Larry Nichols

Lipotoxicity Causes Multisystem Organ Failure and Exacerbates Acute Pancreatitis in Obesity

Unsaturated fatty acids cause lipotoxicity and mediate acute adverse outcomes in obese individuals with pancreatitis. The Burden of Adiposity As if diabetes and heart disease were not burden enough, obese people who suffer trauma, burns, or other critical conditions have an increased likelihood of death. During these exacerbated illnesses, multiple organs can fail, a situation that is particularly hard to reverse. How the presence of excess adipose tissue contributes to the severity of these diseases is not clear, but understanding the mechanisms could provide clues for possible treatments. Pancreatitis is a relatively well-defined disease that tends to be worse in the obese and, in its most severe form, is accompanied by multi-organ failure. By using a combination of patient investigation, in vitro cell studies, and an animal model, Navina et al. have assembled evidence that pinpoints the culprits in the obesity-related complications of this disease: unsaturated fatty acids liberated by lipolysis from adipose tissue. The authors carefully examine the pancreases of 24 patients who had died of pancreatitis. The staining patterns indicated that nonesterified fatty acids, derived by lipolysis of excess intrapancreatic fat, contributed to the pancreatic necrosis in these patients. To test this idea, the authors used a cell culture system and showed that it is unsaturated fatty acids that do the damage, impairing acinar cell activities, inhibiting mitochondrial function, releasing calcium, and causing cell death. But what about the failure of other organs? To answer this question, the authors used obese mice with pancreatitis and, by inhibiting lipolysis with the drug orlistat, were able to prevent the pancreatic-associated rise in serum unsaturated fatty acids and, of most importance, to reduce damage to the lung and kidney, as well as mortality. It is not yet clear which lipase is the critical one for multiorgan failure or where it is located. But once revealed, this potential therapeutic target may specify a treatment that enhances the survival of critically ill obese patients. Obesity increases the risk of adverse outcomes during acute critical illnesses such as burns, severe trauma, and acute pancreatitis. Although individuals with more body fat and higher serum cytokines and lipase are more likely to experience problems, the roles that these characteristics play are not clear. We used severe acute pancreatitis as a representative disease to investigate the effects of obesity on local organ function and systemic processes. In obese humans, we found that an increase in the volume of intrapancreatic adipocytes was associated with more extensive pancreatic necrosis during acute pancreatitis and that acute pancreatitis was associated with multisystem organ failure in obese individuals. In vitro studies of pancreatic acinar cells showed that unsaturated fatty acids were proinflammatory, releasing intracellular calcium, inhibiting mitochondrial complexes I and V, and causing necrosis. Saturated fatty acids had no such effects. Inhibition of lipolysis in obese (ob/ob) mice with induced pancreatitis prevented a rise in serum unsaturated fatty acids and prevented renal injury, lung injury, systemic inflammation, hypocalcemia, reduced pancreatic necrosis, and mortality. Thus, therapeutic approaches that target unsaturated fatty acid–mediated lipotoxicity may reduce adverse outcomes in obese patients with critical illnesses such as severe acute pancreatitis.

Coronary atherosclerosis and cardiovascular mortality in hemophilia

Although mortality in individuals with hemophilia is 2- to 3-fold higher than the general population, ischemic heart disease mortality is 50–80% lower than the general population [1–5]. Moreover, hemophilia carriers whose factor VIII levels are low, but not deficient, also appear to have low death rates of ischemic cardiac disease [6]. Elevated circulating factor VIII levels [7], as well as fibrinogen [8] and von Willebrand factor [9], are considered risk factors for cardiovascular disease. Yet, it is possible that low factor VIII levels may reduce the likelihood of clot formation, even in the presence of cardiovascular risk factors, such as smoking or elevated cholesterol, and, thereby, decrease coronary thrombosis and myocardial infarction in individuals with hemophilia.

Smooth muscle cell hypertrophy of renal cortex arteries with chronic continuous flow left ventricular assist

BACKGROUND Pathophysiology of long-term continuous flow left ventricular assist is not well described. With many of these devices becoming available, it is important to examine for possible pathologic effects. In this study we examined the relationship between diminished pulsatility and pathologic changes in renal cortical arteries. METHODS Twenty-nine calves were implanted with various continuous flow left ventricular assist systems in a left ventricle-descending thoracic aorta bypass configuration. Pulsatility was quantified by pulse pressure and pulsatility index. Pathologic changes of the renal cortex arteries were described and evaluated by medial thickness, medial/vascular cross-sectional area ratio, and smooth muscle cell count, to quantify hypertrophy or hyperplasia. Seven calves, which underwent a sham-implant, were used as controls. RESULTS Systolic arterial pressure, pulse pressure, and pulsatility index were significantly lower and diastolic pressure was significantly higher than before implant in pump-implanted animals. Twenty-three of 29 pumpimplanted calves (79.3%) had medial smooth muscle cell hypertrophy in renal cortex arteries, whereas none of sham-implanted calves had any abnormal lesions. When the pump-implanted calves were grouped according to the presence of smooth muscle cell hypertrophy, there was a clear trend toward lower pump flow rate in calves with lesions. Renal function was within the normal range in all calves. CONCLUSIONS There appears to be a relationship between smooth muscle cell hypertrophy in renal cortex arteries and continuous flow left ventricular assist. Furthermore, although the pathologic changes are likely multifactorial, these lesions appear to be related to lower pump assist rates.

