Celiac disease and idiopathic pulmonary hemosiderosis: a literature review of the Lane-Hamilton syndrome.

Lane-Hamilton syndrome (LHS) presents a medical emergency, with 14% mortality due to Idiopathic Pulmonary Hemosiderosis (IPH) in acute phase. Despite the clinical severity of this entity, there has been no published review in the international literature, resulting in lack of awareness and delayed diagnosis.A rigorous search of international databases yielded a total of 80 LHS cases from January 1971 to August 2020. We analyzed 44 children (8.56 ± 4.72 years, 21 boys) and 36 adults (33.61 ± 13.41 years, 12 men) to present the clinical manifestations, radiological and immunological pattern, therapeutic approaches and outcome of LHS. We also elaborated on clinical and laboratory findings' associations to propose diagnostic indexes and clarified differences based on age distribution.Celiac disease (CD) and IPH diagnosis was made concurrently in 46 patients, whereas in 21 patients, the diagnosis of LHS was delayed for 2.5y (3 months-11 years). Hemoptysis (n = 56, 70%), dyspnea (n = 47, 58.8%), anemia (n = 72, 90%), and iron deficiency (n = 54, 67.5%) were most commonly observed. Medical history revealed recurrent episodes of hemoptysis (n = 38) and persistent iron deficiency anemia (n = 25) in need of multiple blood transfusions or iron supplementation. Patchy infiltrate opacities to consolidation predominated in children, whereas bilateral diffuse ground-glass opacities in adults. Duodenal biopsy was performed in 66 cases (diagnostic 87.8%), BAL in 51 (diagnostic 74.5%), and surgical lung biopsy in 20. Anti-tTG titer was positive in all 24 (54.6%) children and 19 (52.8%) adults that documented this assay. Prednisone or methylprednisolone pulse therapy and GFD were initiated in the acute phase, whereas chronic therapy included GFD, along with long-term prednisone in refractory cases. Three cases with severe respiratory failure or hemodynamic instability were intubated and a further three succumbed.A thorough understanding of LHS may reveal further diagnostic indexes and a consensus on therapy guidelines. Screening for CD is essential in all IPH cases for timely recognition and favorable outcome.

Idiopathic pulmonary haemosiderosis in paediatric patients: how to make an early diagnosis.

BACKGROUND: Idiopathic pulmonary haemosiderosis (IPH) is a rare but potentially lethal condition in paediatric patients. This condition is considered an immune-mediated disorder, but its pathogenesis is still unknown. Idiopathic pulmonary haemosiderosis is characterized by the classical triad of haemoptysis, iron-deficiency anaemia, and diffuse parenchymal consolidation on chest radiology. Unfortunately, this triad of signs is not frequent in children at the onset of this disease, resulting in a delay in diagnosis and a negative outcome. CASE PRESENTATION: This case report describes a 4-year-old girl who was admitted for an acute episode of lower respiratory tract infection associated with severe dyspnoea, polypnoea, and severe anaemia (haemoglobin levels, 5.9 g/dL). She had a history of previous similar episodes, with anaemia treated unsuccessfully with iron supplementation and managed through repeated blood transfusions in the acute phase. She did not experience haemoptysis. A computed tomography (CT) scan of the thorax showed ground-glass opacity suggestive of pulmonary haemorrhage. After other causes of intra-alveolar haemorrhage were excluded, IPH was confirmed by the presence of siderophages in bronchoalveolar lavage. Immunosuppressive corticosteroid treatment was immediately started with a good clinical response. CONCLUSION: This case highlights the fact that IPH should be suspected in children with recurrent lower respiratory tract infections who have a history of iron-deficiency anaemia who shows no signs of improvement with iron supplementation and may require repeated blood transfusions. The absence of haemoptysis does not exclude the diagnosis of IPH in children. An early and prompt diagnosis is recommended in order to start adequate immunosuppressive treatment.

Anti-Thyroid Peroxidase Antibodies and Male Gender Are Associated with Diabetes Occurrence in Patients with Beta-Thalassemia Major.

