Rhabdomyolysis associated with cocaine abuse.

There have been recent reports of rhabdomyolysis associated with cocaine abuse. The pathologic findings from these cases have not been described. Pathologic abnormalities in two fatalities with cocaine-associated rhabdomyolysis, including one with hyperpyrexia, acute renal failure, and disseminated intravascular coagulation, are discussed in detail. Skeletal muscle in both cases showed necrosis without evidence of vasculitis, polarizable foreign crystals, or other specific lesions. The individual with renal failure showed acute tubular necrosis with granular myoglobin casts in tubules. The mechanism of cocaine-associated rhabdomyolysis is unclear, but potentially includes ischemia due to vasoconstriction, direct toxicity, hyperpyrexia, and increased muscle activity from agitation or seizure. Adulterants may also play a role. In unexplained cases of rhabdomyolysis, toxicologic evidence of cocaine should be sought. In those cases of rhabdomyolysis associated with acute renal failure, the presence of cocaine in blood may be prolonged because of impaired renal clearance.     

Acute cardiac events temporally related to cocaine abuse

The increasingly widespread use of cocaine in the United States has been accompanied and perhaps exacerbated by the misconception that the drug is not associated with serious medical complications. In particular, the potential for cocaine to precipitate life-threatening cardiac events needs to be reemphasized. We report the clinical and pathological findings in seven people in whom nonintravenous "recreational" use of cocaine was temporally related to acute myocardial infarction, ventricular tachycardia and fibrillation, myocarditis, sudden death, or a combination of these events. We also review data on 19 previously reported cases of cocaine-related cardiovascular disorders. Analysis of all 26 patients indicated the following findings: the cardiac consequences of cocaine abuse are not unique to parenteral use of the drug, since nearly all the patients took the drug intranasally; underlying heart disease is not a prerequisite for cocaine-related cardiac disorders; seizure activity, a well-documented noncardiac complication of cocaine abuse, is neither a prerequisite for, nor an accompanying feature of, cardiac toxicity of cocaine; and the cardiac consequences of cocaine are not limited to massive doses of the drug. Although the pathogenesis of cardiac toxicity of cocaine remains incompletely defined, available circumstantial evidence suggests that cocaine has medical consequences that are equal in importance to its well-documented psychosocial consequences.     

Thrombotic microangiopathy in cocaine abuse-associated malignant hypertension: report of 2 cases with review of the literature

Cocaine is one of the most commonly used illicit drugs. Acute renal failure is an emergent complication in patients with acute cocaine intoxication. It is well known that rhabdomyolysis and vasoconstriction can be important pathogenetic mechanisms resulting in acute renal failure in these patients. Clinically, although cocaine abuse is associated with elevated blood pressure, persistent accelerated hypertension reaching levels diagnostic of malignant hypertension is uncommon. Cocaine-induced malignant hypertension associated with morphologic features of thrombotic macroangiopathy has been rarely mentioned in the literature. We report 2 cases of cocaine abuse-associated malignant hypertension with renal failure. Kidney biopsies revealed thrombotic microangiopathy with fibrinoid necrosis of arterioles and glomerular tufts. Cocaine-mediated endothelial injury and platelet activation may play important pathogenetic roles in cocaine abusers who develop acute renal failure and malignant hypertension.     

Nephrotoxic tubular and interstitial lesions: morphology and classification

Nephrotoxic renal injury, and especially drug nephrotoxicity is now a common cause of acute renal failure. The most common patterns of renal injury produced by nephrotoxins, tubular damage, and interstitial nephritis, are discussed here. Toxic agents which are primarily tubular toxins include certain antibiotics, cisplatinum, anesthetics, and radiocontrast agents. In tubules injured by toxins, alterations range from subtle ultrastructural abnormalities to extensive tubular necrosis. Mechanisms of tubular injury include direct tubular cell toxicity, and alterations in intrarenal blood flow producing secondary tubular damage. Other commonly used therapeutic agents, including the penicillins, other antibiotics, and non-steroidal anti-inflammatory agents, produce renal dysfunction by inducing interstitial nephritis. Long-term analgesic abuse is associated with a particularly striking interstitial damage with frank papillary necrosis. Criteria for differentiating primary tubular injury with inflammation and primary interstitial nephritis with tubular injury are discussed. Individual commonly-used therapeutic agents are considered in some detail, with discussion of both clinical and morphological aspects of drug nephrotoxicity.     

