Lane-Hamilton syndrome – Is it really a needle in a haystack?SA Mondkar1, MS Tullu1, P Sathe2, M Agrawal1
1 Department of Pediatrics, Seth G.S. Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India
2 Department of Pathology, Seth G.S. Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.JPGM_1163_20
Source of Support: None, Conflict of Interest: None
Keywords: Alveoli, gluten-free diet, hemosiderosis, lungs
Idiopathic pulmonary hemosiderosis (IPH) is a rare disease presenting with anemia and recurrent acute, or chronic respiratory symptoms, caused due to pulmonary alveolar bleeds. It is often progressive and the ongoing deposition of hemosiderin leads to fibrosis and interstitial lung disease. Celiac disease, also known as gluten-sensitive enteropathy is a multisystem disorder characterized by intestinal and extra-intestinal manifestations of an immune reaction to gluten from wheat (and related prolamines from rye and barley). The most common extra-intestinal presentation of celiac disease is iron deficiency anemia. The association of pulmonary hemosiderosis with celiac disease, first described by Lane and Hamilton in 1971, is recognized as the 'Lane–Hamilton syndrome' and is considered to be a rare phenomenon. Only six cases have been reported from India (to date).
A five-year-old girl was admitted to our institution for the first time in November 2016, with complaints of fever, cough, breathlessness, and paleness for 20 days. There was no history of recurrent lower respiratory tract infections, tuberculosis, or cardiac disease. There was neither a history of pica, chronic diarrhea, bleeding, nor personal or family history of repeated blood transfusions. Her birth history and developmental history were normal except that she had severe bilateral sensorineural hearing loss diagnosed during infancy, with poor compliance to the treatment advised. The child was immunized completely as per age and consumed a vegetarian diet. On examination, at the time of admission, the child was afebrile but had tachycardia, tachypnea, respiratory distress, severe pallor, stunting, and rickets (frontal bossing, wrist widening, and pectus carinatum). The respiratory system examination revealed bilateral fine crepitations; the rest of the systems were normal.
Hemoglobin estimation revealed severe anemia with a hemoglobin level of 2.3 gm/dL. The chest radiograph showed bilateral pulmonary infiltrates, suggestive of bronchopneumonia, which was confirmed on the HRCT of the chest (however, the images are not available). The child was extensively investigated for the cause of her anemia. Her peripheral blood smear showed macrocytosis, anisocytosis, poikilocytosis, and blood indices revealed dimorphic anemia [Table 1]. Direct and indirect Coombs test, as well as Sickling test, were negative. The liver and renal functions as well as stool and urine examination were normal. Serum lactate dehydrogenase levels were elevated (1,224 IU/L; normal range 8–30 IU/L). The coagulation profile was normal. The anti-HIV antibody, Anti-hepatitis C antibody, and HBsAg antigen tests were negative. An abdominal ultrasound showed mild hepatomegaly. In view of (i) severe anemia with stunted growth; (ii) High anti-tissue transglutaminase (TTG) IgA antibody levels (>200 U/mL; normal range: 0–10 U/mL); and (iii) Upper gastrointestinal endoscopy showing reduced mucosal folds with scalloping in the duodenum and the duodenal biopsy showing partial villous blunting with intraepithelial lymphocytes, the final diagnosis of celiac disease was made. The child initially received packed cell transfusions, parenteral course of vitamin B12, amoxicillin with clavulanate for pneumonia and dobutamine for congestive cardiac failure, and was discharged on a gluten-free diet (GFD), oral iron, folic acid, vitamin B12, and calcium supplements but the compliance to this treatment and diet was poor.
The child was admitted for the second time in May 2017, with similar complaints as before. Blood investigations revealed similar findings as previously, and the child was treated on similar lines. She was admitted for the third time in September 2017 with the same complaints. Interestingly, the child had persistent bilateral pulmonary infiltrates, initially attributed to congestive cardiac failure (CCF) or bronchopneumonia, but these infiltrates persisted even after treatment for the CCF [Figure 1]. Workup for tuberculosis (TB) was negative (Mantoux and gastric lavage negative).
