sudden death due to acute pancreatitis: autopsy ...

Journal of Forensic Medicine & Toxicology Vol. 25 No.2, July-December 2008

SUDDEN DEATH DUE TO ACUTE PANCREATITIS: AUTOPSY OBSERVATIONS O. P. Murtyl', Anshoo AgarwaF, Radha Krishnan 3

ABSTRACT

INTRODUCTION

Acute pancreatitis is a protean disease which is usually mild and seljlimiting in most cases. The disease is severe and is associated with a high mortality in 5 - 20% ofcases due to systemic complications culminating in multi-organ failure and shock.

Acute pancreatitis remains an enigma and continues to pose a challenge to the physicians as the most difficult predictor with regard to clinical course and outcome. Acute pancreatitis is defined as simply as acute inflammation in the pancreas.It is usually associated with necrosis of intrapancreatic fat and acini. Unlike other inflammatory disorders, the causal role of infectious agents and autoimmunity in acute pancreatitis is negligible. The majority of cases of acute pancreatitis are associated with recovery but about 25% of patients have severe disease with high mortalityl, 2. and 3• Alcohol and gall stone obstruction are the most common causes of acute pancreatitis. It is a severe form of acute pancreatitis associated with hemorrhages and fat necrosis in and around the pancreas. It mainly occurs in adults and in 80% cases is associated with alcohol or gallstones.

Acute pancreatitis (AP) in a subset ofpatients presents as sudden unexpected death and is diagnosed for the jirst time during autopsy. The majority of cases of sudden unexpected death can usually be attributed to a past history ofillness, clinicalfeatures or characteristicjindings on postmortem examination. The forensic pathologist or the medical examiner faces the daunting task of determining the cause ofdeath in those cases without any antecedent causes, suspected violence, suicide or homicide and with no clinical history ofillness. Acutepancreatitis is not an uncommon cause ofsudden death. We herein report jive cases ofacute hemorrhagic pancreatitisfrom the Forensic Pathology Unit ofUniversity Malaya, Kuala Lumpur, Malaysia. lWo patients presented as sudden death at home while three others died within 24 hours of hospitalization. Alljivepatients hadsimilarjindings ofacute hemorrhagic pancreatitis on post mortem examination. Pancreatitis associated organ failure was one of the most important determinants of mortality. Clinical correlates of organ failure included respiratory distress, hypotension and anuria. While biliary etiology represents the main cause in various clinical studies, it had an insignificant role in our jive cases ofsudden death undergoing medico-legal autopsy. Etiological factors included alcoholism in one and idiopathic causes in four patients. Autopsy based studies provide valuable information and a holistic approach to the study ofacute pancreatitis.

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It mainly occurs in adult 40-70 years.

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Onset is sudden after a bout of alcohol or heavy meal.

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Present as acute abdomen.

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Elevation of serum amylase levels within the first 24 hours, and serum lipase level after 3-4 days.

Acute pancreatitis is associated with significant risk of mortality and morbidity. Complications ofacute pancreatitis include both local and systemic conditions. The characteristic features of acute pancreatitis presenting as a stormy abrupt onset with death occurring soon after hospital admission and those cases presenting as sudden unexpected death are not well studied 3. Significant causes of deaths that occur in the first two weeks ofhospitalization are shock and multi-organ failure (MOF) 1,4,5,6,7. Systemic complications may occur in the absence of local complications and include renal insufficiency, cardiac failure, acidemia and disseminated intravascular coagulation. Local complications include pseudocysts, ascites, fistulas, colonic infarction and gastrointestinal hemorrhage4, 7-9. The postmortem studies related to fatal acute pancreatitis, in particular medico legal autopsies are few 9• 12 •

Keywords: acute hemorrhagic pancreatitis; prognostic scores; complications; sudden death.

2&3 Department ofPathology, Faculty ofMedicine, University Technology MARA, Shah Alam, Kuala Lumpur, Malaysia 40450

We report five cases, all presenting with similar finding of acute hemorrhagic pancreatitis on autopsy and presenting either as sudden death or death shortly after hospital admission.

