Elizabeth A. Manci

Causes of death in sickle cell disease: an autopsy study

Summary. More precise analysis of causes of death is needed to focus research efforts and improve morbidity and mortality in sickle cell disease. In this study, the morphological evidence of the cause of death was studied in 306 autopsies of sickle cell disease, which were accrued between 1929 and 1996. The most common cause of death for all sickle variants and for all age groups was infection (33–48%). The terminal infection was heralded by upper respiratory tract syndromes in 72·6% and by gastroenteritis in 13·7%. The most frequent portal of entry in children was the respiratory tract but, in adults, a site of severe chronic organ injury. Other causes of death included stroke 9·8%, therapy complications 7·0%, splenic sequestration 6·6%, pulmonary emboli/thrombi 4·9%, renal failure 4·1%, pulmonary hypertension 2·9%, hepatic failure 0·8%, massive haemolysis/red cell aplasia 0·4% and left ventricular failure 0·4%. Death was frequently sudden and unexpected (40·8%) or occurred within 24 h after presentation (28·4%), and was usually associated with acute events (63·3%). This study shows that the first 24 h after presentation for medical care is an especially perilous time for patients with sickle cell disease and an acute event. Close monitoring and prompt aggressive treatment are warranted.

Gastric mucosal injury in the rat. Role of iron and xanthine oxidase

Recent studies have implicated oxygen free radicals in ischemia-reperfusion injury to the gastric mucosa. The aims of the present study were to test the hypothesis that the enzyme xanthine oxidase is the source of the oxygen radicals in the ischemic stomach and determine the importance of the iron-catalyzed Haber-Weiss reaction in generating the cytotoxic oxygen radicals. Gastric mucosal clearance of 51Cr-labeled red blood cells was measured during a 30-min control period, a 30-min ischemic period (hemorrhage to 25 mmHg arterial pressure), and a 60-80-min reperfusion period (reinfusion of shed blood). In untreated (control) rats, a dramatic rise (100-fold) in the leakage of 51Cr-labeled red blood cells into the gastric lumen was observed only during the reperfusion period. After the reperfusion period, gastric mucosal damage was further assessed using gross lesion area and histology. Rats were placed on a sodium tungstate diet (to inactivate xanthine oxidase), or treated with either deferoxamine (an iron chelating agent) or superoxide dismutase (a superoxide scavenger). All three interventions substantially reduced 51Cr-labeled red blood cell clearance and gross lesion area relative to untreated rats. However, tissue injury assessed histologically was similar in both treated and untreated animals. The results of this study support the hypothesis that oxygen free radicals mediate the hemorrhagic shock-induced extravasation of red blood cells. The data also indicate that xanthine oxidase is the source of the oxy-radicals and that the iron-catalyzed Haber-Weiss reaction is largely responsible for hydroxyl radical generation in this model.

Collagenous colitis in children

Collagenous colitis, a disorder characterized by increased subepithelial collagen deposition associated with an inflammatory infiltrate in the lamina propria, has been reported infrequently in children. An 8-year-old girl with collagenous colitis is described who presented with chronic watery diarrhea and abdominal pain. Biopsy specimens of the colonic mucosa showed the pathological features of collagenous colitis. The patients symptoms resolved following corticosteroid therapy. Collagenous colitis should be considered in the differential diagnosis of children with chronic diarrhea.

Regional variations in the levels of zinc, iron, copper, and calcium in the term human placenta

This study investigated the influence of the location of the sampling site during elemental analyses of 21 human term placentae. The levels of iron, zinc, copper and calcium in fetal membranes, umbilical cords and placental discs were measured by atomic absorption spectrophotometry and compared. The disc samples were obtained from central (peri-insertion and mid-disc fetal and maternal halves), and peripheral regions. Significant variations were found. Copper was present in highest levels (17.2 +/- 2.0 micrograms/g dry weight) in the fetal membranes. Calcium levels were highest (712 +/- 47 micrograms/g dry weight) in the periphery of the placental disc. Iron levels were highest (558 +/- 14 micrograms/g dry weight) in the central regions of the disc. Zinc levels were lower (50.3 +/- 1.4 micrograms/g dry weight) in the fetal half of the mid-disc regions than in the maternal half (56.0 +/- 1.2 micrograms/g dry weight). This study demonstrates the importance of defining the location of the sampling site in studies involving elemental analysis of the placenta.