The cardiac 2D echocardiography showed a small patent ductus arteriosus. A (repeat) HRCT chest revealed interstitial thickening and bilateral alveolar shadows (ground-glass opacities), suggesting a radiological differential diagnoses of interstitial lung disease, diffuse alveolar hemorrhage, pulmonary edema, or Pneumocystis jiroveci pneumonia [Figure 2]. A bronchoalveolar lavage (BAL) was done, showing mature bronchial cytology with a few inflammatory cells. The child was discharged with a plan to do pulmonary function tests as the parents did not wish to undergo further investigations at that time. The child was readmitted for the fourth time in November 2017 with similar complaints and was given packed cell transfusions. Gastric lavage for hemosiderophages was done and was negative. Since the first BAL had not yielded a confirmatory result, it was deemed prudent to go ahead with a thoracoscopic lung biopsy rather than repeating the BAL. Histopathological examination revealed an irregular expansion of the alveolar spaces with widening of the interstitium. The majority of the alveolar spaces were filled with pigment-laden macrophages. Occasional peribronchial lymphoid aggregates were seen. The pigment was confirmed to be Hemosiderin on Prussian blue staining [Figure 3], [Figure 4], [Figure 5]. Thus, a diagnosis of extensive pulmonary hemosiderosis without capillaritis was made.
The patient was further investigated for the cause of pulmonary hemosiderosis. Serum ferritin level was done, which was normal (242 mcg/L). Urine analysis and renal function tests were done to rule out Goodpasture's syndrome and were normal.Anti-nuclear antibody (ANA), anti-double stranded DNA antibody (dsDNA), anti-phospholipid antibody (APLA), anti-nuclear cytoplasmic antibody (cANCA), anti-glomerular basement membrane antibodies (for ruling out other/auto-immune causes), were planned, however, the parents did not consent for the same due to monetary issues. The presence of celiac disease with pulmonary hemosiderosis led to the eventual diagnosis of the 'Lane–Hamilton syndrome.' The child was treated with a course of oral corticosteroids (Prednisolone, 2 mg/kg/day) for 6 weeks, with a GFD, following which a dramatic improvement in both the anemia and pulmonary infiltrates was seen [Figure 6].
At the time of the first admission in November 2016, our clinical differential diagnoses were severe anemia causing CCF versus acute infectious pneumonia, due to the acuteness of the respiratory symptoms. The chest radiograph and HRCT chest (bronchopneumonia) supported this diagnosis. Indeed, then the child improved significantly following blood transfusions, intravenous dobutamine, and antibiotics. On further investigations, the child was diagnosed with celiac disease, which further explained the reason for the severe anemia (leading to CCF), and clinical improvement following the restoration of the hemoglobin levels. Between the first and the second admission (6 months apart), the patient was fairly asymptomatic, before she presented with anemia and acute respiratory symptoms again, and hence, was treated on similar lines (again). It was during the third admission with similar complaints (when the pulmonary infiltrates were noted to be persistent on the chest radiograph) that we decided to investigate the child further. A cardiac 2D echocardiography was done to rule out an underlying congenital heart disease, which did reveal a small patent ductus arteriosus (however, it was not significant enough to cause the CCF). An HRCT of the chest was hence repeated, wherein the differential diagnoses of the interstitial lung disease and pulmonary hemorrhage (ground-glass opacities with interlobular septal thickening), were our first pointers toward the possibility of pulmonary hemosiderosis, considering that the child was a known case of celiac disease and was having recurrent anemia. At this point in time, a bronchoalveolar lavage (BAL) was done, but it was inconclusive. Since diffuse alveolar hemorrhage (causing pulmonary hemosiderosis) can also present with recurrent acute symptoms, we decided to proceed with a lung biopsy, which is the gold standard for the diagnosis. Sure enough, the biopsy revealed extensive pulmonary hemosiderosis with hemosiderin-laden macrophages involving most of the alveoli, thus confirming the diagnosis. This explained the recurrent severe anemia requiring blood transfusions as well the recurrent respiratory symptoms coinciding with the occurrence of the pulmonary hemorrhages. After confirming the diagnosis of pulmonary hemosiderosis, the child was investigated further for other secondary causes of diffuse alveolar hemorrhage leading to hemosiderosis. Blood investigations for vasculitis were planned, however, these could not be done due to financial constraints. It may be noted that there was no evidence of vasculitis on the lung biopsy. Thus, the presence of celiac disease with IPH clinched the diagnosis of the 'Lane–Hamilton syndrome.'