Acute and chronic toxic nephropathies

Toxic nephropathies manifest morphologically as glomerulonephritides, vasculitides, tubular necrosis, and acute or chronic tubulointerstitial disease. The most common toxicity is acute interstitial nephritis owing to hypersensitivity. However, focal segmental glomerulosclerosis and necrotizing angiitis secondary to heroin abuse, membranous glomerulopathy owing to gold, penicillamine and captopril, thrombotic microangiopathy associated with mitomycin and tubular necrosis owing to cyclosporine A, cisplatin, aminoglycosides, and cephalosporins are also reviewed. The mechanisms of toxicity are poorly understood in most cases, but hypotheses related to cyclosporine A, cisplatin, gold, aminoglycosides, cephalosporins, intravenous narcotics, sulfonamides, and methotrexate are summarized.     

Intracerebral hemorrhage associated with cocaine abuse

With the current epidemic of cocaine abuse, there have been many clinical reports of cocaine toxicity, including stroke. Autopsy findings were reported in only one case of intracerebral hemorrhage associated with cocaine abuse. We describe the autopsy toxicological findings in a case of sudden death in a young person due to intracerebral hemorrhage associated with cocaine abuse. In view of the present epidemic of cocaine abuse, cocaine toxicity should be considered in the differential diagnosis of intracerebral hemorrhage. We suggest that the pharmacodynamic effects of cocaine on the cerebral vasculature is the most likely cause.     

Pathology of the liver with bone marrow transplantation. Effects of busulfan, carmustine, acute graft-versus-host disease, and cytomegalovirus infection.

The morphologic changes in the livers of autopsy specimens from recipients of 62 allogeneic bone marrow transplants were reviewed and characterized in specimens from patients who had had apparent drug toxicity, graft-versus-host disease (GVHD), and disseminated cytomegalovirus (CMV) infection. Two conditioning protocols were associated with significant hepatic toxicity. Two of 3 recipients on whom autopsies were performed who had been prepared with high doses of carmustine, cyclophosphamide, and total body irradiation had undergone acute hepatic failure and submassive necrosis with periportal sparing. Seven of 9 patients prepared with busulfan (16 or 20 mg/kg) and cyclophosphamide had moderate to marked centrilobular sinusoidal fibrosis and associated hepatocellular atrophy and necrosis. Twenty of the patients had acute cutaneous GVHD with associated hepatic dysfunction, including 8 with disseminated CMV infection. Of the 12 patients without concomitant CMV infection, 5 had an early onset of GVHD and had predominantly periportal and focal midzonal hepatocellular necrosis, and 7 had acute GVHD with later onset with predominantly bile duct injury. Fifteen patients had evidence of disseminated CMV infection. Whereas CMV infection alone was associated with both hepatocellular and bile duct injury, detectable virus infection was not a requirement for hepatocellular or bile duct injury associated with GVHD.     

Effect of Cocaine Administration on Concanavalin A-Stimulated T-Lymphocyte Proliferation in Rats

There is a high prevalence of cocaine abuse among Americans. There is an increasing concern over the rise of infectious diseases among individuals in this drug abuse population. This concern may be due, at least in part, to a direct effect of cocaine on the immune system. The present study investigated the effects of cocaine administration on optimal mitogen-induced proliferation in rats. Following cocaine administration, splenic lymphocytes were isolated and T-lymphocytes incubated with concanavalin A. When T-lymphocytes were isolated 30 minutes following cocaine administration, a significant enhancement of optimal mitogen-stimulated proliferation was observed at 0.1 mg/Kg cocaine. Enhancement of proliferation was seen 20 hours following cocaine administration at 0.1, 1.0 and 10 mg/Kg. However, these results were not statistically significant. Cocaine administered once daily for seven days had no effect on mitogen-induced proliferation. These results suggest that cocaine administration has a limited effect on optimal mitogen-stimulated proliferation.     