Corresponding Author: I * Professor (Dr.) O.P. Murty Professor of Forensic Pathology University of Malaya, Kuala Lampur, Malaysia [email protected] 47


Casualty department early in the morning with complaints ofacute abdominal pain. He died within 24 hours ofhospital admission and hence a forensic autopsy was performed.

CASE REPORTS CASE 1: A 30-year old adult male, Bangladeshi was found dead in his sleep. His brother had tried awakening him one morning around 6 30am. He had been well prior to this and had not suffered from any known medical illness. He was married with five children but presently living alone.

PATHOLOGIC FINDINGS ON POST MORTEM The histopathological features ofthe pancreatic lesions in all these five patients were similar. Hence, they are described together. External examination: Cyanosis offingernai I beds was seen in cases one, three and five.

CASE 2: A 43-year old Indian male presented to the Emergency and Casualty department with complains of severe abdominal pain, vomiting, difficulty in breathing. He was a chronic alcoholic for the last ten years. There was no history of other known medical illness.

Internal Examination: All five cases had similar gross frndings in the pancreas.

Physical examination revealed the patient to be alert, tachypnoeic, pale with no evidence ofjaundice. Examination of abdomen showed tense and tender abdomen; bowel sounds were heard.

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The pancreas showed evidence of inflammation, was enlarged & edematous.

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Areas ofmarked hemorrhage were seen in all the cases (figure 1 and 4).

Labs: A full blood examination was done. WBC: 21,000 mmJ Total protein was 91 gIL, total bilirubin was 62ummoVL, and conjugated bilirubin was 7. The serum amylase was markedly elevated to 2,171 ill. Radiology: Chest X ray, abdomen plain X ray: Normal CT abdomen: Features of acute pancreatitis. The patient died within 24 hours of admission and an autopsy was performed. CASE 3: A 40-year old adult male, Indonesian, was found dead in his sleep. The scene was undisturbed and there was no history of any previous illness. He was living alone. No other history was available. A full blood picture showed an elevated WBC count of23,000 mm J • Liver function tests: Total protein 92 gil, total bilirubin- 62 ~mmoVI, conjugated bilirubin-7. Serum amylase was elevated markedly to 2,241 ill.

Fig 1: Marked hemorrhage ofthe entire pancreatic area with loss of normal appearance and markings •

Extensive softening and liquefactive, gray white necrosis was seen (figures 3, 4).

CASE 4: A 40-year old adult Indonesian female was brought to the Emergency and Casualty department with complaints of severe abdominal pain, mild fever (100"'% F) and vomiting. She had been experiencing dull epigastric pain for the last 3 days. She had been vomiting on and offsince the previous evening. She died soon after admission. She had not taken any form of treatment for the pain. There was no history of medical illness. She was married with 4 children. She had come to Malaysia 8 months ago. Fig 2: Massive retroperitoneal pancreatic parenchyma, haemorrhagic areas with clots and embedded pancreatic tissue; frrm, edematous

CASES: A 50-year old Chinese presented to the Emergency and 48


Fig 3: Cut section ofpancreas with foci ofhemorrhage (red) and yellow (fat necrotic) areas. Extensive and diffuse necrosis give chalky-white appearance ofpancreatic tissue (areas showing little saponification due to cheation ofCalcium with fatty acids by liberated pancreatic enzymes with fat necrosis)

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Necrosis of pancreatic acini and the elastic tissue of the arteries and arterioles with surrounding areas of hemorrhage (figure 6, 7).

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Necrosis of peripancreatic and omental fat

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Inflammatory cell reaction with influx of neutrophjls, lymphocytes and plasma cells (figure 7).

Fig 5: Marked hemorrhage ofpancreatic parenchymal tissue with necrotic tissue

Fig 6: Areas of hemorrhage with adjacent acini seen on microscopy with widespread necrosis of pancreatic parenchyma

Fig 4: Extensive hemorrhage and necrotic areas of pancreas and areas. Necrotic areas are yellow, chalkywhite appearance ofpancreatic tissue •

Fat necrosis of omental fat and large bowel mesentery was seen as chalky white areas.

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There was massive retroperitoneal hemorrhage (figure 2).

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Blood stained ascitic fluid with white flecks ofnecrosis was found.