BACKGROUND: Intensive transfusion schedule and iron-chelating therapy prolonged and improved quality of life in patients with ß-thalassemia (ß-T) major. However, this led to an increased risk of developing impaired glucose tolerance or diabetes. In this study we analyzed variables associated with the occurrence of impaired glucose tolerance or diabetes in patients with ß-T major. METHODS: 388 Sardinian patients were included. Age, gender, duration of chelation therapy, body mass index, and markers of pancreatic and extrapancreatic autoimmunity were analyzed. RESULTS: Multiple logistic regression analysis showed that anti-thyroid peroxidase (TPO) antibodies (Ab) (OR = 3.36; p = 0.008) and male gender (OR = 1.98; p = 0.025) were significantly associated with glucose impairment, while the other variables were not. Ferritin levels were significantly higher in TPOAb positive compared to TPOAb negative patients (4870 ± 1665 µg/L versus 2922 ± 2773 µg/L; p < 0.0001). CONCLUSIONS: In patients with ß-T major a progressive damage of insulin-producing cells due to secondary hemosiderosis appears to be the most reasonable mechanism associated with glucose metabolism disorders. The findings need to be confirmed with additional well designed studies to address the question of whether TPOAb may have a role in the management of these patients.

Idiopathic pulmonary haemosiderosis with celiac disease (Lane-Hamilton syndrome) in an adult - a case report.

Idiopathic pulmonary haemosiderosis (IPH) is a rare disorder of unknown cause characterised by haemoptysis, diffuse alveolar infiltrates and iron-deficiency anaemia. IPH predominantly affects children; it is rare in adults, in whom it usually manifests before 30 years. In adults, course is protracted with a better prognosis, in contrast to children. Even rarer is the Lane-Hamilton syndrome, a condition in which IPH is associated with celiac disease. Only 15 cases of Lane-Hamilton syndrome affecting adults are reported in literature. Treatment of IPH is based on anecdotal case reports and case series because of its rare occurrence. High-dose steroids reportedly reduce morbidity and mortality and delays or stops disease progression; more effectively in adults than children. In Lane-Hamilton syndrome, a gluten-free diet for the celiac disease in addition to steroids for IPH, is the mainstay of therapy. The optimal treatment duration of steroid therapy is not known but anecdotally a more prolonged course results in improved outcome. We report a case of a young woman who presented with exertional dyspnoea, intermittent haemoptysis, severe anaemia and lung infiltrates but no gastrointestinal complaints. After extensive work-up, she was diagnosed with Lane-Hamilton syndrome based on a diagnosis of IPH made from lung biopsy and concomitant celiac disease because of positive anti-gliadin antibody and endomyosial antibody and jejunal biopsy. She was treated with sustained low-dose steroid therapy for a year and a gluten-free diet with resolution of her symptoms, anaemia and lung infiltrates. At 4 years of follow-up, she remains stable, without recurrence.

Multiparametric Cardiac Magnetic Resonance Survey in Children With Thalassemia Major: A Multicenter Study.

BACKGROUND: Cardiovascular magnetic resonance (CMR) plays a key role in the management of thalassemia major patients, but few data are available in pediatric population. This study aims at a retrospective multiparametric CMR assessment of myocardial iron overload, function, and fibrosis in a cohort of pediatric thalassemia major patients. METHODS AND RESULTS: We studied 107 pediatric thalassemia major patients (61 boys, median age 14.4 years). Myocardial and liver iron overload were measured by T2* multiecho technique. Atrial dimensions and biventricular function were quantified by cine images. Late gadolinium enhancement images were acquired to detect myocardial fibrosis. All scans were performed without sedation. The 21.4% of the patients showed a significant myocardial iron overload correlated with lower compliance to chelation therapy (P<0.013). Serum ferritin ≥2000 ng/mL and liver iron concentration ≥14 mg/g/dw were detected as the best threshold for predicting cardiac iron overload (P=0.001 and P<0.0001, respectively). A homogeneous pattern of myocardial iron overload was associated with a negative cardiac remodeling and significant higher liver iron concentration (P<0.0001). Myocardial fibrosis by late gadolinium enhancement was detected in 15.8% of the patients (youngest children 13 years old). It was correlated with significant lower heart T2* values (P=0.022) and negative cardiac remodeling indexes. A pathological magnetic resonance imaging liver iron concentration was found in the 77.6% of the patients. CONCLUSIONS: Cardiac damage detectable by a multiparametric CMR approach can occur early in thalassemia major patients. So, the first T2* CMR assessment should be performed as early as feasible without sedation to tailor the chelation treatment. Conversely, late gadolinium enhancement CMR should be postponed in the teenager age.

