Autopsy Findings In Sickle Cell Disease

Carlos T. Escoffery, D.M. (Path); and Suzanne E. Shirley, D.M. (Path)
Carlos T. Escoffery, D.M. (Path) is a Senior Lecturer in the Department of Pathology
at the University of the West Indies in Mona, Jamaica.
Suzanne E. Shirley, D.M. (Path) is a Lecturer in the Department of Pathology
at the University of the West Indies in Mona, Jamaica.

Introduction

Sickle cell disease (SCD), whether in its homozygous form (HbSS) or as a combination of HbS with another abnormal hemoglobin e.g. HbSC, has a variable clinical course. The pathologic findings seen at autopsy encompass a combination of changes that vary in predictability and importance, and may or may not be directly related to the cause of death. Despite the prevalence and importance of SCD, there have been few large necropsy studies, even though many now accept that SCD by itself is not an adequate explanation of death.

This article aims to review the autopsy findings that may be seen in SCD, with an emphasis on the principal gross pathologic features rather than on comprehensive microscopic findings or detailed discussions of the pathophysiologic processes involved. An attempt will be made to emphasize the importance and frequency of those lesions that have been shown to be directly related to the cause of death in SCD. While we will attempt to relate our findings to the referenced medical literature, some of our pathologic observations are derived from the experience gained from the numerous post mortem examinations that have been performed in our department on Jamaican patients with SCD.

General External Features

There are certain external physical features of SCD that tend to be consistent and characteristic in life, but may also be noted at autopsy. These findings are well documented in a textbook on SCD by Serjeant.1 This book contains many clinico-pathological observations based on the study of Jamaican patients with SCD. In general, the body habitus in adult patients is that of slim build, and obesity is uncommon. The mean weight of both children and adults is subnormal. SCD patients tend to have long thin limbs, narrow pectoral and pelvic girdles, and increased antero-posterior chest diameter. Mean height is reduced in childhood, but tends to normalize during adolescence and into adulthood.

Bossing of the frontal and parietal areas of the skull may be seen due to bone marrow expansion secondary to increased erythropoiesis—when the skull is opened, the vault shows widening of the diploic space with thinning of the outer table. Scleral icterus reflects the hyperbilirubinemia consequent on chronic hemolysis, and the pallor of the mucous membranes mirrors the chronic anemic state. Both of these findings will vary with acute exacerbations of the relevant chronic steady state of the patient.

Deformity and/or shortening of the digits may occur as a consequence of dactylitis (hand-foot syndrome) in early childhood. An adduction deformity and shortening of the lower limb is seen in some patients as a consequence of avascular necrosis of the femoral head. This is a common occurrence that develops most frequently in late adolescence or early adult life with an overall prevalence of about 10%.2 Chronic ulcers, typically affecting the area around the ankles above the malleoli (less frequently on the anterior shin or dorsum of the foot), are common with a prevalence of up to 75% in sickle cell anemia (HbSS). They are invariably found in adults, being distinctly uncommon in children. Most ulcers have a "punched out" appearance with well-defined margins, slightly raised edges, and a granulating base. Chronic subcutaneous fibrosis may be a sequel of ulceration, and occasionally is severe enough to cause fixed flexion deformity of the ankle joint

Brain


Figure 1. Brain of a 21-year-old man with HbSS with a large intracerebral hemorrhage.		 Strokes are not uncommon in patients with SCD and incidence figures of up to 26% have been quoted.3 Though cerebrovascular accidents (CVA) in SCD may be due to intracerebral hemorrhage (Figure 1) or subarachnoid hemorrhage (SAH), most are due to cerebral infarction with the majority of them occuring in children and teenagers.4-6

Ohene-Frempong et al.7 in a longitudinal clinical study from 23 clinical centers across the USA, found a prevalence rate of 4% for CVA in SCD. They also found a high incidence of infarctive CVA in children and teenagers, and in addition documented that the 20-29 year age group had the highest incidence of hemorrhagic CVA.

