Thymic Hypertrophy and Sudden Unexpected Death In Adults –A Retrospective Study Of 56 Autopsy Cases

Status thymico-lymphaticus, also termed as “status lymphaticus”or simply “lymphatism”, was first used in the publications in 1911, whose most important feature and essential diagnostic sign is enlargement of the thymus. This condition involves a combination of constitutional anomalies: hypertrophy of the thymus, general hyperplasia of the lymphatic system (such as the spleen and lymph nodes), hypoplasia of the cardiovascular system with aortic narrowing, and hypoadrenal. The condition is sometimes terminated by sudden death usually in children ^{1, 2}, but few cases were reported in adults. Whether hypertrophic thymus increases the risk of the sudden unexpected death in adult (SUDA), the frequency of presence of the other anomalies, and the relationship between clinical, macroscopic and microscopic findings, there was no systemic study especially in Chinese. On the other hand, although status thymico-lymphaticus had ever been explained as a cause of SUD in patients without other determined positive anatomic findings, by now, some were questioning whether it really existed as a disease or a pathological entity.

The thymus is a lobulated organ covered by a capsule. It enlarges during childhood, and atrophies at puberty. The normal weight of the thymus varies with the age ³. As one ages the thymus slowly shrinks, eventually degenerating into tiny islands of fatty tissue. The thymus of older people is scarcely distinguishable from surrounding fatty tissue. The criteria used to identify hypertrophy of thymus are complicated and challengeable, but we can’t dodge. Thymic hypertrophy is defined as thymic enlargement beyond the upper limits of normal for the age but accompanied by a microscopically normal gland. As usual, the weight of the thymus is usually used for determination of hypertrophy. In few previous studies the great variations had been found in the weight of the normal adult thymuses, maximum weights are difficult to define. The established or recommended size and weight criteria for normal thymus are still controversial. Combined of the data in Chinese people and the Surgical Pathology Criteria from Stanford University School of Medicine (http://surgpathcriteria.stanford.edu/), we used >35g for 18-25 years, >25g for 26-39 years and >15g for 40-60 years as the criteria of thymic hypertrophy.

In this study, the deaths which had no clear cause found at post mortem were classed as “unexplained”. Of all the cases, 7 were diagnosed as “sudden manhood death syndrome (SMDS)”. SMDS is defined as a disorder found in Southeast Asia, particularly Thailand, Philippines and Japan, which causes sudden cardiac death during sleep with known or unknown cardiac disease ⁴. Such a rapid death is often attributed to a cardiac arrhythmia and has no apparent structural cardiac disease in some cases. For seven cases diagnosed as SMDS in this study, we classified three of them which had no positive pathological findings of cardiac disease into “unexplained” and the other four cases which had definite positive cardiac lesions into “Cardiovascular diseases”.

In recent years, previously undetected cardiac or other lesions, readily demonstrated at autopsy, have changed our understanding of SUD and status thymico-lymphaticus. By review of post mortems of 30 years, we found, thymic hypertrophy increased significantly the risk of SUDA (6.9 folds) in both male and female. What’s more, SUDAs associated with thymic hypertrophy were quite younger (22.5 years) than those without it. Instead of a disease entity “status thymico-lymphaticus” is a systematic abnormality with thymic hypertrophy as a feature involving mainly immune and/or cardiovascular system.