Acute bone marrow stromal injury in the dog

A 5-year retrospective study of bone marrow reports was conducted to identify dogs with acute marrow stromal injury. Of 382 reports that were included in the study, acute stromal alterations were identified in 27 (7.1%). Disease conditions associated with these inflammatory changes included nonregenerative immune-mediated hemolytic anemia (IMA), systemic lupus erythematosus, immune-mediated thrombocytopenia, infectious diseases, drug treatments, and idiopathic conditions. Pathologic changes associated with acute stromal injury included coagulation-type necrosis, individual cell necrosis, dilated sinusoids, interstitial edema, hemorrhage, multifocal fibrin deposits, and multifocal neutrophilic infiltrates. Nonregenerative IMA tended to be associated with individual cell necrosis and evidence of vascular injury and acute inflammation. Infectious diseases tended to be associated with coagulation-type necrosis vascular injury and acute inflammation. Microabscesses were observed only in dogs with bacterial infections. Acute stromal injury associated with drug treatments were associated with coagulation-type necrosis but not with vascular injury or acute inflammation. The pattern of these changes may be useful in suggesting possible causes.     

Progressive interstitial collagen deposition in Coxsackievirus B3-induced murine myocarditis.

Myocardial fibrosis can be produced in certain inbred strains of mice after coxsackievirus B subtype 3 (CVB3) infection. The mechanism responsible for this interstitial matrix alteration is unknown. The presumption is that fibrosis occurs in areas of myocyte damage and inflammation associated with viral infection, analogous to scar formation after cell injury in other organ systems. To test this hypothesis, we examined the hearts of A/J strain mice infected with three CVB3 variants (Crowell [CVB3-CR], Woodruff [CVB3-WD], and Lerner [CVB3-LR]), each known to cause different degrees of acute myocardial injury. With these three variants, virus was present in the heart until day 28 after inoculation but was absent thereafter. Fourteen days after inoculation, inflammation with myocyte necrosis was seen in discrete foci throughout the myocardium with all three variants. Collapse and disorganization of the usually delicate connective tissue matrix identifiable by silver impregnation was seen in these areas of myocyte injury. Persistent, diffuse lymphocytic infiltration of the myocardium was seen 55 days after inoculation with CVB3-WD and CVB3-LR, but hearts initially infected with CVB3-CR showed only rare interstitial lymphocytes comparable to uninfected control hearts. The focal scars produced by myocyte necrosis 14 days after inoculation were accentuated and heavily collagenized 55 days after inoculation with CVB3-WD and CVB3-LR; however, these foci were indistinct 55 days after inoculation with CVB3-CR. Furthermore, the usually delicate network of interstitial collagen fibers surrounding individual myocytes became thickened throughout the heart 55 days after inoculation with CVB3-WD and CVB3-LR, away from visibly scarred areas produced early after infection with these variants. This diffuse reticulin thickening was not seen after infection with the Crowell variant. Only the virus variants associated with persistent interstitial inflammation at day 55 developed major collagen matrix alterations and interstitial fibrosis. We conclude that this persistent interstitial lymphocytic infiltration reflects altered immune function related to specific virus variants in this animal strain. We postulate that these lymphocytes are part of a delayed immunopathogenic response uncoupled from the original viral injury and inflammatory damage. Potential mechanisms by which this interstitial lymphocytic infiltration results in fibrosis are discussed.     

The histology at various stages of acute rejection in concordant xenogeneic heart transplantation. A sequential study in rodents.