Extracorporeal life support for a 5-week-old infant with idiopathic pulmonary hemosiderosis.

UNLABELLED: Idiopathic pulmonary hemosiderosis is a rare disease defined by the triad of iron deficiency anemia, hemoptysis, and diffuse pulmonary infiltrates on chest radiograph. Idiopathic pulmonary hemosiderosis is known to cause dyspnea and, in some cases, acute onset of massive pulmonary hemorrhage which is traditionally treated with conventional mechanical ventilation or high-frequency oscillation in conjunction with immunosuppressive therapy. In this case report, we describe a 5-week-old infant presenting with hemoptysis, massive pulmonary hemorrhage, and significant hypercapnic respiratory failure. The patient failed conventional ventilation but responded well to extracorporeal life support that was initiated early in his course. Idiopathic pulmonary hemosiderosis was suspected in light of his response to high-dose steroids and was confirmed by subsequent lung biopsies. CONCLUSION: Patients with severe pulmonary hemorrhage secondary to idiopathic pulmonary hemosiderosis can be safely supported with extracorporeal life support when conventional therapies have been exhausted.

Hemodialysis-associated hemosiderosis in the era of erythropoiesis-stimulating agents: a MRI study.

BACKGROUND: Most dialysis patients receiving erythropoesis-stimulating agents (ESA) also receive parenteral iron supplementation. There are few data on the risk of hemosiderosis in this setting. METHODS: We prospectively measured liver iron concentration by means of T1 and T2* contrast magnetic resonance imaging (MRI) without gadolinium, in a cohort of 119 fit hemodialysis patients receiving both parenteral iron and ESA, in keeping with current guidelines. RESULTS: Mild to severe hepatic iron overload was observed in 100 patients (84%; confidence interval, [CI] 76%-90%), of whom 36% (CI, 27%-46%) had severe hepatic iron overload (liver iron concentration >201 µmol/g of dry weight). In the cross-sectional study, infused iron, hepcidin, and C-reactive protein values correlated with hepatic iron stores in both univariate analysis (P<.05, Spearman test) and binary logistic regression (P <.05). In 11 patients who were monitored closely during parenteral iron therapy, the iron dose infused per month correlated strongly with both the overall increase and the monthly increase in liver iron concentration (respectively, rho=0.66, P=.0306 and rho=0.85, P=0.0015, Spearman test). In the 33 patients with iron overload, iron stores fell significantly after iron withdrawal or after a major reduction in the iron dose (first MRI: 220 µmol/g (range: 60-340); last MRI: 50 µmol/g (range: 5-210); P <.0001, Wilcoxon's paired test). CONCLUSIONS: Most hemodialysis patients receiving ESA and intravenous iron supplementation have hepatic iron overload on MRI. These findings call for a revision of guidelines on iron therapy in this setting, especially regarding the amount of iron infused and noninvasive methods for monitoring iron stores.

Cardiac T2 measurements in patients with iron overload: a comparison of imaging parameters and analysis techniques.

Measurement of cardiac T2 has emerged as an important tool to noninvasively quantify cardiac iron concentration in order to detect preclinical evidence of toxic levels and titrate chelation therapy. However, there exists variation among practitioners in cardiac T2 measurement methods. This study examines the impact of different imaging parameters and data analysis techniques on the calculated cardiac R2 (1/T2) in patients at risk for cardiac siderosis. The study group consisted of 36 patients with thalassemia syndromes who had undergone clinical magnetic resonance imaging assessment of cardiac siderosis using a standardized protocol and who were selected to yield a broad range of cardiac R2 values. Cardiac R2 measurements were performed on a 1.5-T scanner using an electrocardiogram-gated, segmented, multiecho gradient echo sequence obtained in a single breath-hold. R2 was calculated from the signal intensity versus echo time data in the ventricular septum on a single midventricular short-axis slice. There was good agreement between R2 measured with a blood suppression prepulse (black blood technique) and without (mean difference 6.0 ± 10.7 Hz). The black blood technique had superior within-study reproducibility (R2 mean difference 1.6 ± 8.6 Hz versus 2.7 ± 14.6 Hz) and better interobserver agreement (R2 mean difference 3.4 ± 8.2 Hz versus 8.3 ± 16.5 Hz). With the same minimum echo time, the use of small (1.0 ms) versus large (2.2 ms) echo spacing had minimal impact on cardiac R2 (mean difference 0.3 ± 8.7 Hz). The application of a region-of-interest-based versus a pixel-based data analysis also had little effect on cardiac R2 calculation (mean difference 8.4 ± 6.9 Hz). With black blood images, fitting the signal curve to a monoexponential decay or to a monoexponential decay with a constant offset yielded similar R2 values (mean difference 3.4 ± 8.1 Hz). In conclusion, the addition of a blood suppression prepulse for cardiac R2 measurement yields similar R2 values and improves reproducibility and interobserver agreement. The findings regarding other variations may be helpful in establishing a broadly accepted imaging and analysis technique for cardiac R2 calculation.