In this series the mortality rate was 26% for hemorrhagic stroke, and no deaths occurred after infarctive stroke. Char & Serjeant6 in an autopsy study on 114 Jamaican patients with SCD found a 16% incidence of CVA with roughly equal incidence of  infarctive and hemorrhagic types, and observed that infarction occurred at a median age of 10 years.

SAH is a relatively uncommon cause of stroke in SCD and the majority is associated with intracranial (berry) aneurysms.8 The aneurysms in SCD are unusual in that they have a high incidence of multiplicity and often arise in unusual sites. Oyesiku et al.3 reported a 60% incidence of multiple aneurysms in a series of 15 patients—a total of 30 aneurysms being found in the 9 affected patients—one patient having up to 5 aneurysms. Some of the unusual locations in which they found aneurysms included the ophthalmic artery and the anterior choroidal artery. Preul et al.8 reviewed 44 cases of intracranial aneurysms in SCD, and found that 57% of patients had multiple aneurysms with an average of 3 aneurysms per patient. They also noted that a large number of the aneurysms occurred in the posterior circulation (vertebrobasilar axis), which is conspicuously different from the distribution in the general population.

Meningitis predominantly affects younger patients, and is most often bacterial in nature, with pneumococcus (Streptococcus pneumoniae) being the most common etiological agent.4,9-10 The brain is often swollen and edematous with purulent exudate varying in extent and amount. Pneumococcal meningitis is uncommon in adults but when it occurs, it carries a high risk of mortality.11

Cardiothoracic

Heart

Cardiomegaly is a characteristic finding and most children with SCD develop cardiomegaly in the first 5 years of life. Adults typically have cardiomegaly with biventricular hypertrophy.12 Cases of myocardial infarction in the absence of significant major coronary artery disease have been documented, and the features of typical ischemic heart disease are said to be rare in SCD.13 Right heart failure has occurred in patients with pulmonary hypertension due to multiple thrombotic occlusion of small and medium-sized pulmonary arteries.14 Congestive cardiac failure (CCF), when seen, is not commonly due to the usual causes such as hypertension, ischemic heart disease, valvular diseases etc., and unexplained CCF in some patients has giving rise to the hypothesis of a specific "sickle cell cardiomyopathy." This entity is unsubstantiated and doubt has been cast as to its existence by those who suggest that cardiac dysfunction in SCD can usually be explained by the adverse effects of concurrent disease on the diminished cardiac reserve of chronic anemia.12

James et al.15 reported autopsy findings in the hearts of 2 patients—neither of whom were diagnosed as sicklers in life, but in whom the capillaries and small arteries of the heart were packed with sickled erythrocytes—both of which showed abundant foci of old and recent degeneration in the sinus node, atrioventricular node, bundle of His and the coronary chemoreceptor. They suggested that these findings might indicate that some patients with SCD who die a sudden death without significant autopsy findings might have an element of lethal cardiac electrical instability. The significance of these findings is uncertain, but they do indicate the need for detailed cardiac examination at autopsy in SCD.

Lungs

The clinical presentation of acute pulmonary pathology in SCD has been termed the "acute chest syndrome" (or simply "chest syndrome" by some)—a term that appears to invoke a certain amount of diagnostic confusion. In the Jamaican study by Thomas et al.9 the term encompassed disease due to pneumonia, pulmonary embolism or both. In some studies in the UK, acute chest syndrome was used to characterize acute pulmonary failure without an infective cause or where any infective component was considered to be minor or remote from the lungs.16-17 In the USA the basic definition of the syndrome appears to be that of chest pain, fever and pulmonary infiltrate(s) on chest x-ray.18-20

Despite these clinical differences, the pathologic findings in such settings include:

  1. Varying degrees of bronchopneumonic consolidation, which may be extensive and sometimes necrotizing, and may be accompanied by fibrinous, fibrino-purulent, or purulent pleural exudation (Figure 2).
  2. Pulmonary thromboembolism with or without pulmonary infarction; these thrombi may be small and peripheral, or massive and central.
  3. Fibrous pleural adhesions, sometimes quite dense and extensive; these reflect organization of pleural exudates related to prior episodes of pneumonia and/or pulmonary infarction.