In an attempt to describe early morphologic changes in heterotopic xenogeneic heart transplantation a sequential study was performed in a hamster-to-rat model. Mild morphologic changes observed after four to six h were characterized by slight interstitial edema and focal myocyte damage with fragmentation and loss of myofibrillar elements. No lymphocytic infiltration appeared. Moderate morphologic changes observed after 12-24 h were characterized by moderate interstitial edema, and the appearance of mild hemorrhage and scattered extravasated neutrophilic granulocytes. The myocardium had more widespread areas with myocyte damage, sometimes with small foci of necrotic cells and adjacent neutrophilic granulocytes and macrophages. Vascular changes with perivascular edema and swelling of the endothelium were seen and a few neutrophilic granulocytes could be found in the vessel walls. No lymphocytic infiltration appeared. Severe morphologic changes observed after 44-48 h or at the time of complete rejection were characterized by severe interstitial hemorrhage, appearance of widespread necrosis and marked vascular changes with development of leukocytoclastic-like vasculitis, possibly with thrombosis. Only a few lymphocytes appeared. The findings were essentially different from those observed in allogeneic heart transplantations, where classical first-set allograft rejection was seen. In normal donor hearts and syngeneic transplanted hearts used as controls, no significant morphologic changes were demonstrated. On the basis of this study we consider xenogeneic acute rejection to be primarily of the humoral type.     

Anabolic/androgenic steroid abuse and thrombosis: is there a connection?

Anabolic/androgenic steroid abuse is an increasing medical and public health problem. The uncontrolled use of these agents has been associated with numerous toxic side-effects including deleterious cardiovascular changes. The most widely reported to these latter changes include the development of adverse lipid profiles and hypertension. Acute thrombosis has only recently been linked to androgen abuse. Such a causative link has been proposed in reports of acute myocardial infarction and stroke in several athletes using androgens. Unfortunately, there exists no direct evidence that androgens are thrombogenic in humans. However, indirect experimental data suggests that androgens affect platelet aggregation, coagulation proteins and the vascular system in ways that facilitate thrombosis. Androgens also increase several anticoagulant and fibrinolytic proteins. However, they have not been shown to protect from thrombosis in high risk patients. Existing data supports a possible thrombogenic effect of exogenous androgens. Further studies are needed to clarify the hemostatic influence associated with androgen abuse in weightlifters. The abuse of these agents may diminish if acute thrombosis becomes clearly and scientifically associated with their uncontrolled use.     

Acute pancreatitis

Acute pancreatitis is characterized by the occurrence of necroinflammatory changes in the pancreas. Three types of necrosis may be distinguished: (1) interstitial tissue necrosis, which subsequently may also involve acinar and ductal cells, (2) ductal necrosis, and (3) acinar necrosis. The first type of necrosis is autodigestive in nature and is typical of the most common forms of acute pancreatitis, which are associated with alcohol, bile duct disease, metabolic conditions, and other rare factors. Clinically, these types of pancreatitis may be either mild or severe (Atlanta classification). The mild form is also known as edematous pancreatitis, because there is edematous swelling of the pancreas combined with tiny foci of interstitial (fat) necrosis. Severe or necrotizing pancreatitis shows large areas of often hemorrhagic necrosis of the pancreatic and particularly the peripancreatic tissue. The ductal type of necrosis is rare and may be seen in pancreatitis associated with prolonged circulatory failure. The acinar type of necrosis is caused by infectious agents. Complications of acute pancreatitis, such as pseudocyst, bleeding, and infection, determine the course of the disease.     

Limb ischaemia after intra-arterial injection of Temazepam gel: histology of nine cases.

AIMS--To record the histopathological findings associated with intra-arterial injection of Temazepam gel by nine drug misusers. METHODS--Standard histological examination and immunocytochemistry for endothelial markers (factor VIII related antigen, Ulex europaeus lectin) were carried out. RESULTS--Intra-arterial injection of Temazepam gel may cause severe vascular injury and lead to amputation of fingers or limbs. Histological changes include myocyte necrosis, interstitial oedema, extensive arterial, venous, and capillary thrombosis, and sometimes vasculitis, endothelial swelling, and denudation. CONCLUSIONS--Inadvertent injection of Temazepam gel into arteries may cause catastrophic ischaemic damage, possibly as a result of toxic effects on endothelial cells.     