Recurrent blood transfusions, too, are known to cause pulmonary iron overload and hemosiderosis, however, the following points go against transfusion-related iron overload (as a cause of hemosiderosis) in our patient:
From the pathology point of view for the differential diagnosis, a few hemosiderin-laden macrophages can be seen in the lung in blood dyscrasias, chronic heart failure, pulmonary hypertension, infections, or neoplasia. However, extensive accumulation of hemosiderin-laden macrophages, progressing to chronic pulmonary disease is seen in (i) IPH with pulmonary hemorrhage and (ii) Secondary pulmonary hemorrhage associated with immunologically-mediated renal or vascular disease. These can be differentiated based on the clinical, laboratory, and immunopathologic findings (as was done in our case).
IPH, also known as the 'Ceelen–Gellerstedt syndrome,' is predicted to have an incidence between 0.24 and 1.23 cases per million children per year as observed from case analyses conducted in Sweden and Japan., IPH is diagnosed by a triad of iron deficiency anemia, pulmonary infiltrates on chest X-ray and hemoptysis with no other known cause. However, this classic triad is uncommon in children. Pulmonary hemorrhage may not manifest as hemoptysis, especially in younger children. In most pediatric patients, IPH manifests as anemia and cough (at least, initially). The clinical presentation is a spectrum and may be acute symptoms—coinciding with acute episodes of hemorrhage, with episodic cough, dyspnea, hypoxia, fever, and wheezing (triggered by airway irritation and inflammation by blood), or may present as a chronic disease with cough, fatigue, or pallor. Clubbing may develop in some patients. Typical chest radiographic findings include diffuse, bilaterally symmetrical lung infiltrates, with apical sparing, as was seen in our patient. HRCT findings may often be non-specific and may be suggestive of interstitial lung disease. Sputum, gastric lavage, or bronchoalveolar lavage (BAL) fluid analysis may show hemosiderin-laden macrophages, but these investigations were non-contributory in our patient. Lung biopsy is the gold standard investigation to confirm the diagnosis of pulmonary hemosiderosis and is worthwhile in patients with microcytic hypochromic anemia with respiratory symptoms (where other causes of anemia have been ruled out). The presence of hemosiderin-laden macrophages diffusely throughout the alveoli confirms the diagnosis of pulmonary hemosiderosis. Histopathology also helps in ruling out pulmonary hemosiderosis due to capillaritis/vasculitis. However, the diagnosis of IPH is one of exclusion and needs to be proven non-immune-based on immunological tests. Pulmonary hemosiderosis following diffuse alveolar hemorrhage may also occur as an adverse effect to certain drugs like Propylthiouracil, Amiodarone, Nitrofurantoin, D-Penicillamine, and anticoagulants and a detailed history regarding the offending drug is, thus, important.
Celiac disease (CD) is a multisystem immune-mediated disorder with gluten-sensitive enteropathy characterized by life-long intolerance to ingested gluten in genetically susceptible individuals. It is diagnosed by a combination of symptoms, anti-TTG IgA or anti-deamidated forms of gliadin peptides IgG antibodies or anti-endomysial antibodies, presence of HLA DQ2 or DQ8, typical duodenal biopsy findings, and remission of clinical, serological, and biopsy findings on a GFD. Duodenal biopsy with histopathology is the gold standard in diagnosing CD. The CD is characterized by increased intraepithelial lymphocytes, proliferation of crypts of Lieberkuhn, partial or total villous atrophy with hypoplasia of small-bowel architecture, as described by the Marsh classification (our patient was classified as Marsh stage 3). In India, the prevalence of CD is 1.54% by serology and 1.04% by histology.
