Textbook of Iatrogenic Pathology

This chapter includes general aspects regarding the definitions and mechanisms of occurrences of adverse drug reactions (ADRs). They can be realized through non-immunological (type A reaction) or immunological (type B reaction) pathways and can be dose-dependent or independent. A new type of ADR is encountered in oncology departments in patients taking monoclonal antibodies. It is known as drug-induced apoptosis and is presented in this chapter. The mechanisms and classification of the severity of these reactions, as well as the particularities of acute, chronic and chronic-delayed ADRs, are also explored. The severity can be patient- or drug-related. In the chapters that follow, specific system- and organ-related ADRs are presented.

This chapter includes general aspects regarding the mechanisms of radiation-induced lesions and specific organ-related effects of radiotherapy, from the cardiovascular system to bone marrow. For oncologists, understanding the mechanisms of radiation-induced carcinogenesis and knowing the estimated time taken for postradiotherapy occurrence of metachronous tumors is mandatory for proper patient follow-up. We here analyze all lesions of the skin and internal organs, leaving aside tumors for this chapter. The acute and chronic effects of radiotherapy are presented in detail, and the grading system of oral mucositis is also outlined.

This chapter covers the general aspects regarding the mechanisms of the four specific branches of iatrogenic immunopathology: iatrogenic immunodeficiencies, iatrogenic-induced lymphoproliferative diseases, hypersensitivity-induced lesions and immunopathology of transplantation. Understanding the four types of hypersensitivity reactions is mandatory for understanding the details of drug-induced lesions in organs. Mechanisms and complications of transplantation of solid organs are shown in detail.

This chapter includes a synthesis of data regarding cardiovascular-related lesions induced by medical drugs or radiotherapy, and also relates to the specific injuries that can be caused by diagnostic and/or therapeutic interventions. The effects of chemotherapeutics and non-chemotherapeutic drugs on the myocardium are analyzed in detail, with a focus on anthracycline-induced cardiovascular effects in children. Some of the disorders are illustrated using representative pictures taken during autopsies. Although a common technique, insertion of prosthetic grafts can lead to complications, such as thrombosis, aberrant neointimal hyperplasia or dehiscence. Percutaneous vascular intervention complications can be related to the catheter or to the intervention itself. The differences between in-stent restenosis and postoperative thrombosis are also presented. The final part of this chapter is dedicated to open heart surgical intervention complications.

This chapter includes a synthesis of data regarding the lesions of the lungs and airways that can be induced by medical drugs or diagnostic and/or therapeutic interventions. Drug-induced lesions are difficult to identify and mainly relate to laryngeal or pulmonary edema, hypersensitivity pneumonitis and diffuse alveolar damage with hyaline membranes. In patients taking anticoagulants, the occurrence of spontaneous hemothorax or aberrant thromboembolism should also be taken into account. Diagnostic procedures that involve the airways are sometimes, though rarely, followed by complications that include post intubation croup, ulcerations or granulomas, but infrequent iatrogenic tracheal rupture and injuries to cranial nerves are also reported. Mechanical ventilation and hyperbaric oxygen therapy can be followed by pulmonary edema, interstitial emphysema or pneumothorax. In preterm babies, Wilson-Mikity syndrome and intraventricular brain hemorrhage can occur following oxygen therapy. All of these data are examined in detail in this chapter.

This chapter includes a synthesis of data regarding iatrogenic injuries of the gastrointestinal tract. In the first section, medical drug-induced lesions are analyzed, while the following sections refer to the diagnostic and/or therapeutic interventions that involve the gastrointestinal segments. ADRs come in a wide spectrum of manifestations, from mucosal inflammation to severe lesions, such as Stevens-Johnson syndrome. The most common agents involved in severe reactions are non-steroidal anti-inflammatory drugs (NSAIDs). Proton pump inhibitors (PPIs) are responsible for the occurrence of cystic polyposis of the stomach. Intestinal iatrogenic disorders primarily involve enterocolitis, but strange complications, such as bezoar formation or intestinal rupture, are also reported. Complications relating to endoscopic examinations, laparotomy and laparoscopy are also presented in detail.

This chapter presents a synthesis of data regarding the iatrogenic injuries of the peritoneum and retroperitoneum. Similar to the previous chapters, medical druginduced lesions and the consequences of diagnostic and/or therapeutic interventions are presented in detail. Iatrogenic retroperitoneal fibrosis can emerge following radiotherapy or as a consequence of long-term use of drugs such as beta blockers or antiepileptic substances. Pneumoperitoneum is usually a postoperative transient lesion, but it can also be a severe consequence of barotrauma or mechanical ventilation. The causes and consequences of iatrogenic peritonitis and ascites are also analyzed.