Anatomo-pathologic findings in 25 autopsy cases of AIDS

Pathologic findings in 25 autopsies of AIDS. The common and severe changes of the central nervous system, lungs, adrenals, heart, kidneys and gonads are reviewed in a series of autopsies of AIDS. In the brain, HIV infection induces directly inflammatory infiltrates including the typical multinucleated giant cells described by Sharer. In addition, primary lymphomas are seen as well as reactive and inflammatory lesions that are caused by opportunistic infections, such as those of poliomavirus, Cytomegalovirus and Toxoplasma gondii. In the lung, interstitial inflammation prevails, which may be related to direct HIV infection and include rare multinucleated giant cells like the ones described by Sharer. Opportunistic infections are often associated, and are commonly sustained by Cytomegalovirus and Pneumocystis carinii. A peculiar findings is the evolution from septal inflammation to fine fibrosis and hyaline degeneration, either focal or diffuse. We believe that the severe respiratory insufficiency that is commonly seen in the advanced stages of AIDS could be related to the interstitial damage. In the adrenal gland, the most common change is Cytomegalovirus infection affecting both the cortex and the medulla, and inducing massive necrosis in the cortex with little or no reaction. Again, adrenal involvement should be related to adrenal functional insufficiency, which may be over-looked clinically because of the preponderant lesions of other sites. In the heart, myocarditis is often discrete, and may be complicated by perivascular fibrosis and rare foci of myocytolysis; in some cases primary lymphomas may also develop. In the kidney, several histological lesions are found, including glomerular damage with segmental necrosis, cortical areas of hyporeactive necrosis, and mild interstitial inflammation. In the gonads, the changes are partly induced by drug abuse, and consist of atrophy with secondary hypoplasia of the germ cells and interstitial fibrosis. In conclusion, the most important abnormalities consist of opportunistic infections, hyporeactive necrosis, fibrotic evolution of the inflammatory infiltrates and neoplasias (Kaposi's sarcoma and lymphomas). In this work, the changes of the lymphoid organs are only mentioned, for they have been widely reviewed elsewhere.     

Experimental myocarditis induced by two different coxsackievirus B3 variants: Aspects of pathogenesis and comparison of diagnostic methods

The ability of two coxsackievirus B3 (CBV3) variants to induce myocarditis in BALB/c mice was studied and plaque-forming assay, polymerase chain reaction (PCR), in situ hybridization, and immunohistochemistry were compared for detecting viruses and viral components in the myocardium. The virological findings were related to histopathologic and ultrastructural changes in the myocardium. CBV3-W induced severe myocarditis characterized by massive myocyte necrosis. Widely distributed myocyte damage clearly preceded modest inflammatory infiltrates in the myocardium. In contrast, CBV3-MI induced mild myocardial injury. Both variants caused fulminant pancreatitis with nearly complete necrosis of the exocrine pancreas. CBV3 RNA was identified by PCR in the myocardium of CBV3-W-infected mice until the end of the follow-up period of 14 days. Moreover, semiquantitative results were obtained when the PCR/ hybridization results were analyzed by a phosphor imaging system. lmmunohistochemistry and in situ hybridization from formaldehyde-fixed, paraffin-embedded specimens were highly similar in detecting viral components during the early stages of the myocardial injury. The results indicate that: (i) direct viral damage plays an essential role in acute murine CBV3-induced myocarditis, (ii) PCR appears a useful and sensitive diagnostic method in acute myocarditis, and (iii) immunohistochemistry as a specific and relatively rapid method might be practicable also in studying the early stages of acute myocarditis from archival clinical material. © Wiley-Liss, Inc.     