Intradural Extension of a Sacrococcygeal Teratoma

Intradural extension of a sacrococcygeal teratoma (SCT) is extremely rare and only well-documented in presacral tumors that have been associated with a familial history, anorectal stenosis, and sacral dysraphism. This case documents the extension of a type I SCT into the dural sac with attachment to the filum terminale. A full-term female was transferred to our tertiary newborn intensive care unit with a sacral mass measuring 12 x 13 cm. It protruded from the buttocks and displaced the anus anteriorly. Rectal examination showed no presacral component. Radiographs demonstrated calcification in the soft tissue mass and a normal-appearing sacrum with the last sacral segment not visualized. At operation during dissection of the cephalad component, the SCT extended into the spinal canal. Neurosurgical consultation resulted in a sacral laminectomy which revealed the tumor to be attached to the tip of the filum terminale. The tumor was removed in toto with all sacral roots preserved. The infant required a second operation to revise a wound dehiscence and suspected cerebrospinal fluid leak. The final pathology report was benign SCT. Follow-up at 2 years showed no recurrence, normal sphincter tone, and a normal computed tomography scan. This represents the first well-documented intradural extension of a Type I SCT with attachment to the spinal cord. This extremely rare occurrence requires awareness with the availability of neurosurgical support to expedite operative management.

Idiopathic neonatal iron-storage disease

A 21-day-old infant presented with anemia, conjugated hyperbilirubinemia, hypoproteinemia, and a severe coagulopathy. The hospital course was marked by progressive hepatic failure, encephalopathy, and renal insufficiency. The infant died on day 15 of hospitalization. Postmortem examination showed diffuse hepatic fibrosis and marked siderosis of the liver, pancreas, kidney, adrenal glands, and the duodenal epithelium, with sparing of the reticuloendothelial system. These findings were characteristic of idiopathic neonatal iron-storage disease. Previously reported cases are summarized and discussed. An increased awareness and understanding of this rapidly fatal disorder will be important for genetic counseling and possibly in defining an aberrant mechanism in the handling of iron.

A tungsten-supplemented diet delivered by transplacental and breast-feeding routes lowers intestinal xanthine oxidase activity and affords cytoprotection in ischemia-reperfusion injury to the small intestine

Ischemia-reperfusion injury has been implicated as playing a major role in the development of necrotizing enterocolitis, a major cause of morbidity and mortality in the newborn. A tungsten-supplemented molybdenum-free diet can reduce xanthine oxidase (XO) enzyme activity in the intestine, which in turn reduces the generation of oxygen radicals after an ischemia-reperfusion insult. This study evaluated the ability of this diet to be effective by indirect means, ie, transplacental and breast-feeding routes. XO activity of the intestine was measured in three groups of CD-1 white rats: I, weanlings fed the tungsten diet or standard chow for 1 week; II, 1-day-old rat pups whose mothers were maintained on the tungsten or standard chow for 7 to 10 days prior to term; and III, rat pups at 1 and 3 weeks after birth whose lactating mothers were maintained on the tungsten or standard chow. Some animals from group III also underwent either a 30- or 60-minute episode of occlusion of the superior mesenteric artery (SMA) to evaluate the protective effects of the diet. XO activity was significantly reduced in all groups receiving the tungsten diet (P less than .0001). Blinded histopathologic studies of the entire small bowel showed significantly less villar necrosis (P less than .05) and fibrosis (P less than .0001) in the tungsten-treated group than in the controls. In the 60-minute occlusion study all tungsten-group animals survived, whereas 7 of 12 in the control group died of intestinal infarction within 24 hours (P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiofaciocutaneous syndrome (CFC) with congenital peripheral neuropathy and nonorganic malnutrition : An autopsy study