Fig7a

The other organs did not show any significant pathology. There was no evidence of any etiological factor leading to acute pancreatitis in four ofthe five patients, as there was no evidence of gall stone or biliary sludge and no history of alcoholism. One Indian male had a previous history of alcoholism but there were no stigmata ofchronic attacks of pancreatitis in this patient. Fig7b: Fig 7 (a & b) : Areas of pancreatic necrosis with adjacent areas of markedly dense inflammatory cell infIltrate

IllSTOPATHOLOGY •

Extensive hemorrhage of pancreatic lobules and acini (figure 5).

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pancreatitis and the need for it to be considered in the differential diagnosis of all patients presenting with upper abdominal pain l4 . Sudden calamitous onset of an "acute abdomen" must be differentiated from other diseases such as ruptured acute appendicitis, perforated peptic ulcer, acute cholecystitis with rupture, and occlusion ofmesenteric vessels with ischemia. Though the major symptom, abdominal pain may vary widely in intensity from the typical sharp incapacitating pain to mild bearable pain with more or less asymptomatic onset. Several cases of acute pancreatitis have been reported in which diagnosis was not made until autopsies have been reported22 ,3, 11.

CAUSE OF DEATH: The cause of death in all cases was determined to be acute hemorrhagic, necrotizing pancreatitis. DISCUSSION

Acute pancreatitis is a prototype of diseases that are characterized by a wide ranging spectrum of clinical presentations from mild, self-limiting, transitory illness to devastating severe hemorrhagic form showing massive pancreatic necrosis and an associated high mortality. Most of our knowledge ofpancreatitis comes from the shadows cast by disease. Since alcohol is one ofthe major etiological agents; we can safely assume that the disease has been prevalent for thousands of years. History offers numerous accounts of diseases that might have been acute pancreatitis, an early example being the fatal illness of Alexander the Great (323BC) 13. More than a century has passed since Reginald Fitz described this disorder 14, yet the overall mortality rate has not fallen since 1970 3,11,12, in spite of major advances that have been made in the understanding of the patho-physiological mechanisms, radiological and laboratory investigations to diagnose and ., treat acute pancreatitis.

Studies by Bettina show that it is imperative to differentiate the morphological characteristics ofnecrotizing from edematous pancreatitis in order to estimate prognosis. The presence and extent of necrosis both intra- and extra pancreatic have been shown to be important factors determining the onset ofcomplications such as organ failure or pancreatic infections 1. Wijffels et al report the early occurrence ofnecrosis in acute pancreatitis, within a period of2 to 4 days after onset ofsymptoms. The course of acute necrotizing pancreatitis is complicated most often by the development of multi-organ fa~lure, shock, sepsis and culminating in death in 15-56% 'pf cases. Hence, it is of paramount importance to differe1\ltiate mild from severe forms of acute pancreatitis l9 . Our fi1\ldings concur with the above studies. In all our cases, tfie pancreas showed extensive hemorrhage of the parenchyma. Necrosis of the pancreas was also a striking feature. Fat necrosis of the peripancreatic and omental fat was seen. Evidence of inflammatory response was seen on histology.

In our report, two ofthe male patients died in their sleep and with no definitive etiological association. Similar reports have been reported by Anderson, Appleros et af and Wilson et af who found that up to 1I3 rd of patients dying from acute pancreatitis, died at home, without being admitted to the hospital and in one study 75% of these cases were alcoholics I6 ,17,18. In another series, the incidence of acute pancreatitis diagnosed first at autopsy was found to be between 30-42%3. The etiological cause was difficult to distinguish in these cases and they found alcoholism and idiopathic causes to be more common in patients dying suddenly compared to biliary pancreatitis 3,5,11,12,16. Venkatesan et al have reported alcohol to be the cause in 80% of patients with severe pancreatitis, biliary disease and idiopathic causes contributing 10% each4.