Unusual presentation: pulmonary hemosiderosis with celiac disease and retinitis pigmentosa in a child.

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease characterized by anemia, hemoptysis and recurrent alveolar hemorrhage. The combination of IPH and celiac disease (CD) is extremely rare. We report a 9-year-old boy with Lane-Hamilton syndrome, co-occurrence of pulmonary hemosiderosis with CD. This presentation is unique presentation because he has also retinal pigmentation.

Quantification of myocardial iron overload by cardiovascular magnetic resonance imaging T2* and review of the literature.

Heart failure due to myocardial iron overload remains the leading cause of death in patients with transfusion-dependent anemias. Iron overload-induced cardiomyopathy is reversible if intensive chelation therapy is instituted on time. Thus, early detection of myocardial iron deposition is imperative to prevent overt heart failure. Conventional cardiac monitoring, including physical examination, electrocardiography, echocardiography or serum ferritin levels fail to predict manifest or subclinical myocardial involvement resulting from iron overload. Cardiovascular magnetic resonance imaging T2* (cMRI-T2*, pronounced T2 star) times correlate well with myocardial iron levels. This timely review focuses on the utility of cMRI-T2*, for the preclinical detection of myocardial iron overload and monitoring of myocardial iron content during chelation therapy.

Low serum ferritin levels are misleading for detecting cardiac iron overload and increase the risk of cardiomyopathy in thalassemia patients. The importance of cardiac iron overload monitoring using magnetic resonance imaging T2 and T2*.

The incidence of cardiomyopathy was monitored in a 6-year follow-up study involving 56 transfused thalassemia patients treated with deferoxamine (DFO), deferiprone (L1) or their combination. During this period, five female patients on regular subcutaneous or intravenous DFO presented with cardiac complications. Three patients suffered congestive heart failure and the other two arrhythmias. Four of the five patients maintained serum ferritin levels of about 1 mg/L or below and the fifth about 1.5 mg/L for several years prior to the cardiomyopathy. Cardiac magnetic resonance imaging (MRI) T2* and T2 was performed in four patients after the cardiomyopathy, identifying the presence of moderate-to-heavy siderosis. The treatment of the five patients has since changed, involving mainly the use of L1. Low serum ferritin levels appear to be misleading for detecting cardiac iron overload and this may increase the risk of cardiomyopathy. The MRI T2 and T2* relaxation time measurements are a more accurate method of detecting cardiac iron overload. Chelation therapy using L1 or appropriate L1/DFO combinations can reduce cardiac iron overload and the mortality rate in thalassemia patients.

Idiopathic pulmonary haemosiderosis--a case report.

Idiopathic pulmonary haemosiderosis (IPH) is a disorder characterised by the triad of haemoptysis, diffuse parenchymal infiltrates on chest roentgenogram and iron-deficiency anaemia. It is a diagnosis of exclusion and the prognosis is bleak despite the varied management options. We report a case of IPH occurring in a child who presented at four months of age with cough, wheeze, haemoptysis and pallor and whose symptoms are currently controlled with high-dose inhaled budesonide and low-dose oral prednisolone.

Chloroquine in idiopathic pulmonary hemosiderosis. A case report.