Many phenotypic manifestations have been reported in cardiofaciocutaneous (CFC) syndrome, but none, to date, are pathognomonic or obligatory. Previous histopathological studies reported findings in skin and hair; no autopsy studies have been published. We report the clinical and autopsy findings of a 7‐year‐old boy with severe CFC syndrome and malnutrition of psychosocial origin. Manifestations of CFC, reported previously, included macrocephaly and macrosomia at birth; short stature; hypotonia; global developmental delays; dry, sparse thin curly hair; sparse eyebrows and eyelashes; dilated cerebral ventricles; high cranial vault; bitemporal constriction; supraorbital ridge hypoplasia; hypertelorism; ptosis; exophthalmos; depressed nasal bridge; anteverted nostrils; low‐set, posteriorly‐rotated, large, thick ears; decayed, dysplastic teeth; strabismus; hyperelastic skin; wrinkled palms; keratosis pilaris atrophicans faciei; ulerythema ophryogenes; hyperkeratosis; gastroesophageal reflux; and tracheobronchomalacia. Additional findings, not previously reported, include islet cell hyperplasia, lymphoid depletion, thymic atrophy and congenital hypertrophy of peripheral nerves with onion bulb formations. Although the islet cell hyperplasia, lymphoid depletion, and thymic atrophy are nonspecific findings that may be associated with either CFC or malnutrition, the onion bulb hypertrophy is specific for a demyelinating–remyelinating neuropathy. These findings implicate congenital peripheral neuropathy in the pathogenesis of the developmental delays, feeding difficulties, respiratory difficulties, ptosis and short stature in this case. Additional studies of other cases of CFC are needed.

Sustained treatment of sickle cell mice with haptoglobin increases HO-1 and H-ferritin expression and decreases iron deposition in the kidney without improvement in kidney function

There is growing evidence that extracellular haemoglobin and haem mediate inflammatory and oxidative damage in sickle cell disease. Haptoglobin (Hp), the scavenger for free haemoglobin, is depleted in most patients with sickle cell disease due to chronic haemolysis. Although single infusions of Hp can ameliorate vaso‐occlusion in mouse models of sickle cell disease, prior studies have not examined the therapeutic benefits of more chronic Hp dosing on sickle cell disease manifestations. In the present study, we explored the effect of Hp treatment over a 3‐month period in sickle mice at two dosing regimens: the first at a moderate dose of 200 mg/kg thrice weekly and the second at a higher dose of 400 mg/kg thrice weekly. We found that only the higher dosing regimen resulted in increased haem‐oxygenase‐1 and heavy chain ferritin (H‐ferritin) expression and decreased iron deposition in the kidney. Despite the decreased kidney iron deposition following Hp treatment, there was no significant improvement in kidney function. However, there was a nearly significant trend towards decreased liver infarction.

High protein diet attenuates histopathologic organ damage and vascular leakage in transgenic murine model of sickle cell anemia

Previous reports have shown that a high protein diet improves weight gain and decreases expression of inflammatory markers in weanling Berkeley transgenic sickle cell mice. The effect of this diet on the underlying histopathology, however, has not been studied. Age-matched, male C57BL/6 controls (n = 24), Berkley sickle mice (n = 31) and Townes sickle mice (n = 14) were randomized in a terminal experiment at weaning to isoenergetic diets, with either normal (20%) or high (35%) amount of energy from protein, by replacing dextrin. Tissue sampling for blinded histologic study and scoring of changes at baseline and after 3 months of feedings showed progressive siderosis and infarcts in spleen, kidney, and liver in all sickle groups, and no significant changes in age- and sex-matched normal controls. High-protein (35%) fed Berkeley sickle mice had significantly fewer (p < 0.01) infarcts in spleen (35.7% less), liver (12.5% less), and kidney (28.6% less) and lower histopathologic scores (p < 0.01) for chronic tissue injury in liver and spleen than matched normal-protein (20%) fed Berkeley sickle mice. In addition, high-protein fed Townes sickle mice had less vascular leakage (∼36%) in the heart, lungs, and brain and a better survival rate (21%) than matched normal-protein Townes sickle mice. This is the first report of histopathologic evidence that a high protein:calorie diet attenuates sickle cell related chronic organ injury in transgenic sickle cell mouse models.