This chapter presents a synthesis of data regarding iatrogenic injuries of the liver, gallbladder and pancreas. For each of these organs, medical drug-induced lesions are presented. The second part of the chapter includes the consequences of diagnostic and/or therapeutic interventions for the above-mentioned organs. The liver is the second most common organ involved in drug effects, following the skin. Its destruction can be an indication for transplantation. The hepatic disorders include metabolic disturbances, cholestasis, hepatitis, cirrhosis and risk of malignancy. The biliary channels can be injured during open surgical interventions or laparoscopic cholecystectomy, leading to fistulae, peritonitis, bilirrhagia and even death. Endoscopic retrograde cholangiopancreatography (ERCP) can be associated with local complications, such as pancreatitis and cholangitis, but pneumothorax, pneumomediastinum and pneumoretroperitoneum are also encountered in rare cases.

This chapter presents a synthesis of data regarding acute and chronic drugrelated lesions of the kidneys and urinary tract, as well as the urologic injuries that can result from diagnostic and/or therapeutic interventions. Reversible or irreversible renal injuries can be caused by prerenal, intrarenal or postrenal damage. Identification of the pathomechanism is mandatory for proper treatment of the side effects. Those drugs that are excreted through the kidneys can induce ischemic or obstructive lesions and can predispose the patient to stone formation. Analgesic nephropathy is a particular type of nephritis that can be reversible after drug cessation. Glomerulonephritis can be caused by several drugs, including vaccines, anti-inflammatory agents and beta blockers. Regarding surgical interventions, upper urinary tract deterioration can occur following direct injuries or as a consequence of iatrogenic lumbosacral spinal cord lesions. Complications relating to peritoneal dialysis are also presented in detail.

The female genital system and breast can be injured by drugs or during diagnostic and/or therapeutic interventions. Drug-induced lesions of the female genitalia primarily involve contact dermatitis and fixed drug eruptions. Galactorrhea can be caused by several drugs, including neuroleptics and antihypertensive agents. In females with breast cancer, tamoxifen can induce endometrial hyperplasia and transformation into carcinoma. Diagnostic and therapeutic procedures rarely lead to severe complications, but such complications are specific and require knowledge for clinicians. The final section of this chapter is reserved for specific lesions related to pregnancy and the effects of the intrauterine environment on newborns.

Similar to the female genital system, the male genitalia can be injured by drugs or during diagnostic and/or therapeutic interventions. The drug-induced lesions of the male genitalia that are analyzed in this chapter include contact dermatitis, fixed drug eruptions, scrotal blisters and other specific lesions, such as red scrotum syndrome and scrotum hemangioma. Iatrogenic functional disorders are also presented in detail. The final section of this chapter is dedicated to surgical-related lesions of the male genitalia.

Bone marrow and lymphoid tissue can be damaged by medications or radiation and are particularly susceptible to injury in bone marrow transplant recipients. Iatrogenic bone marrow suppression is a common in-hospital complication, the therapeutic management of which is difficult. In patients with cancer, aggressive treatment usually induces bone marrow damage, but this can be prevented using specific colony-stimulating factors. Heparin-induced thrombocytopenia is a distinct lesion with unusual clinical features. Its two types of manifestation are presented in this chapter, together with other lymphoid tissue-specific iatrogenic disorders.

The skin and liver are the most common organs affected by the side effects of drugs. Drug-related damage to the skin and subcutaneous tissue is presented in detail in this chapter. Benign lesions include contact dermatitis and eczematous eruptions. Severe drug-induced injuries include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis, bullous dermatoses and other hypersensitivity syndromes. The specific characteristics and responsible agents of these conditions are offered in tables in this chapter, and particular types of drug-induced lesions are also presented. A significant part of the chapter focuses on the effects of targeted cancer therapies on the skin and subcutaneous tissue. Granulomas and vaccine-induced lesions are also examined.

Iatrogenic neurological disorders can be induced by several factors, such as pharmacological agents prescribed for treatment or prevention (drug-induced neurological disorders [DIND]), complications of diagnostic and treatment procedures, like cerebral angiography or lumbar puncture, organ transplantation (related to the surgical procedure of transplantation, post-transplant immunosuppression, opportunistic infection or the inherent disorders that lead to transplantation), radiation therapy, etc. Iatrogenic neurological effects may be devastating due to the higher potential irreversibility of central nervous system, peripheral nervous system, neuromuscular junction (NMJ) and/or muscular system involvement. DIND represent the majority of iatrogenic neurological disorders. Drugs may directly induce neurological damage (through primary neurotoxicity, such as damage to the bloodbrain barrier [BBB], disturbances of brain energy metabolism, ion channels/neurotransmitters disturbances, mitochondrial dysfunction, metabolitemediated toxins, drug-induced selective cell death) or do so indirectly (cardiovascular, hematological or renal effects). Identification of DIND is important because early recognition and drug withdrawal can prevent irreversible damage. The numerous intrinsic risk factors for DIND should be well known by medical practitioners.