We found, as an independent factor, thymic hypertrophy increased significantly the risk of SUDA (6.9 folds) in both male and female. What’s more, SUDAs associated with thymic hypertrophy were quite younger (22.5 years) than those without it. As same as SUDA, thymus hypertrophy had male predominance. It was thought that the thymus atrophy is due to the increased circulating level of sex hormones, and chemical or physical castration of an adult results in the thymus increasing in size and activity ⁹. So we are not surprised to see that histologic characteristics of the thymus are not identical in the two sexes ¹⁰, and it is likely to attribute the sex difference in the present study to the levels of sex hormones. In the previous studies the great variations had been found in the weight of the normal adult thymus, which was explained by intermingled parenchyma and fat in the involuted thymuses, and it was difficult to decide what to weigh ^{10, 11}. In this study, the corrected weight of thymus was also calculated in 10 low-power fields by the weight of thymus × (1- the area of mediastinal fat %). We found the thymic weight correlated positively to its corrected weight (r=0.769, p<0.001), and both the thymic weight (r=-0.419, p=0.009) and the corrected weight (r=-0.701, p<0.001) correlated negatively to the age. In the same age group, the weight of thymus reflects the amount of thymic parenchyma and is convenient to be used as an indicator for thymic hypertrophy.

Although a majority of patients with hypertrophic thymus had a variable number of accompanied anomalies described as the typical characteristics of status thymico-lymphaticus, for example hyperplasia of the lymph nodes and spleen, hypoplasia of the heart and adrenal glands, and aorta narrowing, all of them were not associated with SUDA, because the significant differences existed only between SUDAs with and without thymic hypertrophy groups, but not between thymic hypertrophy with and without SUDA groups. Other congenital anomalies were also found on the patient with thymic hypertrophy, for example hypoplasia of the kidney and congenital megacolon, though they were rare if compared with lymphaticus-associated anomalies. No disease conditions and deaths were identified for these accompanied anomalies. Our date showed that cardiovascular diseases accounted for a little more SUDAs than other causes in patients with thymic hypertrophy. The association between cardiovascular diseases and thymic weights were also reported by Kendall. He found the deaths where cardiovascular conditions were the cause of death or a contributory factor in the death related with higher thymic wet and lipid weights ³. Mutations of the cardiac ryanodine receptor type 2 (RyR2) gene are known to cause fatal ventricular arrhythmia, syncope and sudden death. When Nishio investigated RyR2 mutations in 18 SUD autopsy cases, he found all the 2 cases with the heterozygous missense RyR2 mutation displayed characteristics of status thymico-lymphaticus. It was possible that the mutation is involved in the hypertrophy of the thymus ¹¹. The multiple anomalies in patients with thymic hypertrophy may be caused by gene mutations. However, which mutations, single-gene or combined mutation, and their relationship with various clinical features and SUDAs still remain unclear.

The unexpected finding was the correlation between adrenal glands and thymus. Vacuolization of the adrenal cortex presented more often in thymic hypertrophy patients with SUDA than those without SUDA, however no difference between SUDAs with and without thymic hypertrophy. So we prefer it as a change related with SUDA rather than a combined anomaly of the thymic hypertrophy. It was documented that the vacuolization seems to indicate glandular hyperactivity for hormone production, and the hypothalamic-pituitary-adrenal axis can respond to stress with an increase in the production of cortisol ¹². Reduced adrenal weight with thinning of the cortex and thymomegaly with hyperplasia of the thymus cortex was observed in sudden infant deaths. Adrenal cortex hypofunction was indirectly confirmed by the presence of thymomegaly. Long-lasting glucocorticoid deficiency in secondary hypocorticoidism may cause sudden death following minor environmental causes ¹³. In the present study hypoplasia of the adrenal glands was found on 11 of 56 patients with thymic hypertrophy. However, one patient with thymic hypertrophy show nodular hyperplasia of the adrenal cortex, meanwhile adrenal tumors (adrenocortical adenoma and adrenal pheochromocytoma) were seen in three patients with thymic hypertrophy, which haven’t been documented. The thymus from a 27-year old man who died of coronary artery thrombosis and accompanied by adrenal pheochromocytoma was weighted even to 183g. It seems development and involution of the thymus closely relates with function of the adrenal glands and various hormones. The influence is complicated and maybe varies with age or other body conditions.

