Armanni–Ebstein Lesions in Terminal Hyperglycemia

Armanni–Ebstein lesions (AEL) occur in deaths related to uncontrolled diabetes mellitus. To investigate the relationship between AEL and terminal hyperglycemia, we retrospectively reviewed 71 cases with vitreous glucose levels ≥11.1 mmol/L; 27 (38%) cases had AEL (vitreous glucose 14.0–77.3 mmol/L); and 44 cases (62%) did not (vitreous glucose 11.1–91.9 mmol/L). There was no significant difference (p = 0.271) in vitreous glucose levels between the cases with AEL (mean 39.2, SD 16.7 mmol/L) and those without (mean 34.2, SD 19.8 mmol/L). Similarly, there was no difference in the degree of dehydration, renal failure, or osmolality. However, there was a significantly higher level of β‐hydroxybutyrate among the cases with AEL compared to those without (p = 0.007), suggesting that ketoacidosis may facilitate the development of AEL. Given the possible synergistic role of β‐hydroxybutyrate, the correlation between AEL and terminal hyperglycemia in animal studies may not be applicable to humans. AEL may also possibly occur with sublethal elevations in glucose.     

How Useful is Basal Renal Tubular Epithelial Cell Vacuolization as a Marker for Significant Hyperglycemia at Autopsy?

Basal vacuolization of renal tubular epithelial cells (so-called Armanni-Ebstein phenomenon) has been attributed to hyperglycemia causing accumulation of cytoplasmic glycogen. Review of 34 autopsy cases with significant hyperglycemia (vitreous glucose ≥ 15 mmol/L/270 mg/dL) was undertaken to determine whether there was any significant association between the degree of hyperglycemia and the severity of this morphological change (graded as 0, 1+, 2+, and 3+). No association was demonstrated. Review of the subgroup of 14 cases with terminal hyperglycemia without ketoacidosis was then undertaken to assess the effect of hyperglycemia in isolation on renal tubular epithelial cells. Vitreous glucose levels in these 14 cases ranged from 17 to 49.7 mmol/L (306-894.6 mg/dL) with a mean of 26.25 mmol/L (472.5 mg/dL) and β-hydroxybutyrate levels ranged from 0.02 to 2.55 mmol/L (0.36-45.9 mg/dL) with a mean 0.79 mmol/L (14.22 mg/dL). Not one of the latter cases displayed basal vacuolization. No relationship between basal vacuolization of renal tubular epithelial cells at autopsy and terminal hyperglycemia could, therefore, be demonstrated.     

The Interplay Between Diabetes and Pancreatitis: Two Case Reports of Sudden,Natural Deaths and a Review of the Literature

Diabetes mellitus (DM) is a common disease involving insulin resistance or deficit that, when left unchecked, may cause severe hyperglycemia and subsequent end‐organ damage. Acute pancreatitis (AP) is inflammation of the pancreas that can lead to significant morbidity and mortality. AP and DM both account for a significant amount of sudden deaths, and rarely both disease processes may be present in the same decedent, causing some difficulty in wording the cause of death statement. Although much research has been directed at studying the causes and risk factors for AP and DM, there is a complex interplay between these diseases that is not fully understood. This study presents two autopsy cases of sudden, natural deaths that illustrate this interplay, along with a review of the literature. An algorithm for differentiating AP and DM is then discussed in the context of the presented cases as a proposed aid for forensic pathologists in the certification of such deaths.     

