European Journal of Cardiovascular Medicine

Sudden unexpected natural death (SUND) in adults is of interest to all professionals from medicine specifically SUND in adult who did not suffer from any chronic illness which could cause death. SUND has a specific pattern which keeps changing with modernisation leading to changing lifestyle and demographics owing to the migration of population. ⁽¹⁾

There is no standard definition of sudden deaths occurring in adult population; therefore, this study follows the SUND as mentioned by Marianne et al, “Natural death occurring instantaneously or within 24 hours of onset of symptoms, in a patient who may or may not have a known pre-existing disease, but in whom the mode and time of death is unexpected.” ⁽²⁾

The unexpected nature of the death is important in such cases more than suddenness of death. Suspicion usually arises when an individual is found dead, and nobody witnessed it. ⁽³⁾ According to the World Health Organisation (WHO), “Death is said to be sudden and unexpected when a person not known to have been suffering from any dangerous disease, injury or poisoning is found dead or dies within 24 hours after the onset of terminal illness.”⁽⁴⁾

The incidence of sudden death differs in different geographical location mainly because of the difference in the prevalence of the disease across the globe owing to factors such as environment, genetics, socio economic and others. ^{(5) The} first Indian study on this subject was published by Kasthuri et al. ⁽⁶⁾

The aim of the present study was to analyse spectrum of histopathological findings to identify age and sex distribution, various risk factors and causes associated with sudden and unexpected natural deaths (SUNDs) in adults. It was also aimed to highlight incidental findings in autopsy.

This study was conducted in tertiary care hospital which caters to lower and middle-income group population. Autopsy is asked for whenever the cause of death is unknown and sudden. Histopathological study of 100 cases was analysed based upon the inclusion and exclusion criteria.

Study details:

A retrospective study was carried out in a tertiary health care system in Mumbai for 2 consecutive years

Sample size: 100 cases

Inclusion criteria:  Adult patients of age group above 18 years, who died instantaneously or within 24 hours of onset of symptoms, with no history of any pre-existing diseases.

Specimens with proper information and records and specimens properly labelled and fixed with relevant documents, received at histopathological department.

Exclusion criteria: 

Suspected cases of suicide, homicide and poisoning cases.

Known cases of any diseases, maternal mortality cases.

Inadequate sample, autolysed sample.

Procedure:

The organs relevant to the case concerned were sent for histopathological examination by forensic experts from various locations (BMC hospitals) after completing the autopsy at mortuary. In most of the cases, heart, liver, spleen kidneys, brain and lungs were sent in 10 % formalin.  Sometimes additional findings such as tumor masses or inflammations were detected while carrying out post mortem examination. Those were also received along with relevant documents. All organs sent were identified and examined grossly. Representative tissue bits from concerned organs were processed in a routine manner. Sections were stained with routine haematoxylin and eosin (H & E) stains and special stains as per requirement. The histopathological (gross and microscopic) examination of tissues/organs done were studied, compiled, and evaluated.

Statistical Method-

The data collected was entered in the excel sheet and analysis was carried out.

Ethical Considerations:

Patient name and details were available only to the following people, the study doctor and staff, ethics committee. Study was initiated after approval from IEC (Institutional Ethics Committee).

Out of 100 cases, (22%) cases were in the age group of 40-50 years, followed by (19%) cases in the age group of 30-35 years (Table 1). Out of 100 cases 75 were males (75%) and 25 cases were females (25%, figure 1). The male: female ratio is 3:1. 

Out of 100 cases, 83 cases (83%) were brought dead and 17 cases (17%) died within 24 hrs. On history taking, (56%) cases were found unconscious, (15%) cases had symptoms of giddiness and (14%) cases had respiratory distress.

Out of 100 cases, there was an overlap of morphology seen in multiple systems. Cases with more than one system involved were (41%). The respiratory system involvement was seen in (75 %) and cardiovascular system involvement was seen in (44%) of cases. Four cases showed no significant findings in any of the organs. Involvement of different systems is shown in table no 2.

 Of the total 100 cases of SUND, involvement of 75 cases revealed pathology in the lungs at autopsy. Twenty three percent cases were in age group 30-35 years. Pulmonary haemorrhage/congestion was seen in 26 cases (34.67%) and pulmonary oedema seen in 23 cases (30.67%) (figure no 2 and table no 3).

Of the total 100 cases of SUND, 44 cases revealed pathology in the heart at autopsy.  Sixty one % cases were showing features of atherosclerosis. Myocardial infarction was seen 27cases (27%), (table no 4 and figure no 3). Other pathologies included were left ventricular hypertrophy (9%) and aortic dissection (2.27%).

Of the total 100 cases of SUND, 12 cases revealed pathology in the genitourinary system. Acute tubular necrosis (ATN) was the most common finding and was seen in five cases (41.66%). One incidental finding, seen in kidney, was renal cell carcinoma, in a male patient, who was 56 years old (Table no 5 and figure no 4).