Figure 2. Extensive bronchopneumonia with thick purulent pleural exudate in a 31-year-old male sickler.

Chronic lung disease may also be found in the form of organization of thrombi and progressive obliteration of the pulmonary vascular bed. Sickle cell chronic lung disease is an important entity and a leading contributor to mortality in young adults causing pulmonary failure and cor pulmonale consequent to an obstructive arteriolar vasculopathy.21

Abdomen

Hepato-biliary System

The main pathologic findings that may be seen in the liver are well described in papers by Bauer et al22 and Schubert23. Hepatomegaly is seen in 80-100% of cases at autopsy, the typical finding being that of a large, smooth liver. This finding is ascribed to chronic sinusoidal congestion by sickled erythrocytes with an element of sinusoidal obstruction by Kupffer cells distended with phagocytosed red cells. Significant fibrosis is relatively common with the severity increasing with age. The incidence of cirrhosis ranges from 16 to 29%, the presumed causes including hypoxic injury due to sickling, hepatitis, gallstones, right heart failure and iron overload. However, there is a significantly high percentage of cases in which the cause is unknown. The importance of SCD as a definite cause of cirrhosis is still uncertain and is an uncommon finding in Jamaican patients. Hepatic infarction of a part of, or a complete lobe, has been documented, but is rare.

There is a high incidence of gallstones caused by the continual high levels of bilirubin excretion consequent on chronic hemolysis. Cholelithiasis is common in children from as young as 5 years of age.24 The prevalence increases with age with up to about 60-70% of adults being affected.23,25 Typically the stones are multiple, are of the black "pigment" type (Figure 3), and are composed of calcium carbonate and bilirubinate. Acute and chronic cholecystitis do occur in some patients, but the frequency is uncertain and there is no clear relationship between the presence of cholelithiasis and clinical symptomatology, especially due to the common confounding occurrence of hepatic crises.23,26 Choledocholithiasis is well documented but the occurrence of the condition in unselected patients with SS disease is unknown; the prevalence rate is probably in the order of the 14-18 %.23

Spleen

At autopsy, the spleen is frequently enlarged in young children, but progressive atrophy tends to be the norm in older children and adults (Figure 3). In adults, the spleen is often reduced to a fibrous nubbin.27 With acute splenic sequestration the spleen is markedly congested and enlarged, sometimes massively.


Figure 3. Multiple "pigment" gallstones in the gallbladder, and a fibrotic, atrophic spleen (less than one-third of the normal weight) in a 53-year-old male with HbSS.

Duodenum

De Caestecker and Bates28 reviewed the issue of duodenal ulcer in SCD and noted that dyspeptic symptoms were said to be common with relatively high prevalence rates of duodenal ulcers. They noted, however, that these prevalence rates were either the same as for age and sex matched controls, or were difficult to interpret in those studies where there was no knowledge of the general population prevalence. The issue of whether or not there really is a greater risk of duodenal ulceration in SCD remains undecided and needs further investigation by case control studies.

Kidney

As a general rule, renal weights are normal in young children, increased in older children and young adults, and decreased in patients over 40 years. The glomeruli are enlarged and hypercellular and because they tend to be congested with red blood cells, are often easily seen on the capsular surface as pin-point hyperemic dots, especially in younger patients. In older patients, chronic renal failure is associated with scarred shrunken kidneys with a coarsely granular subcapsular surface, papillary necrosis and gross distortion and scarring of the pelvicalyceal system. There is progressive partial or total fibrosis of the glomeruli with age, the pathogenesis of which is unknown, but which does not appear to be due to papillary necrosis or immune complex glomerulonephritis.29

