weakness and easy fatigability. There was a history of anorexia, dysphagia, odynophagia, and occasional episodes of vomiting in the last 2 months but no abdominal pain. There was no use of non-steroidal anti-inflammatory drugs or proton-pump inhibitors. Patient did not experience fever or any respiratory symptoms. There was no vaginal bleeding (normal menstruation) or a previous surgical intervention. Also, there was no drug allergy or a recent hospital admission. Patient experienced normal menstrual periods (light menses lasting 3 days), without any recent weight loss (although she had lost 15 kg 2 years ago) with no other significant constitutional symptoms. Patient is a non-smoker and has never taken alcohol in any form. There is no family history of any chronic condition as well.
On physical examination, vital signs observed were oral temperature of 36.6°C, heart rate of 88 beats per minute, respiratory rate of 18 breaths/min, blood pressure of 128/70 mm Hg, and saturations of 97% on room air. General physical examination showed the patient to be extremely pale with conjunctival pallor, no scleral icterus, no oral ulcers and absence of jaundice, cyanosis, clubbing, or lymphadenopathy. Examination of the cardiovascular system showed regular pulse with normal character. There were normal first and second heart sounds, and no heart murmurs. Respiratory system did not show increased work of breathing. Chest expansion was normal, and percussion notes were resonant. Chest sounds were equal and bilateral, with no added sounds. Gastrointestinal and genitourinary systems showed non-tender and soft, non-distended abdomen, without organomegaly, absence of abdominal masses, normal bowel sounds, and hernial orifices all were intact. In the extremities, there was massive non-pitting edema on both ankles and feet with normal range of movement and neurovascular examination.
The patient underwent a basic blood investigation at the referring facility and was found to have severe IDA (hemoglobin 2.9 g/dL). Her liver and renal function tests were normal. Plan of management involved ECG, chest X-ray, further blood investigations, and occult stool analysis. Blood transfusion protocol was activated and patient was admitted for further inpatient management.
Esophagogastroduodenoscopy (Fig. 1) was performed. Examination of the esophagus showed no active or altered blood anywhere. White patches were seen sticking to the esophageal wall mainly in the lower esophagus and hardly flushed, representing candida esophagitis. No blood was seen in the stomach. Antrum, incisura, and body all normal. Fundus was seen to be normal on retroflexion. Examination of the duodenum showed normal D1 and D2 bile. Campylobacter-like organism (CLO) test was obtained. Endoscopic diagnosis was candida esophagitis. Colonoscopy (Fig. 2) was done and showed a completely normal colonic mucosa from anus to terminal ileum. There were no erosions, ulcers, masses, diverticulosis, or polyps. There were also no internal or external hemorrhoids. Her endoscopic biopsy of lower esophagus confirmed diagnosis of candida esophagitis (Fig. 3).
Patient was started on fluconazole 200 mg. Her HIV test (HIV antigen and antibody), celiac autoantibodies, stool ova, and parasite came out negative. Pan-computed tomography (CT) was also done to rule out hidden malignancy and was completely normal. The patient tolerated full oral diet. She was discharged home on oral iron tablets, esomeprazole, and fluconazole (for a total of 14 days) with a follow-up. Her hemoglobin remained stable on a 1-month follow-up with normal liver and renal function panel. She remained symptom-free without recurrence of anorexia, nausea, dysphagia, odynophagia, malena, fatiguability, or weight loss. There were no side effects of treatment and no signs and symptoms suggesting recurrence. The patient is pending 6 months follow-up.
Esophageal infections are also primarily seen in immunocompromised individuals. Common agents of infection include Candida spp. Cytomegalovirus, and herpes simplex virus. There appear to be very limited studies on severe IDA and candida esophagitis. IDA has been associated previously with large diaphragmatic hernias, although this has been a seemingly controversial finding. Ruhl and Evehart performed a controlled analysis that showed that hiatal hernia contributed to an increased risk of IDA. The incidence of IDA also increased in patients who were diagnosed with esophagitis. However, the study by Ruhl and Evehart had a smaller number of esophagitis patients, and as such, the relationship failed to attain statistical significance. The results of these studies confirmed that hiatal hernia played a major role in gastrointestinal bleeding.