Of the total 100 cases of SUND, 13 cases revealed pathology in the central nervous system (CNS). Four cases were seen in age group 30-35 years of age.  Cerebral oedema was the most common pathology and was seen in four cases (30%), (table no 6). 

Gastrointestinal tract (GIT) cases include one case of  pancreatitis, two cases of oesophageal varices and 19 cases of liver pathologies (Figure 5). Total cases of gastrointestinal and related system were 22 cases (table no 7). Acute pancreatitis was seen to be associated with chronic alcoholism. Both the cases of oesophageal varices were associated with liver cirrhosis.The most common liver pathology was steatosis which was seen in seven cases (30.43%), liver cirrhosis was seen in five cases (21.74%). Three cases showed changes of disseminated pathology. Features of shock liver were seen in two cases.

Spleen showed pathology in three cases. All three spleen involvement cases showed disseminated pathology. One case showed features of sickle cell anemia in spleen while one case had leukemic infiltrates and another case showed features of milliary tuberculosis in spleen.

Out of 100 cases of SUND, eight cases with interesting morphology were found incidentally at autopsy (table no 8, figures 6 to 10). Incidental findings are those findings which were not diagnosed before terminal event nor the patient had any past history or significant symptoms related to these conditions. Of total eight incidental cases four cases had pathological lesions disseminated to multiple organs. They were disseminated intravascular coagulation (DIC), sickle cell anaemia (SCA),  leukaemia and miliary tuberculosis (MTb). Four cases were confined to single organs.

Out of 100 cases of SUND, four cases showed no significant pathology. Age group was between 28-45 years.  All four cases were brought dead in the hospital. Two females were found unconscious with no past history and two males had history of giddiness. 

Table no 1: Showing agewise distribution of total number of cases

Table no 2: Showing distribution of cases according to the involvement of various  systems

Table no 3: Showing different pathological findings of Respiratory system

Table no 4: Showing different pathological findings of Cardiovascular system

Table no 5: Showing different pathological findings of Renal system

Table no 6: Showing different pathological findings of Central nervous system

Table no 7: Showing different pathological findings of GIT and Hepatobiliary system

Table no 8: Showing Incidental histopathological findings

Figure 1: Pie chart showing gender distribution

Figure 2.2: Lung pathology 2 (A&B, Chronic passive congestion- showing areas of hemorrhage and hemosiderin laden macrophages in the lung parencyma, C-Aspiration pneumonitis- bronchial wall filled with vegetable matter, D- Hyaline membrane disease- showing eosinophilic granular material)

Figure 2.1: Lung pathology 1 (A-Lobar Pneumonia- showing inflammatory infiltrate in the alveoli, B Interstitial pneumonia- showing inflammatory infiltrtate in the interstitium and alveolar spaces, C- Hemorrhage in patchy areas of lung parenchyma, D- Pulmonary edema- showing alveoli filled with pink homogenous fluid)

Figure 2.3: Lung pathology 3 (A&B showing lung adenocarcinoma)

Figure 3.1: Heart pathology1 (A-Atherosclerosis, B- Atherosclerosis with cholesterol clefts, C-Acute myocardial infarction, D-Healed myocardial infarction)

Figure 3.2: Heart pathology 2 (A-Aortic dissection showing focus of dissection and fibrosis, B-Elastic Verhoeff- Van Gieson stain showing fragmentation of elastic fibres, C- Masson’s Trichrome showing deposition of collagen in the Aortic wall)

Figure 4.1: Kidney Pathology 1: (A&B- Showing hemorrhage within the tubules; C&D- showing hemorrhage in glomerular tufts and interstitium)

Figure 4.2: Kidney Pathology 2: (A-End stage renal disease- glomerular sclerosis and interstitial fibrosis, B-Thyroidisation of tubules,C- Cloudy change of tubules, D- Acute tubular necrosis)

Figure 5.1: Liver pathology: (A- Macrovesicular steatosis, B- Congestion, C-Chronic passive congestion, D-Liver cirrhosis)

Figure 5.2: Oesophagus showing varices

Figure 5.3: Pancreatic pathology (Autolysis, A-Gross of atrophic pancreas showwing loss of acinar architecture, B,C & D- Coagulatibe necrosis without inflammation)

Figure 6: Meningioma- characteristic whorls and syncytium is noted

Figure 7: Sickle cell anaemia- Note the  Sickle cells in (A- Pancreas, B- Brain, C-Lung alveoli, D- Liver)

Figure 8: Leukemic infiltrates (A- Gross of heart showing grey white mass in bith the ventricles, B&C- Section from the heart showing leukemic inflitration in the musculature, D- Lung showing  leukemic infiltration in the alveoli and interstitium)