This report describes an 11-year-old boy with idiopathic pulmonary hemosiderosis. His only presenting symptom was severe anemia due to iron deficiency. Idiopathic pulmonary hemosiderosis was diagnosed nine years after the onset of symptoms. During this period many invasive and non-contributory investigations were performed. This report describes the patient's diagnostic problems, clinical features and dramatic improvement with chloroquine (250 mg/day) after failing to respond to megadose methylprednisolone (30 mg/kg). One year later, chloroquine was discontinued. The patient has remained in remission since March 1994. Chloroquine should be used for this life-threatening condition since it is less toxic than other immunosuppressive drugs.

Cutaneous oxalate deposition in a hemodialysis patient.

We describe calcium oxalate and amyloid arthropathy with cutaneous calcinosis without vitamin C supplement. A 34-year-old woman developed glomerulonephritis requiring chronic hemodialysis. Seven years after beginning hemodialysis, multiple crystal deposits appeared in her skin; she also presented with arthralgia and gait disturbance. A skin biopsy was performed, which disclosed calcium oxalate deposition. In addition, a right femoral neck prosthetic replacement was performed. Pathologic examination of the hip synovia revealed diffuse calcium oxalate, amyloid, and iron deposition. Calcium oxalate and amyloid arthropathy with synovial hemosiderosis was diagnosed, and therapy with desferal and high-flux membrane dialysis was started. Clinical improvement occurred after 6 months.

MR marrow signs of iron overload in transfusion-dependent patients with sickle cell disease.

Magnetic resonance (MR) marrow signal in the axial and appendicular skeleton of 13 transfusion-dependent and chelated pediatric patients with sickle cell anemia (SSD) was compared with marrow signal in six non-transfusion-dependent patients with SSD. Hepatic, pancreatic, and renal MR signal were also evaluated. Indication for hypertransfusion therapy was primarily prior history of stroke. Transfusion-dependent patients had evidence of iron deposition throughout the imaged marrow and the liver, despite deferoxamine chelation therapy. Non-transfusion-dependent patients did not demonstrate grossly apparent signs of iron overload. Red marrow restoration was present in the spine, pelvis, and long bones and, in some patients, within the epiphyses. Marrow edema secondary to vaso-occlusive crises was evident in the metaphyses and diaphyses of long bones in areas of both red and fatty marrow and was best seen using fat-saturated T2-weighted imaging techniques.

[Hemosiderosis in thalassemia major. Quantitative study with magnetic resonance (MR)]. / L'emosiderosi nella talassemia major. Studio quantitativo con risonanza magnetica (RM).

Hemosiderosis, which results from transfusional therapy and from increased absorption of dietary iron, is a severe complication of thalassemia major. The complication is also very difficult to manage. An accurate determination of the total amount and of the distribution of body iron stores is essential for prognostic purposes and to evaluate the efficacy of chelation therapy. Therefore, a suitable tool for the noninvasive depiction of iron overload is to be hoped for. MR imaging has been usefully employed, of late, to this purpose. Sixteen thalassemic patients have been studied to evaluate iron depositions using a 1.5 T magnet. Signal intensities from liver, pancreas, spleen, bone marrow, and heart were considered. The signals were dramatically lower than the normal values obtained in a sex- and age-matched group; the differences were due to the iron. Iron distribution appeared inhomogeneous, with the highest overload in liver and bone marrow. Since cardiomyopathy represents the first cause of death in thalassemic patients, the relationship between cardiac function and iron overload in the heart has been thoroughly investigated. Finally, the authors conclude that MR will become a widely employed method for assessing iron overload and will contribute to improve the management of thalassemia major.

The clinical manifestations of chronic iron overload.

Primary or genetic haemochromatosis is an inherited disease characterized by an inappropriate degree of iron absorption with accumulation of excessive amounts of tissue iron. Parenchymal iron accumulation results in the typical clinical features of the disease including hepatic cirrhosis, diabetes, testicular atrophy and skin pigmentation. The disease is inherited in an autosomal recessive manner. The gene for the disease has not been identified but is tightly linked to the A locus of the histocompatibility complex on chromosome 6. The approximate homozygote frequency in Caucasians is 0.3% with an equal sex ratio. Excessive body iron stores have been described in a number of other conditions, particularly alcoholic liver disease. There is increasing evidence that many of these individuals are in fact also suffering from genetic haemochromatosis. Diagnostic tests including serum iron, transferrin saturation, serum ferritin and liver iron concentration make it possible to detect sufferers of the disease. Screening relatives of affected individuals with these tests allows a diagnosis to be made before permanent tissue damage has occurred. Removal of excess iron stores by repeated phlebotomy is the primary treatment. If iron is removed before significant tissue damage has occurred, the complications and natural course of the disease will be prevented provided reaccumulation of iron does not occur. Excessive iron accumulation with resultant organ damage also occurs in anaemias associated with ineffective erythropoiesis and after excessive parenteral iron administration or repeated blood transfusions. Similar clinical features may be seen. Chelation therapy is the mainstay of treatment in these cases where long-term venesection is not possible.