The relationship between IDA and esophagitis has been slightly examined better than that with hiatal hernia. It is worth mentioning that in a recent series of patients who had positive fecal blood tests and were referred for further evaluation and who were without documented active gastrointestinal bleeding or IDA, esophagitis was observed to be the most common lesion in the upper gastrointestinal and was present in nearly 10% of cases. It is also worth mentioning that in a series of IDA patients, esophagitis has consistently presented among elderly and middle-aged persons, and among premenopausal women as well.
IDA is primarily caused by a lack of iron. Its development is triggered by insufficient iron for the synthesis of hemoglobin. Major causes include increasing demand for iron by the body tissues and blood loss. Females of reproductive age like the patient in our case, pregnancy, menstruation, blood loss, nutritional deficiency, and malabsorption are primary predisposing factors. Diagnosis of this condition depends on the patient’s clinical history, with questions bordering around the dietary intake the presence of blood in stools, which could indicate gastrointestinal bleeding. In females, the clinician may ask questions about heavy menstruation or uterine bleeding.
Candida spp. is abundant in the oral cavity and can exist in the mouth of healthy persons without any detrimental effect to the host. Oral candidiasis links with internal diseases with immunodeficiency, including thymoma, diabetes, endocrine disorders, HIV infection, and IDA. Fletcher et al reported that saliva from mouth lesions in IDA patients contained Candida spp.
Studies by Kumar and Choudhry showed that oral candidiasis in patients with IDA was the result of impaired cellular immunity. On the other hand, it is also worth mentioning that impaired cellular immunity has failed to demonstrate Candida spp. growth in saliva because it was discouraged in patients both with oral lesions and without it. Many studies have illustrated a reduced thickness in the epithelium and low enzyme levels in the buccal epithelium of patients with IDA.
According to Bhattacharya and Misra, IDA has an adverse effect on the body’s normal defense system as it compromises the body’s immune system to fight pathogens. IDA also has a negative influence on the normal defence mechanism of the body against infections. It is also important to note that IDA, acting either locally or via systemic mechanisms, may affect oral and EC pathogenesis. It also seems that IDA determines the balance between T-helper (Th) 1 or Th2 effector cells and leads to a deviation in Th2 response, thus contributing to a recurrence of candidiasis.[17,18]
The management of EC needs systemic antifungal therapy. The first-line treatment is with oral fluconazole 200 to 400 mg daily for 14 to 21 days. If a patient is unable to tolerate oral medications, intravenous fluconazole 400 mg daily can be used. Alternative treatment options include oral itraconazole 200 mg daily or voriconazole 200 mg twice daily for 14 to 21 days. Side effects are rarely significant and can include headache, nausea, vomiting, abdominal pain, and diarrhea. Azole drugs are teratogenic during the first trimester of pregnancy. Alternatives include amphotericin B for use in pregnant patients. Refractory EC can occur and may require second line agents for treatment. Long-term antifungal prophylaxis may be required to prevent relapse and recurrence.
Patients with severe IDA might have a higher level of susceptibility to oral and EC or vice versa. There is limited literature on association between EC and severe IDA. This association may exist and our case highlights the need for further studies.
Hany A. Zaki: Conceptualization, Data curation, Writing- Original draft preparation, Haris Iftikhar: Conceptualization, Writing- Reviewing and Editing, Project administration, Funding acquisition, Khalid Basher: Writing- Reviewing and Editing, Noheir Moustafa Taha: Data curation, Writing- Reviewing and Editing, Amr Elmoheen: Writing- Original draft preparation, Writing- Reviewing and Editing.
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