Lead poisoning

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Chronic ingestion of lead in humans causes an anaemia that is usually normochromic or slightly hypochromic. Red cell lifespan is shortened and there is a mild rise in reticulocytes, but jaundice is rare. Basophilic stippling is a characteristic, although not universal, finding and it is thought to be due to precipitation of RNA, resulting from inhibition of the enzyme pyrimidine 5'-nucleotidase. Siderotic granules, and occasionally Cabot rings, are found in circulating red cells. The bone marrow shows increased sideroblasts, in some patients with ring sideroblasts. Red cell protoporphyrin and coproporphyrin are raised, as are urinary excretion of ALA, coproporphyrin III and uroporphyrin I.

The cause of the anaemia appears to be multifactorial. Haemolysis, probably due to the blocking of sulphydryl groups, with consequent denaturation of structural proteins, and damage to mitochondria with defective haemoglobin production due to inhibition of the enzymes of haem synthesis, are the major factors.

Figure 3.6 Sideroblastic anaemia. Erythroblasts showing perinuclear rings of iron (Perls' stain).

Table 3.9 Siderocytes and sideroblasts.

Siderocyte Mature red cell containing one or more siderotic granules (Pappenheimer bodies)

Normal sideroblast Nucleated red cell containing one or more siderotic granules, granules few, difficult to see, randomly distributed in the cytoplasm, reduced proportion of sideroblasts in iron deficiency and anaemia of chronic disorders

Abnormal sideroblasts Cytoplasmic iron deposits (ferritin aggregates): increased granulation, granules larger and more numerous than normal, easily visible and randomly distributed, proportion of sideroblasts usually parallels the percentage saturation oftransferrin (e.g. haemolytic anaemia, megaloblastic anaemia, iron overload, thalassaemia disorders) Mitochondrial iron deposits (non-ferritin iron): ring sideroblasts in inherited and acquired sideroblastic anaemias

Inherited sideroblastic anaemias

These are rare disorders manifesting mainly in males, usually in childhood or adolescence, but occasionally presenting late in life, when they need to be distinguished from the more common acquired 'refractory anaemia with ring sideroblasts'.

X-linked sideroblastic anaemia

In most reported families, inheritance has followed an X-linked pattern. More than 25 different mutations of erythroid-specific ALAS2, located at Xp11.2l, have been identified. All have been single-base substitutions. Most lead to changes in protein structure, causing instability or loss of function. They are found scattered over the seven exons (out of 11) encoding the C-terminal, catalytically active part of the protein. Mutations affecting the promoter have also been shown to cause disease. Function may be rescued to a variable degree by administration of pyridoxal phosphate - the essential cofactor for ALAS2 - the best responses occurring when the mutation affects the pyri-doxal phosphate-binding domain of the enzyme. The response is better if iron overload is reduced by phlebotomy or chelation.

A rare form of X-linked sideroblastic anaemia (ASAT), refractory to pyridoxine, is caused by abnormalities in the ATP-binding cassette transporter gene (ABC7) at Xq13.3. This form is associated with early-onset, non-progressive cerebellar ataxia. A useful diagnostic distinction is the presence within the red cells of increased zinc protoporphyrin, despite adequate iron stores, rather than the low/normal levels found in patients with abnormalities in ALAS2. The anaemia is mild to moderately severe. Three abnormalities of protein structure have been described, and these lie within 34 amino acids of one another at the C-terminal end of the transmembrane domain.

Female carriers of X-linked sideroblastic anaemia may show partial haematological expression, usually with only mild or no anaemia, although, rarely, with a severe dimorphic anaemia. This may depend on variation in the severity of the defect, as well as the degree of lyonization of the affected X-chromosome. Late onset in some patients suggests that the degree of lyonization may change with age. Iron loading may also aggravate the defect in haem synthesis in both males and females with sideroblastic anaemia.

Patients with X-linked sideroblastic anaemia show a hypochromic, often microcytic, anaemia. There may be a few circulating siderocytes, normoblasts and cells with punctate basophilia, but these features become pronounced only if the spleen has been removed. The bone marrow shows erythroid hyperplasia and the erythroblasts tend to be microcytic with a vacuolated cytoplasm. There are many (> 15%) ringed sidero-blasts. The ineffective erythropoiesis is not usually accompanied by bone deformities, but some bossing of the skull and enlargement of the facial bones may result from the erythroid expansion. The spleen may be enlarged. Patients may present with severe iron overload even when the anaemia is relatively mild, but the rate of iron loading is accelerated if red cell transfusions are needed. Iron loading, however, aggravates the anaemia.

Mitochondrial DNA mutations

Deletions of mitochondrial DNA, sometimes associated with duplications, are known to be the cause of Pearson marrow-pancreas syndrome, typically consisting of sideroblastic anaemia, pancreatic exocrine dysfunction and lactic acidosis. This is a severe disorder of early onset, presenting usually with failure to thrive, persistent diarrhoea and lactic acidosis. All haemopoietic cell lineages can be affected, and the anaemia is typically macrocytic with prominent vacuoles in cells of both myeloid and erythroid lineages.