Figure 9: Miliary tuberculosis (Multiple epithelioid cell granulomas seen A- Lung, B-Liver, C-Kidney &D- Spleen)

Figure 10.1: Gross image of Renal cell carcinoma

Figure 10.2: Histopathology of Renal cell carcinoma

In the present study, the age of the deceased ranged from 18 to 70 years and, maximum number of deaths occurred in the age group of 30-40 years, followed by 40-50 years age group. This is concordant with the study by Chaturvedi et al , Zanzad et al , Meina Singh et al (31-40 years) and YP Sah (31-50 years) et al. (7-10) However, Kasthuri et al (23-50 years) reported lower age group and Dinesh Rao et al reported higher age group (56-65 years) as compared to present study. (6,11)

Most of the cases of SUND were seen in males (75%) in present study. This is in accordance with the study conducted by Chaturvedi et al (76.6%) and similar to studies by Sarkioja et al (82%) Dinesh Rao et al (83.3%), and Zanzad et al (84%).(7,8,11,12)

Out of 100 cases, maximum cases (83%) presented with brought dead. This is corresponding to study by Gupta S et al, who showed maximum cases as brought dead (90 %).(13) On history, maximum cases (56%) had history of unconsciousness. No other studies have commented upon predominant clinical symptoms.

Predominant system involved in our study was respiratory system (75%). This is similar to the findings of Panchal et al who also found that the most common organ involved was lung (85.5%).(14) However, in most studies, the predominant system involved was the cardio-vascular system. Pandiyan et al and Chaturvedi et al reported predominant involvement of the cardio-vascular system in (55%) cases.(7,15) This apparent difference could be attributed to the fact that lung parenchymal oedema is generally the most common terminal event. 

In the respiratory system, the commonest finding was edema (29.4%), and edema with congestion and haemorrhage together, amounted to (49 %). Second common finding was nontuberculous infections (10%) and tuberculous infection (6 %).  Study by Panchal et al also reported Pulmonary edema in (68.5%) of cases.(14)

In the current study, overall involvement of cardiovascular cases was (44%), which is in concordance with the study by Zanzad et al with (49.55%).(8) However, these findings are different from the studies performed by Chaturvedi et al, (7.8%), Panchal et al (68%), Dinesh Rao et al (66%), Sarkioja et al found (83%), Sah et al (66%) and Singh et al (32.7%) in the involvement of CVS.(7,9-12,14) The possible cause for the discrepancy could be that in our study the terminal lung event, edema, was taken into consideration. Ischemic heart disease (IHD) was also observed in (61.3%) cases similar to that mentioned by Panchal et al (58%).(14)

The Renal system was found to be involved in 12% cases. Maximum cases showed features of ATN which showed concordance with study by Arunalatha et al and Panchal et al. (14,16)  Findings of ATN can have significant clinical implications. Acute tubular necrosis can result from various factors, such as ischemia (lack of blood flow), nephrotoxic substances, sepsis, or certain medications. The presence of ATN in the kidney during an autopsy may indicate underlying kidney injury that was not diagnosed or adequately managed during the person's life. This finding can provide insights into the potential causes of kidney dysfunction, guide the investigation of contributing factors, and inform medical decision-making for surviving family members.

Additional forensic tests, such as toxicology screenings, can be performed to determine if any substances played a role in the development of ATN or contributed to the sudden death.

The CNS was involved (13%) cases. This is similar to the findings of Chaturvedi et al, and Zanzad et al,  who reported 12% cases with CNS involvement.(7,8) Amongst these, cerebral oedema was seen in 30 % cases. Only study by Panchal et al, showed higher preponderance of brain edema.(14) Other studies such as Chaturvedi et al, showed cerebral vascular accidents (9.8%).(7) Our study had subarachnoid haemorrhage as second most common pathology (23%) seen in CNS which is comparable to Sarkioja T et al study which showed (10.4%) cases.(12)

The GIT system was involved in (22%) of the cases. In them, the predominant pathology was steatosis which correlates with other studies as Panchal et al, Arunalatha et al, and Patel et al.(14,16,17) The presence of steatosis as a histological feature in the autopsy of sudden death can have several significant implications. Further analysis like toxicological testing, can be performed to determine if substances or medications played a role in the development of steatosis or contributed to the person's sudden death. Detecting steatosis can prompt further investigation into the person's medical history and lifestyle factors, potentially leading to a better understanding of their overall health and potential risk factors for other diseases.

Incidental meningiomas are not rare at autopsy. The incidence of meningioma at autopsy is reported to be between 1 to 2%. Nakasu et al, found intracranial meningiomas in (2.7%) autopsies, of which (2.3%) were incidental cases.(18) In our study we found one case (1%) of meningioma.