Acute Invasive Sinusitis Due to Trichoderma longibrachiatum in a Liver and Small Bowel Transplant Recipient

We describe a case of acute invasive sinusitis due to an unusual moniliaceous fungus, Trichoderma longibrachiatum Rifai 1969 (a member of the class Hyphomycetes), in a small bowel and liver transplant recipient treated with tacrolimus (FK-506) and prednisone. The patient was successfully treated with surgical debridements and amphotericin B followed by oral itraconazole.

Intravascular Talcosis due to Intravenous Drug Use Is an Underrecognized Cause of Pulmonary Hypertension

Intravenous injection of illegal drugs or medications meant for oral administration can cause granulomatous disease of the lung. This intravascular talcosis results in pulmonary fibrosis and pulmonary hypertension. Nine cases of histologically confirmed intravascular talcosis were reviewed with specific attention given to the clinical histories in these patients. Five autopsy cases were included in this series with detailed investigation in the anatomic features associated with intravascular talcosis and pulmonary hypertension. All nine patients showed perivascular and/or intravascular deposition of polarizable foreign material in their lungs. Intravascular talcosis as a result of previous intravenous drug use was not clinically suspected in any patient despite clinically diagnosed pulmonary hypertension in five. All patients showed dilatation of the right and left heart, but none had dilatation of the aortic valve. Congestive heart failure with hepatosplenomegaly was also common. We conclude that intravascular talcosis is an underdiagnosed cause of pulmonary hypertension in patients with known history of intravenous drug use.

Occult nonhematopoietic malignancies present at autopsy in solid organ transplant patients who died within 100 days.

Background. Patients are at an increased risk for developing malignancies after transplantation. Lymphomas, skin malignancies, Kaposi’s sarcomas, and cervical/vulvar neoplasms are the most common, but visceral malignancies are also well documented, with a reported frequency ranging from 1% to 6%. These visceral tumors represent a mix of neoplasms that were clinically occult at the time of transplantation and those that arise de novo after transplantation. Little information, however, is available on the frequency of clinically occult malignancies at the time of transplantation and their contribution to the number of posttransplant malignancies. Methods. A retrospective study was performed of all patients who received an organ transplant from January 1981 to June 1997 and died within 100 days, a time interval in which epithelial malignancies found at autopsy were presumed to have been present, but clinically occult, at the time of transplantation. Results. A total of 375 patients were studied who received the following organ transplants: 231 liver, 52 heart, 26 heart and lung, 32 lung, and 34 kidney. Eleven malignancies were identified for an overall frequency of 2.9% and included three thyroid carcinomas, three carcinoids of the small bowel, two lung carcinomas, one laryngeal carcinoma, one renal cell carcinoma, and one seminoma. Conclusion. The 2.9% frequency of malignancies seen in this study suggests that a small, but significant, number of patients have occult malignancies at the time of transplantation and that these occult tumors contribute substantially to the number of malignancies that present clinically after transplantation.

Cardiac Injury Is a Common Postmortem Finding in Thrombotic Thrombocytopenic Purpura Patients: Is Empiric Cardiac Monitoring and Protection Needed?

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal disease. Early implementation of therapeutic plasma exchange (TPE) has decreased the mortality rate from >90% to <10%. However, fatalities still occur in these patients. The goal of this study was to characterize the causes of death and related postmortem findings in patients with TTP in the current era of emergent TPE to identify possible areas for improvement in the care of these patients. We analyzed clinical history, laboratory and histopathologic findings, and causes of death of patients with active TTP or TTP in clinical remission autopsied at our institution over 22 years. Of 18 patients, 15 had TTP judged to be a cause of death: it was an underlying cause of death in five cases, intermediate in three, and contributing in seven. The most common immediate causes of death were cardiac arrest and myocardial infarction. The most common TTP‐related findings at autopsy were thrombi/emboli in heart (9), lung (11), brain (3), kidney (7), followed by hemorrhages in heart (7), lung (8), brain (2), kidney (7), and infarcts in heart (5), lung (4), brain (6) and kidney (3). Analysis of the cases with TTP as a cause of death suggests that the mechanism of death is commonly cardiac in origin. Proactive measures to monitor and protect the heart may be beneficial in these patients.