The association of IPH with CD is a rare condition, first described by Lane and Hamilton in 1971, and hence, referred to as the 'Lane–Hamilton syndrome.', This association has garnered importance because, whereas pulmonary hemosiderosis due to secondary causes requires steroids and other immunosuppressants and may not always have a favorable prognosis, the institution of a gluten- free diet for CD results in the remission of IPH in a majority of the patients with Lane–Hamilton syndrome.,, Khemiri et al. conducted a study wherein patients with IPH were screened for CD, and an association was found in 44.4% of the patients. Le Clainche L et al. conducted a similar study and found an association in 6.6–8.7% of the cases. Singhal et al. conducted a comprehensive review of literature in 2013, over and above that conducted by Agarwal et al. in 2007, and found that 35 cases with Lane–Hamilton syndrome have been reported to date., In 2017, Panda et al. noted that only six cases of Lane–Hamilton syndrome have been reported from India so far. However, the Lane–Hamilton syndrome may be more common than has been diagnosed so far. This assumption was further studied by Singhal et al., who observed that various studies have found a high prevalence of CD (2–14%) in patients of iron deficiency anemia (IDA) of obscure origin, many being resistant to treatment with iron, suggesting that iron deficiency due to malabsorption may not be the only reason for anemia in CD., Conversely, anemia, without gastrointestinal symptoms may be the only clinical presentation in patients with CD, as was with our patient. Unsworth et al. conducted a study in blood donors rejected due to anemia; 32 patients tested positive for anti-endomysial antibodies. Among 25 of those who underwent small-bowel biopsies, 22 (i.e. 88%) were consistent with CD. Apart from 12 patients who had other symptoms (nine had menorrhagia, two had irritable bowel syndrome, one had persistent diarrhea), all others were completely asymptomatic. Another postulated cause of anemia in CD is occult blood loss. However, some studies have negated intestinal blood loss as the cause of anemia in CD by demonstrating an absence of fecal occult blood. Mant et al. measured fecal blood loss in 18 CD patients using 51Cr radiolabeled red cells and found the blood loss exceeding 1.5 mL in only one patient, which was suspected to be the result of an alternate transient gastrointestinal cause. Thus, there is reason to believe that the cause of IDA in CD may be other factors than just malabsorption of iron or gastrointestinal blood loss. This is also supported by the fact that, in CD with pulmonary hemosiderosis as the cause of anemia, iron gets sequestered in the alveolar macrophages as hemosiderin. Multiple case reports of patients with IPH have demonstrated microcytic hypochromic anemia with normal or slightly raised serum ferritin levels., Thus, in spite of normal iron stores (as observed by normal serum ferritin levels), IDA results due to the unavailability of sequestered iron for erythropoiesis. Thus, a significant number of patients with the Lane–Hamilton syndrome may get inadvertently diagnosed only as CD in either the absence of stark pulmonary symptoms or clinically significant bleed. Moreover, the symptoms of pulmonary hemorrhage may often resemble or get masked by those of anemia-related cardiac failure or coexistent pneumonia (as happened with our patient during the initial admissions). Hence, a meticulous follow-up of such patients should be maintained, and in those with disproportionately severe anemia not responding to iron therapy or developing worsening of anemia with recurrent respiratory symptoms, a workup for pulmonary hemosiderosis should be considered.
The mainstay of treatment of Lane–Hamilton syndrome remains a GFD. Most patients undergo clinical and radiological remission of the pulmonary hemosiderosis with GFD alone. Out of the 35 patients with the Lane–Hamilton syndrome evaluated by Agarwal et al. and Singhal et al., 19 (54.2%) demonstrated improvement in pulmonary symptoms with GFD. Khemiri et al. found clinical and radiological improvement in both the respiratory and gastrointestinal symptoms with corticosteroid treatment combined with a GFD, an outcome similar to our patient. However, both the symptoms recurred in one of the patients on stopping the GFD. All six reported Indian cases got symptom-free with GFD alone, not requiring any immunosuppression. Thus, it is clear that diet compliance is a crucial factor in the management of the Lane–Hamilton syndrome.
[Table 2] summarizes the details of the Indian (pediatric) patients diagnosed with Lane–Hamilton syndrome. CD patients with disproportionate anemia should be worked up for IPH to not miss cases of Lane–Hamilton syndrome. Conversely, patients presenting with anemia and pulmonary hemosiderosis should be screened for CD.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]