[Serum ferritin in iron overload]. / Serumferritin bei Eisenüberladung.

Even with uncomplicated iron overload, serum ferritin which can be identified in the circulating blood by sensitive immunochemical methods has a direct and quantitative correlation to the iron stored in the organism. The relation of stored iron and serum ferritin is not linear, but has an exponential character. The diagnostic function of serum ferritin as an indicator of stored iron, however, is virtually not influenced by it. The indications listed in Tab. 3 can be demarcated for diagnostic application in cases of iron overload. Hitherto, the molecular microheterogenicity of serum ferritin has exercised no essential impact on its diagnostic application. High ferritin concentrations may arise in the circulating blood by a number of disease processes listed in Tab. 4, without the simultaneous existence of a respective iron overload of the tissue. These correlations have to be observed in the diagnostic application of determining serum ferritin as well as in methodical possibilities of fault (high dose hook effect), thus limiting the use of serum ferritin as an indicator of stored iron both in case of iron overload and iron deficiency. As in all isolated laboratory investigations, all other clinical and chemical laboratory information available about the individual patient has to be taken into account in each case for interpreting the serum ferritin concentration.

[Iron-overload in patients on maintenance hemodialysis: diagnostic criteria, indications and treatment by desferrioxamine (author's transl)]. / La surcharge en fer chez les patients hémodialysés: critères diagnostiques, indication et résultats du traitement par desferrioxamine.

33 patients with chronic renal failure were divided into two groups. Group I consisted of 8 non-dialysed patients without any clinical or biochemical sign of liver disturbance nor any iron supplementation. Group II consisted of 25 maintenance hemodialysis (MHD) patients treated from 2 to 13 years. 19 subjects had chronic B hepatitis. Total exogenous iron load parenteral iron and/or blood transfusions) was calculated. Body iron overload (hemosiderosis) was assessed by liver iron concentration (LIC) in needle biopsy specimens according to Barry's method (less than 200 microgram/100 mg dry weight) and serum ferritin levels (less than 360 ng/ml). 4 patients whose serum ferritin was increased with or without hepatic fibrosis and with or without any organ dysfunction due to hemochromatosis received i.v. infusions of desferrioxamine in doses of 2 g at each dialysis. Serum ferritin levels were correlated with LIC (p less than 0.001) and iron load (p less than 0.001). Hemosiderosis was noted in 16 MHD patients (group II) and correlated with iron load. Hemochromatosis was noted in 4 patients (group II). 4 hemodialysed patients with iron overload were treated by desferrioxamine from 6 to 18 months. During this therapy, body iron stores fell and organ dysfunction (heart failure, hepatic cytolysis, anaemia, diabetes mellitus improved. Long-term chelation therapy by desferrioxamine was effective and the chelated iron was readily removed by dialysis. These data show the importance of precise evaluation of iron stores in MHD patients.

Comparison of stainable iron in aspirated and needle-biopsy specimens of bone marrow.

A comparison of stainable iron in simultaneously obtained aspirated smears and needle-biopsy specimens from 1,000 patients was undertaken. Significant differences occurred when iron was assessed as absent in the aspirated smear. In only 35% of the corresponding needle-biopsy specimens was iron absent. When only the aspirated smear was used, there was a significant overdiagnosis of iron deficiency. In general, iron tended to be less in the aspirated smear; however, correlations were better when iron stores were assessed as being present or increased in the aspirated smears, for stainable iron in the needle-biopsy specimen was always present in equal or greater amounts. Hemosiderotic smears (increased stainable iron) and needle-biopsy specimens (3+ -4+) correlated well. The aspirated smear and needle-biopsy are complementary procedures, and each has advantages. In the authors' experience, the needle-biopsy was preferable to the aspirated smear for evaluation of iron stores, particularly when iron stores were low or absent.