RENAL CORTICAL NEOPLASMS IN LONG TERM SURVIVORS OF SOLID ORGAN TRANSPLANTATION

BACKGROUND Renal cortical neoplasms have been reported after organ transplantation, but the level of risk as well as the histological features are poorly defined. METHODS A retrospective autopsy-based study was performed to evaluate renal neoplasms occurring in patients who underwent solid organ transplantation, died, and received an autopsy from 1981 to 1997 (383 liver, 125 heart, 52 lung, 39 heart/lung, 98 kidney, 4 bowel). Patients were divided into those with short (less than 101 days), medium (101 days to 5 years), and long-term survival (more than 5 years). The control group consisted of hospital autopsies on nontransplanted patients from the odd-numbered years, 1983 through 1997. RESULTS Renal cortical neoplasms were identified in 32/1325 of nontransplanted patients and 15/701 transplanted patients. In transplanted patients, neoplasms were identified in 14 native and 1 allograft kidney: 2/391 in short-term survivors, 3/234 in medium, and 10/76 in long term survivors. While transplant patients with short and medium length survival had no increased risk for neoplasms, patients with long-term survival showed a 9-fold increase in cortical neoplasms. Transplant patients with neoplasms averaged 47 years of age at death, significantly younger than the average age of 70 for nontransplanted control patients with renal neoplasms. The neoplasms in transplanted patients were all tubulopapillary, except for one clear cell neoplasm and ranged in size from 0.1 to 2 cm. CONCLUSIONS Long-term survivors of solid organ transplants have an 9-fold increased risk of developing tubulopapillary renal cortical neoplasms.

Causes of sudden unexpected death of adult hospital patients

The sudden unexpected death of a hospitalized patient is distressing to the family and the healthcare team. It is also common. Assessment of the causes without autopsy is frequently incorrect. To elucidate the causes of death, 175 cases of adult hospital patients in the University of Pittsburgh Medical Center Health System, who died suddenly and unexpectedly, were investigated with autopsies. The most common cause was judged to be a cardiac arrhythmia, in 58 (33%) of cases, presumptive in 46 cases, because only 12 of these patients were on cardiac monitoring. Of the arrhythmia patients, 36 (62%) had ≥75% coronary artery stenosis and 31 (53%) had histological evidence of myocardial infarction, with 15 (26%) of those with subacute or old myocardial infarction lacking a history of myocardial infarction. Hemorrhage was judged the cause of death in 38 (22%) of cases, including 31 (82%) with endogenous coagulopathy, anticoagulation, or antiplatelet therapy. Pulmonary thromboembolism was judged the cause of death in 27 (15%) of cases. Overall, hemorrhage deserves better appreciation as a cause of sudden unexpected death of hospitalized adults.

Direct connections between the spinal epidural space and the venous circulation in humans.

Background and Objectives: Our previous studies in pigs indicate that direct connections exist between the spinal epidural space and the venous circulation. We wondered if similar connections occur in humans and have extended our investigations to human cadavers awaiting autopsy. Methods: We studied 10 recently dead human bodies. We inserted 2 Tuohy needles into the epidural space of the lower thoracic spine at adjacent interspaces. We infused saline with a constant-flow pump into 1 needle and measured the resulting pressure through the other. Epidural pressure increased to a steady plateau during fluid infusion, and this value was recorded at several flow rates. The pressure decay after flow stopped was also recorded. Then we infused radiopaque contrast, removed the needles, and obtained a computed tomographic scan of the spine from the foramen magnum to the coccyx. Results: Pressure in the epidural space increased to a plateau during saline infusion. Higher flow rates produced higher plateau pressures. Plots of plateau pressure versus infusion rate were linear in all bodies. The slope of the flow-pressure plot gave a steady-state resistance (543 ± 638 mm Hg·s/mL). The time constant of the pressure decay curve allowed calculation of initial capacitance (0.090 ± 0.062 mL/mm Hg). Contrast could be identified in veins around the spinal column in all bodies. Contrast was found most commonly in the deep veins of the neck (7 bodies) and in veins originating in the area of the brachial plexus (7 bodies). Contrast was found less commonly and in smaller amounts in veins draining into the azygous system (5 bodies) and the lumbar veins (5 bodies). No contrast was found in veins in the sacral area. Conclusions: A direct connection between the spinal epidural space and the venous circulation has been demonstrated in human cadavers. The connection is most commonly found in the cervical and upper thoracic spine.