Davis et al. described an unusual renal abnormality in SCD in 199530 — renal medullary carcinoma — a highly aggressive renal neoplasm with a uniformly fatal clinical course. They found the neoplasm in patients with sickle cell trait, and one with HbSC, but not in homozygous sickle cell anemia. Unlike the usual renal carcinoma the dominant mass was in the medulla, and the tumor is thought to arise in the calyceal epithelium in or near the renal papillae. Since this initial report, the tumor has been documented in other patients with sickle cell trait, but still has not been noted to occur in homozygous SCD.31

Skeletal System

The changes in the skull have been mentioned previously. Similar marrow expansion may affect the vertebral bodies, which become flattened with increased width to height ratio. Classically, the upper and lower surfaces of the vertebral bodies become biconcave giving the typical "fish vertebrae" appearance.32 Osteomyelitis may be seen in sicklers, and salmonella infection is a relatively more frequent cause than in the general population. In fact, over 70% of hematogenous osteomyelitis in SCD is caused by salmonellae.10

Causes Of Death In SCD

Having delineated the spectrum of anatomical findings that may be seen in SCD at necropsy, it is instructive to examine the relative frequency of these lesions as causes of death. Data from 4 autopsy studies — one performed in Jamaica9 and the others in the USA33-35 — are depicted in Table 1.

 

The acute chest syndrome (ACS) was the leading cause of death in 2 of the studies. Infection was a significant cause of death in all of the series either in the form of pneumonia—subsumed under acute chest syndrome by Thomas et al.9—septicemia or meningitis. Renal failure (uremia) and cerebrovascular accidents (stroke) also featured consistently, with the latter often occurring concomitantly with other diseases e.g. pneumonia.

Necrotic bone marrow emboli were a significant cause of death in the series by Haupt et al.33 and Parfrey et al.34 This finding is striking and represents the only pulmonary pathology seen in the lungs of patients with SCD at autopsy that is not seen in age-sex-race matched control subjects.33 These emboli apparently occur secondary to the infarction of long bones, and it is noteworthy that of the 16 patients described in the 2 studies quoted above, 6 (38%) were HbSC and 10 (62%) were HbSS.

In the Jamaican series the highest mortality occurred in the younger age groups— one-third of deaths occurred in the first 5 years of life and the greatest mortality for any single year was in the first year. Most of the deaths were due to acute splenic sequestration.9 Parfrey et al.34 also noted that one-third of their patients died in the first 5 years of life, most of these from either infection or ACS.

It is noteworthy that in the 3 studies from the USA an average of 20% of patients with SCD had no anatomical cause of death after detailed postmortem examination.33-35 Of interest, a significant number of these patients died soon after or during an episode of painful crisis. Based on this, Parfrey et al. suggested that painful crisis might actually be a cause of death in SCD.34 In contrast, no anatomical cause of death was identified in 5% of the Jamaican sicklers.9 The authors noted that blood cultures were not available for these patients and therefore septicemia might have gone undetected in some. Data concerning the relationship of death to an episode of painful crisis was not documented.

Conclusion

A variety of gross pathological abnormalities may be seen at autopsy in patients with SCD. Some of these such as cardiomegaly, hepatomegaly and cholelithiasis, are almost invariable, but do not by themselves necessarily connote morbidity in life or an explanation for death. The acute chest syndrome, infections, acute splenic sequestration and chronic renal failure are commonly listed causes of death.. Infections and splenic sequestration are particularly important in children, with pulmonary embolism and renal failure being more important causes of mortality in adults.

It must be remembered that in a significant proportion of patients with SCD, no anatomical cause of death is demonstrated at autopsy. Causes not necessarily discernible in gross autopsy findings, such as septicemia or biochemical abnormalities, should be borne in mind and the relevant adjunctive investigations performed to exclude these. We would recommend that thorough autopsies be performed in as many SCD deaths as possible, so that the pathological processes involved may be comprehensively documented. 

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Jacksonville Medicine / June, 2000

 

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