One case showed features of thyroiditis.  Sinhasan et al, described one case of follicular adenoma as incidental finding in 70-year old male.(19)  Fadesewa et al discovered follicular adenoma in (10.0%) and lymphocytic thyroiditis in (4.6%) of the total glands examined.(20)

In the present study, there was one case of Adenocarcinoma of Lung. This is similar to studies by Sinhasan et al and Garg P, et al.(19,21) Chauhan et al, discovered seven malignant lesions in the lungs, which was Adenocarcinoma.(22)

In this study, we found one case of Sickle cell disease. Although Sickle Cell Disease is not very severe in India as compared to Africa, death due to vaso-occlusive disorder in these patients, should be kept in mind. This has been described by Sheshanna et al and Tailor et al,  who described one case and 17 cases of incidental discovery of Sickle Cell disease at autopsy respectively.(23,24)

In the present study, we found one case of DIC, with presence of microthrombi in the lungs, kidneys and pancreas. These findings are similar to those of Rao et al and Wilde et al who also found majority of microthrombi in the kidneys and lungs.(25,26)

Leukemias often present with nonspecific symptoms such as fatigue, weakness, bruising, recurrent infections, and weight loss. However, these symptoms may be subtle or attributed to other causes. Finding leukemia during an autopsy of a sudden death victim can help explain any unexplained symptoms or medical conditions that the person may have experienced before their demise.

We found one case of leukemic infiltration in various organs. P Arunalatha et al, also found one case of leukemic infiltrates in her study.(16)

The incidental finding of disseminated tuberculosis during an autopsy of sudden death carries profound clinical and public health significance. Disseminated tuberculosis indicates that the infection has spread extensively throughout the body, affecting multiple organs such as the lungs, liver, spleen, and kidneys and can have life threatening consequences. Identification of disseminated tuberculosis during an autopsy highlights the importance of considering tuberculosis as a potential underlying cause of sudden death, especially in regions with a high prevalence of the disease or in immunocompromised individuals. A study by Ghosh et al found prevalence of tuberculosis of (2.4%) in an autopsy study which is comparable to the present study.(27) Also a study by Sangma et found the prevalence of tuberculosis of about (1.67 %) in an autopsy study indicating that tuberculosis remains undiagnosed in most of the cases and can be potentially fatal.(28)

Reporting and documenting incidental lesions in autopsy reports is important. It should be communicated with clinicians and family members regarding these incidental findings to ensure appropriate follow-up care, genetic counselling, or screening recommendations, if necessary.

No significant pathology was found in four cases. This is more than those reported by Zanzad, et al (2.23%), but much less than the 18.75% cases reported by Chaturvedi et al.(7,8)  All four cases were brought dead in the hospital. On history it was found that two female patients were found unconscious and two males had giddiness. No histopathological finding seen in these cases. So cause of death can be electrolyte balance or acute myocardial infarction where morphological changed have not yet taken place but there can be electrical activity or enzymatic disturbances. The key to such research is the availability of a method which allows the early detection of myocardial infarction in a whole heart. Tetrazolium staining has emerged as the most popular method.

Though our study highlighted some interesting findings and substantial information, it has some limitations. There is no agreed universal definition for sudden unexpected death worldwide. So, it is difficult to determine sudden deaths and also majority of cases were brought dead where proper history of patient’s past illness is not provided and clinicopathological correlation is not possible. Most of the time there are no eyewitnesses in event just before death, therefore exact duration between onset of disease and death cannot be assessed. Since we could not examine organs in fresh state, diseases like pulmonary embolism would have been missed. There is no availability of methods such as electrical activity or enzymatic disturbances, early detection of myocardial infarction is not possible. It is important to note that the absence of significant pathology does not guarantee that there are no underlying factors contributing to the sudden death. It highlights the limitations of current diagnostic techniques and emphasizes the need for thorough investigation, including toxicological analysis and ancillary testing.

Histopathology findings play a vital role in understanding the underlying causes of sudden deaths during autopsies. Histopathological examination provides crucial insights into the microscopic changes occurring within various organs and tissues, enabling pathologists to identify specific pathological conditions that may have contributed to the individual's sudden demise. Through the examination of cellular abnormalities, inflammation, necrosis, and other structural alterations, histopathology aids in unravelling the complexities surrounding sudden deaths, including cardiac events, pulmonary disorders, neurological conditions, and drug-related complications. These findings not only contribute to determining the cause of death but also provide valuable information for forensic investigations, public health initiatives, and medical research aimed at preventing similar incidents in the future. The integration of histopathology findings with other autopsy investigations helps establish a comprehensive understanding of the factors underlying sudden deaths and contributes to advancements in medical knowledge and patient care. Importance and benefits of autopsy should be communicated and people should be made aware of autopsy as it can be an important tool of epidemiology, education, and prevention of diseases.

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