In all five ofour cases, there was extensive hemorrhage in the pancreas along with hemorrhage into the peritoneal cavity; hemorrhagic ascitic fluid was also seen. The destruction ofthe elastic tissue ofthe vessels was evident. Acute pancreatitis may have hemorrhagic complications, usually due to erosion of major pancreatic or peri-pancreatic vessels causing massive bleeding into the gastrointestinal tract or abdominal cavity. Though infrequent, this complication is the main cause of death in more than 50% offatal cases ofacute pancreatitis24-26 . The incidence ofbleeding is much higher in necrotizing than in interstitial pancreatitis (13.5 vs.1.5%). Bleeding may be promoted by proteolytic and lipolytic enzymes disseminated by the damaged pancreas. These substances attack contiguous vessels causing elastolytic erosion, which may lead to rupture 23 . At times, invasion of pseudo-aneurysms may also result in acute haemorrhage. Other mechanisms of bleeding include compression by pseudo-cysts or pancreatic abscess27 . Paolo et al in a recent study reported seven cases of acute hemorrhagic pancreatitis with sudden death due to rupture of portal veins 10 .

Tsokos et af in their study found that alcoholism was the cause ofacute pancreatitis in 68% ofpostmortem cases. In his study the role of biliary disease as an etiological factor was very low in outpatient deaths undergoing medico-legal autopsies 3. Frey et af in their extensive study reported that patients with alcoholic pancreatitis were the most lethal and these patients had the highest risk of dying. They reported that the incidence ofalcoholic and idiopathic pancreatitis was highest in African Americans, biliary pancreatitis was hi~hest in Hispanics and Asians had a low incidence ofalcoholic pancreatitis 5. Three ofthe five patients in our report were admitted to the hospital but died shortly after admission. All these three patients presented with acute abdominal pain and one patient was diagnosed as acute pancreatitis. Turner has reported the varied clinical manifestations of acute

An episode of severe acute pancreatitis progresses in 2 phases: An initial phase in the first 10-14 days 50


characterized by systemic inflammatory response syndrome caused by the release of inflammatory mediators and secondary multiorgan failure(MOF). The next phase which begins from 10-14 days after the onset of the acute phase, is dominated by complications due to infection of pancreatic and peripancreatic necrosis and secondary multiorgan failure. Many studies have shown that the majority of deaths occur late in the disease due to pancreatic sepsis3 • Tsokos et al in their study of 27 cases of autopsy found sudden unexpected death caused by acute hemorrhagic pancreatitis in 24 cases where in Prussian blue staining did not reveal hemosiderin laden macrophages demarcating the hemorrhagic necrosis. Earliest findings ofhemosiderin laden macrophages are seen in hemorrhagic lesions after 3 days, thereby lack of demonstration supports that death must have occurred within 3 days of onset of acute pancreatitis3 •

has a positive predictive value of 71 % but is not useful in distinguishing pancreatic necrosis. Williams et al in their study report that patients who had Ranson criteria of 5, Imrie scores>4, 96-hrAPACHE III score of> 30 had a much higher mortality and morbidity ratezo • Laboratory data as predictors of pancreatic necrosis and morbidity: WBC -White blood cell count, LDH - lactic dehydrogenase, AST -aspartate transaminase, PCVpacked cell volume, BUN-Blood urea nitrogen, PO z- Arterial partial pressure of Oxygen, MAP-Mean arterial pressure, HR-heart rate, bpm-beats per minute, Na+ -Sodium, K+ Potassium, GCS-Glasgow coma scale, RR-Respiratory rate. Hematocrit: Hemoconcentration of 47 % on admission or failure of a decrease in hematocrit within 24 hours of admission is a strong risk factor in development of pancreatic necrosis 7 •

In our study of five cases, we found similar results with sudden unexpected death in two patients and death within 24 hours of admission in the other three cases. Our cases are similar to a study of four cases of sudden death by Tong et al who also demonstrated that presentation of acute pancreatitis is mysterious and may produce sudden . and unexpected death, which may not always be preceded by morbid symptoms 8 • Lack ofmorphological evidence of etiology or previous attacks ofpancreatitis was seen in our patients, similar to reports by Tsokos et aP. Poulakkainen et al in their study have indicated that first attacks of the disease are associated with higher mortality rates than episodes of relapsing pancreatitisz4 •

Pancreatic imaging: Contrast enhanced CT scans is a more reliable investigation to detect acute pancreatitis. Contrast - enhanced CT has a very high sensitivity of 92% and specificity of 100%19. The different criteria for diagnosis suggested by Balthazar29 and colleagues, classified into five grades, are as follows: Grade A- Normal Pancreas, Grade B- Focal or diffuse gland enlargement Grade C- Inflammation of pancreas or peripancreatic fat, Grade D- Single ill-defined peripancreatic fluid collection, Grade E- Two or more ill defined collections or the presence of gas in or nearby by the pancreas.