Renal Cortical Pallor—A Useful Macroscopic Marker for Metabolic Derangements at Autopsy

Renal cortical pallor was studied as a potential marker at autopsy of diabetic ketoacidosis in 23 cases, hyperglycemic nonketotic coma in eight cases, and alcoholic ketoacidosis in five cases (vitreous humor glucose level ≥11.1 mM; β‐hydroxybutyrate level ≥5 mM). Renal cortical pallor was noted on macroscopic examination in 10 of 23 cases of lethal diabetic ketoacidosis (43.5%), three of eight cases of fatal hyperglycemic nonketotic coma (37.5%), and in two of five cases of alcoholic ketoacidosis (40%). Histologic examination revealed basal vacuolization of renal tubular epithelial cells in 12 cases, Armanni–Ebstein lesions in 10, and osmotic nephrosis in three. Although renal cortical pallor did not appear to be a particularly sensitive marker for hyperglycemia or ketoacidosis, and did not correlate with the severity of these parameters, it may still represent a useful macroscopic marker for underlying metabolic conditions at autopsy and should therefore prompt measurement of vitreous humor glucose and β‐hydroxybutyrate levels.     

Fatal Diabetic Ketoacidosis—A Potential Complication of MDMA (Ecstasy) Use

A 19‐year‐old woman with insulin‐dependent diabetes mellitus was found dead in bed having allegedly recently taken ecstasy and consumed alcohol. At autopsy, there were microhemorrhages in the brain with subnuclear vacuolization and Armanni–Ebstein changes in renal tubules. Biochemical analyses confirmed diabetic ketoacidosis (vitreous glucose—46.5 mmol/L; β‐OH butyrate—13.86 mmol/L.). Toxicological analyses of blood showed a low level of 3,4‐methylenedioxy‐methamphetamine (MDMA) (0.01 mg/L), with acetone but no alcohol or other common drugs. Death was attributed to diabetic ketoacidosis most likely provoked by mixed MDMA/alcohol ingestion. Although the use of illicit drugs by young individuals with diabetes mellitus is being increasingly recognized, it has been noted that there is minimal information about the relationship between drug use and acute diabetic complications. Toxicological screening of cases of lethal diabetic ketoacidosis in the young may clarify lethal mechanisms in individual cases and also help to determine the extent of this problem.     

Vitreous Fluid and/or Urine Glucose Concentrations in 1335 Civil Aviation Accident Pilot Fatalities*

Abstract: During aviation accident investigations, vitreous fluid and urine samples from pilot fatalities are analyzed for glucose and blood for hemoglobin A_1c (HbA_1c) to monitor diabetic pilots and to discover other pilots with undiagnosed/unreported diabetes. The prevalence of elevated glucose concentrations in fatally injured pilots was evaluated by searching the Civil Aerospace Medical Institute’s Toxicology Database for the period 1998–2005. Out of 1335 pilots involving 363 vitreous fluid, 365 urine, and 607 vitreous fluid and urine analyses, 43 pilots had elevated glucose in vitreous fluid (>125 mg/dL) and/or in urine (>100 mg/dL). Of the 20 pilots whose blood samples were analyzed, nine had >6% HbA_1c—four were known diabetics, and five were unknown diabetics. Urinary glucose levels were elevated in all 13 known hyperglycemic pilots. A considerable number of pilots (30 of 43) had elevated glucose and HbA_1c (5 of 20), suggesting undiagnosed/unreported diabetic conditions.     

An Isolated Perfused Rat Kidney Model for the Evaluation of the Effect of Glucose on Renal Tubular Epithelial Morphology

An isolated perfused kidney model was used to evaluate the effect of hyperglycemia on renal tubular epithelial cell morphology. Ten Sprague–Dawley rat kidneys were perfused with Krebs–Henseleit buffer containing 70 mmol/L of glucose (five for 1 h and five for 2 h). Two control groups consisted of 10 kidneys perfused with Krebs–Henseleit buffer without hyperglycemia (five for 1 h and five for 2 h), and 10 nonperfused contralateral kidneys placed in the same environment for the same duration. The hyperglycemia group had significantly increased renal tubular vacuolization (p < 0.001) compared to both control groups at 1 and 2 h. The isolated perfused kidney model recapitulates the renal tubular vacuolization phenotype found in hyperglycemia and may be a potential tool for the investigation into causal factors in renal histology. The full pattern of the Armanni–Ebstein phenomenon was not, however, reproduced, suggesting that this change requires more time or involves more complex factors.