Self administration of cocaine in monkeys receiving LAAM acutely or chronically

Polydrug abuse remains a common problem among opioid abusers as well as patients in opioid maintenance programs. Although cocaine abuse has been reported in patients receiving methadone, the incidence of cocaine use in patients receiving l-alpha-acetylmethadol (LAAM) has not been well established. The goal of this study was to determine whether acute or chronic administration of LAAM modified the reinforcing effects of cocaine using a self-administration procedure in rhesus monkeys. Four monkeys responded under a fixed ratio (FR) 30 schedule to receive i.v. infusions of cocaine (0.0032-0.32 mg/kg/infusion) in the absence of other treatment, after acute LAAM administration (0.1-1.0 mg/kg, s.c.), and during daily administration of 1.0 mg/kg of LAAM. Cocaine maintained self-administration responding that exceeded responding maintained by saline; acutely administered LAAM had small and variable effects on self administration of cocaine. Daily LAAM administration increased the number of infusions received of at least one dose of cocaine. These studies indicated that LAAM administration did not attenuate the reinforcing effects of cocaine, suggesting that LAAM would not likely alter cocaine abuse in patients undergoing treatment for opioid abuse.     

Chronic interstitial nephritis and mixed cryoglobulinemia associated with drug abuse

Two cases of chronic interstitial nephritis with renal insufficiency were associated with mixed cryoglobulinemia and parenteral drug abuse. Previously recognized causes of interstitial nephritis were not present in either case. Despite extensive interstitial inflammatory infiltrates, no substantial glomerular abnormalities or immune deposits were present in either patient. One patient had a history of intravenous injection of suspended methadone tablets containing talc crystals, and there was evidence of talc embolization in biopsy specimens of liver, spleen, and kidney. Interstitial nephritis associated with drug abuse has not been previously described to our knowledge, but the association in these cases seems not to have been fortuitous and warrants consideration in the evaluation of both parenteral drug abusers and patients with unexplained interstitial nephritis.     

Azathioprine-associated interstitial pneumonitis

Seven renal allograft recipients taking azathioprine (Imuran) for immunosuppression developed bilateral pulmonary infiltrates and a falling pO2 that did not respond to antibiotic therapy. Open lung biopsies revealed changes ranging from diffuse alveolar damage (DAD) to usual interstitial pneumonia (UIP) culminating in pulmonary fibrosis. There was no evidence of immune deposits, eosinophilia, vasculitis, granulomas, or microorganisms by cultures and appropriate stains. Following discontinuance of Imuran, the two cases with DAD revealed a significant clearing of the lung infiltrates, whereas four of five patients with UIP died while suffering from respirator-dependent ARDS. Biopsies showing hyaline membranes, intraalveolar edema and cuboidalization of alveolar epithelium were associated with total doses from 2,850 to 4,355 mg, whereas atypical epithelial hyperplasia, reorganization of distal air spaces, and fibrosis were noted in cases receiving from 5,600 to 28,625 mg of azathioprine. Ultrastructural changes were indistinguishable from those induced by other drugs causing pulmonary toxicity. In three cases atypical epithelial cells were detected cytologically in brushing specimens and appeared identical to those noted in the lung biopsies. Our findings are consistent with the view that azathioprine should be added to the list of agents capable of causing direct, dose-dependent pulmonary toxicity. Accordingly, drug-associated diffuse interstitial pulmonary disease should enter the differential diagnosis of a lung infiltrate that develops in renal transplant patients receiving Imuran.     

Histopathology of drug and toxin induced kidney lesions

An overview is presented of the morphologic patterns associated with drug or toxin induced renal lesions. Most prominent are the arteritis, glomerulonephritis, tubular necrosis, renal cortical necrosis, intratubular crystal deposition, acute and chronic interstitial fibrosis, interstitial granulomas and acute renal insufficiency with normal renal histology. Findings are correlated with the nature of the noxious substances. Sources of error arising from the insufficient specificity of the morphological findings and the differential diagnostic considerations are fully and critically presented. The review can serve to direct the recognition of etiologic relationships through the interpretation of morphological findings in the kidney.