Mitochondrial DNA has its own genetic code and encodes mitochondrial tRNA and ribosomal RNA as well as several mitochondrial proteins. In Pearson's syndrome, deletions may encompass tRNA as well as mitochondrial genes and therefore have an effect on the function of all mitochondrion-encoded proteins, causing a considerable loss of mitochondrial function. The presence of many different mitochondria within nucleated cells enable the coexistence of normal and abnormal species, the proportion of which is likely to vary within different tissues, a phenomenon known as heteroplasmy. The extent to which different tissues are affected depends to some extent on this proportion and detection often requires the study of different tissues. Inheritance is difficult to determine for the same reason and most cases are described as of 'sporadic' occurrence.

Abnormalities of a high-affinity transporter of thiamine

A gene (SLC19A2) encoding a putative thiamine transporter (THTR-1) that is widely and variably expressed has now been mapped to the long arm of chromosome 1 (1q23.3). Abnormalities in this gene are responsible for the thiamine-responsive megaloblastic anaemia (TRMA), or Roger's syndrome. This syndrome is inherited in an autosomal recessive manner and combines diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD), which respond in varying degrees to pharmacological doses of thiamine (vitamin B1). Ring side-roblasts in varying numbers are typically present and onset is usually in childhood, although some symptoms may be present in infancy. A direct link between the presence of the mutation and mitochondrial iron loading has yet to be demonstrated.

There are still a substantial number of cases of inherited side-roblastic anaemias in which the exact underlying genetic defect remains obscure. These cases may or may not show sex-linked inheritance and often show a macrocytic or dimorphic picture.

Acquired sideroblastic anaemias

Primary acquired sideroblastic anaemia (refractory anaemia with ring sideroblasts)

This is a form of myelodysplasia (refractory anaemia with ring sideroblasts), and arises as a clonal disorder of haemopoiesis. The anaemia is often macrocytic with raised red cell protopor-phyrin concentrations, in contrast to X-linked sideroblastic anaemia. Marked erythroid hyperplasia may be present, together with increased iron stores. In these patients, abnormalities in the white cell or platelet precursors are usually absent and the risk of transformation to acute myeloid leukaemia appears less than in other myelodysplastic disorders. Smaller numbers (< 15%) of ring sideroblasts may be present in patients with any of the other myelodysplastic and myeloproliferative diseases. Recent data suggest that acquired defects of mitochondrial DNA may underlie iron transport abnormalities in primary acquired sideroblas-tic anaemia.

Secondary sideroblastic anaemias

Sideroblastic anaemia associated with pyridoxine deficiency has been described, although not completely documented, in a few patients with gluten-induced enteropathy, in pregnancy, and with haemolytic anaemias, such as sickle cell disease and mechanical or autoimmune haemolytic anaemia. Sideroblastic anaemia may be found as a complication of antituberculous chemotherapy, particularly with isoniazid and cycloserine (pyridoxine antagonists). Sideroblastic anaemia occurs in alcoholism if there is associated malnutrition and folate deficiency. Suggested mechanisms include interference with haem formation and pyridoxine metabolism. The anaemia rapidly reverses with abstinence from alcohol, a normal diet and pyridoxine therapy. Chloramphenicol inhibits mitochondrial protein synthesis and in some patients causes ring sideroblast formation, presumably as a result of impaired haem formation in the mitochondria. Lead inhibits several enzymes concerned in haem synthesis and may damage structural mitochondrial proteins. In some cases, ring sideroblasts are visible in the marrow.



Some patients with X-linked sideroblastic anaemia respond to pyridoxine, given initially in doses of 100-200 mg per day. The response is usually partial. Some patients require only small doses (less than 10 mg per day) to maintain a higher haemoglobin concentration.

Pyridoxine therapy is almost always ineffective in primary acquired sideroblastic anaemias. Some secondary sideroblastic anaemias may, however, be completely reversed by pyridoxine therapy. This has been described in alcoholism, haemolytic anaemia and gluten-induced enteropathy, as well as in patients receiving antituberculous chemotherapy, in whom the drugs have been stopped and pyridoxine administered.

Other forms of treatment

Folic acid may benefit patients with secondary anaemia. For refractory patients, the anaemia may remain stable and, if the patient is transfusion independent, no treatment is needed. Patients requiring regular red cell transfusions require iron chelation therapy. Iron loading may aggravate the anaemia and, in some patients, improvement in the anaemia has followed iron removal by phlebotomy or iron chelation therapy. Splenectomy should usually be avoided, as it does not benefit the anaemia and leads to persistently high platelet counts postoperatively, with a high incidence of thromboembolism.

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