Predictors of severity: Early prediction ofthe severity of AP helps the clinician to tailor his therapy and improve outcome. Identification ofpatients with mild disease is done with considerable ease clinically. The importance of assessment is in severe cases with an associated high risk ofmortality and morbidity. Patients admitted to the surgical intensive care unit with severe acute pancreatitis have a variable clinical course from recovery within 7 to 10 days or the development of complications and multiorgan failure lO, 19,ZO. Several predictive prognostic scoring scales exist to predict mortality and morbidity in patients with acute pancreatitis.

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Table 1: Prognostic scoring systems8•14( Modified from Taylor et 8, Mergener & Bailie 14 ) Ranson criteria,,14 Modified Glasgow (Imrie)8 On admission Age> 50 years Age> 55 years

APACHE 118

Age> 45 years

WBC>16,000 fmm 3 WBC>15,000fmm 3 WBC 12,000 fmm 3

Multifactorial scoring systems (Table 1): The prognostic scoring systems include Glasgow Coma score (GCS) or the modified Imrie, Ranson criteria, the Multiple Organ Failure Score and Acute Physiology and Chronic Health Evaluation II (APACHE II) 10,19.Z0.

Blood Glucose> 11.0 mmollL LDH> 350 IV f L

Blood Glucose> 180 mgfdL LDH > 600 IV fL

Rectal temp < 36°C or> 38.4°C MAP < 70 or> 109 mmHg

AST>250UfL

AST>IOO IV fL

Hr109 bpm

48 hours after Albumin 10% BUN > 96 mg fdL

The most commonly followed is the Ranson scoring system Z8 • The prognosis is classified as: A Ranson score 02- minimum mortality risk; score 00-5 is associated with a 10-20% mortality rate. The major disadvantages ofRanson and Imrie systems are that these systems may be used only after 48 hours of admission ofpatients. Both these systems have a low positive predictive value in predicting severity ofdisease, 37% and 59% respectively. The APACHE II score

BUN>1.8 mmollL

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Calcium 2 mg/dL) are associated with significant mortality2,7.

CONCLUSION Misdiagnosis of acute pancreatitis is a common problem. The clinical importance ofdifferentiating between mild first attacks and relapses is very important as it has a direct bearing on mortality. The pivotal role ofcontrast enhanced CT and various prognostic scoring systems needs no emphasis. The significance of forensic pathology is that majority of severe acute pancreatitis present as sudden unexpected death. The major strengths offorensic autopsy based studies are that a full organ based approach to the histopathology and cause may be done instead of only biopsy specimens as in clinical trials evaluating disease. Novel conceptions and approaches to identify genetic polymorphsims combined with the myriad of clinical, laboratory markers and autopsy based studies would provide a more holistic approach in understanding a disease as variable and unpredictable as acute pancreatitis.

Markers ofinflammatory response: C-reactive protein (CRP) is the most widely used single predictor of severity in acute pancreatitis because of its low cost and easy availability. CRP peaks at 72 hours after the IL-l and IL-6 peak. Several potential markers are still under study and include, Procalcitonin(PCT), a propeptide of calcitonin, matrix metalloproteinase (MMP)-l, malondialdehyde and heat shock factor-l (HSF-1Y IL-6 is the most accurate early predictor of severity in acute pancreatitis with great sensitivity and 90% accuracy in the first 24 hours. IL-6 has been shown to be superior to CRP and APACHE II on day 1. IL-l and IL-8 have similar accuracy to IL-6. Tumor necrosis factor a(TNF a) has a low accuracy as a predictor but the anti-inflammatory molecule, soluble TNF receptor (sTNFR) is a better predictor of severity with 96% accuracy and high sensitivity to mortality2,7.

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