SUDAs due to acute hemorrhagic pancreatitis had been reported where diagnosis could not be made until autopsy. Tsokos et al. reported 27 cases of acute pancreatitis that presented as sudden unexpected death. In all cases, the diagnosis was first made at autopsy and the majority of affected individuals died during the very early phage of the disease ^{14, 15}. In the present study, there were 6 patients whose cause of death was attributed to acute hemorrhagic pancreatitis. All of them were males and in the age ranging from 20 to 53 years. Marked male predominance is consistent with Shetty’s study, in which the male to female ratio of the 7 SUDAs due to acute hemorrhagic pancreatitis was 6:1 ¹⁶. We also found more SUDAs were caused by acute hemorrhagic pancreatitis in patients with thymic hypertrophy than without it. Until now, the relationship between thymic hypertrophy and acute hemorrhagic pancreatitis has not been documented. Although much has been known regarding the risk factors, the exact trigger events or pathogenesis still remains obscure ¹⁶. Local inflammation caused by activation of trypsinogen to trypsin, followed activation of inflammatory mediators and released large amounts of oxygen radicals played a key role in pancreatic necro-inflammatory injure ¹⁷. The thymus is a specialized primary lymphoid organ of the immune system. The malfunction of the thymus may induce abnormal inflammatory/immune reaction, which maybe increases the risk of acute hemorrhagic pancreatitis in the patients with thymic hypertrophy. Likewise, infectious diseases and immune-related diseases account for a higher proportion of deaths in patients with thymic hypertrophy than those without it.

The thymus is a complex epithelial organ composed of heterogeneous cell types expressing different CKs ¹⁸. In this study, no SUDA-related markers were found. There is a discrepancy between our results of the CK expression and those published previously ^{19, 20, 21}. Majority previous studies focused on infant and child thymuses, and few cases of immunohistochemical examinations on adult thymuses were documented. It had been found that there were changes of cytokeratin expression in epithelial cells at various stages of thymus involution, which may be related to the aging decline in proliferation of thymocytes ¹⁹. On the other hand, our study indicated that CKs showed distinctly different expression patterns in individuals who had different death causes and different disease background. It seems that morphology and molecular characteristics of the hypertrophic thymuses in adults are closely related with body conditions. Each thymus hypertrophy has its own mechanism which is different among individuals, who have complicated combinations of disorders and/or lesions. Likewise, it is not surprising that Smith didn’t find lymphoid follicles in any of the 100 adult thymuses even with immune-related diseases, when many other authors had found an increase in lymphoid follicles in autoimmune diseases in humans ¹⁰. In the present study, among the 5 patients with autoimmune diseases, only one (with Crohn’s disease) presented lymphoid follicles in the hypertrophic thymus. The relationship between thymic lymphoid follicles and immune-related diseases, as well as dynamic biomarkers during thymus involution and various disease conditions, a large-scale systematic studies maybe necessary, special on hypertrophic thymuses in adults.

In summary, adults with thymic hypertrophy have significantly increased risk of SUDA at young age. In our opinion, instead of a disease entity “status thymico-lymphaticus” is a systematic abnormality with thymic hypertrophy as a feature involving mainly immune and/or cardiovascular system, probably caused by gene mutations. Development and involution of the thymus maybe relates with function of the endocrine organs and hormones. The patients with thymic hypertrophy show diversity in histology, disease conditions and causes of death. In most cases enlargement of the thymus could not be diagnosed during life until postmortem. How to effectively screen this asymptomatic but potentially lethal condition remains a problem. On the other hand, the hypertrophic thymus would maybe be used as an indicator of some immune-related diseases and cardiovascular diseases in the clinical diagnosis.

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1. 1.Mussabekova Saule Amangeldievna, Burkova Elena Igorevna, Dobler Kristina Ergardovna, Muldasheva Balzhan Smailovna, Atmtaev Zhan Zhumagulovich, 2024, Sudden infant death syndrome as a result of thymic-lymphatic dysgenesis, Journal of Clinical Medicine of Kazakhstan, 21(1), 97, 10.23950/jcmk/14266