Iatrogenicity is inherent to endocrinology, being a consequence of treatment (e.g., use of thyroid hormones in large doses to suppress thyroid stimulating hormone [TSH] in thyroid cancer) or occurring due to a lack of patient compliance (e.g., lack of adequate controls in chronic diseases, such as Hashimoto’s chronic thyroiditis). Quite often, it is induced as a side effect of medicines (e.g., long-lasting use of antithyroid agents or glucocorticoids). In this chapter, we review the most important iatrogenic effects, according to the main features of endocrinology. We present certain drugs that can trigger particular syndromes, such as the syndrome of inappropriate antidiuretic hormone secretion (SIAHS), along with preparations with pitressin and complications of treatment performed for pituitary adenomas, potential complications of drugs used to treat pituitary insufficiency in children and other specific features constituting required knowledge for medical practitioners. All therapeutic modalities of hyperthyroidism (medical, surgical, radioiodine) can cause iatrogenic pathology. For example, the euthyroid state is a sine qua non condition of thyroid surgery (except the thyrotoxic storm in advanced stages). Radioiodine treatment, in turn, has its own contraindications. Iodine-containing preparations can activate thyroid autonomies and aggravate autoimmune thyroiditis and overt hyperthyroidism. In hypothyroid elderly and cardiac patients, the thyroid hormone substitution must be applied only after initial cardiovascular treatment, in small, gradually increasing doses. In Addison’s disease, indication of dietary salt reduction alongside glucocorticoid substitution, or the lack of increase in glucocorticoid dose in acute injuries, are serious iatrogenic complications.

The iatrogenic pathology occurring in anesthesiology and intensive care is a consequence of errors made due to ignorance (the incapacity to identify suddenly appearing pathological situations), negligence (deficiencies in applying correct medical conduct) or clinical misjudgment. In the field of anesthesiology, this type of pathology comprises complications in pre-anesthetic, anesthetic and post-anesthetic periods, the consequences of pharmacological effects of the administered anesthetic drugs, technical complications related to airway security, anesthetic machine functioning and monitoring equipment, the anesthetic technique utilized and the differing reactivity of patients to the chosen anesthetic procedure. In intensive care, regarding critical care patients with multiple organ dysfunctions, the main source of iatrogenesis is represented by invasive maneuvers (mechanical ventilation techniques, monitoring, vascular approaches). To all these are added complications related to administered drugs, artificial nutrition, volemic therapy and the high risk of infection.

Surgical intervention remains a trauma for patients even given modern techniques and the use of highly specialized instruments. Any surgical maneuver can cause injuries and complications. The severity of such injuries is determined by the disease itself, the patient's comorbidities and the surgeon's experience. In this chapter, we present the iatrogenic complications arising following major surgeries performed openly or laparoscopically. In the first section, general complications, such as hemorrhage, fever, ileus and abscesses, are presented. Next, organ-related complications occurring during laparotomy, drainage of the abdominal cavity or abdominal wall reconstruction are described in detail. We then turn to the specific intra- and postoperative complications of various organs’ surgical treatment due to erroneous surgery indications, vascular lesions and lesions of the neighboring organs. We describe complications in the surgery of the mediastinum, thoracic and abdominal cavity and describe the particularities of thyroid, lung, esophagus, stomach, small intestine, appendix, colon, pancreas, hepatobiliary tract and hernia surgery and postoperative parietal defects. Complications occurring as a result of laparoscopic intervention, erroneous indications or complications in performing pneumoperitoneum during insertion of the trocars are also presented. Finally, we consider the specific iatrogenic complications arising during minimally invasive bile, hiatal hernia, cardiac achalasia, spleen and morbid obesity (gastric sleeve and gastroplication) surgery.

Gynecological surgery is associated with general risks that also occur in general surgery, but specific lesions are frequently encountered. For example, due to the fact that the genital organs are closely related to the organs of the urinary tract, they can easily be injured. These injuries primarily include lesions of the urinary bladder and ureters, but intestinal and nerve damage can also occur. Regarding drugs, dose- and time-dependent effects are controversial. These effects include thromboembolic complications, myocardial infarction, cerebrovascular accidents and even the carcinogenic risk of development of an endometrium or breast cancer.

Complications in neurosurgery can occur during diagnostic procedures, such as lumbar puncture, lumbar drainage, suboccipital cisternal tap or cerebral/spinal angiography, or during neurosurgical procedures. Severe complications during or subsequent to lumbar puncture are extremely rare and include brainstem herniation, infection, subdural hematoma and subarachnoid hemorrhage. Insertion of a catheter into the lumbar subarachnoid space to drain the cerebrospinal fluid (CSF) can also be followed by infection or overdrainage. The complications of cisternal tap include hemorrhage in the cisterna magna and piercing of the medulla oblongata that can cause cardiac or respiratory arrest. The iodine-based contrast agents used for cerebral angiography can cause allergic reactions and epileptic seizures. Iatrogenic complications during surgical procedures can occur at any stage pre-, intra- or immediately postoperative. Complications occur during patient positioning, rendering this step of paramount importance to the success of surgery. Infectious and cosmetic complications can occur during skin disinfection, incision of the skin of the scalp and surgical incision of the skull. Dural lesions can lead to cerebrospinal fluid leak or fistulae. Corticotomy or corticectomy should be realized cautiously and external to functional areas. Ligation or coagulation of brain vessels can lead to cerebral infarction (arterial or venous) with loss of cerebral function. Iatrogenic lesions in different regions of the brain lead to specific neurological manifestations. Lesions in the anterior fossa can lead to anosmia, abulia or behavioral alterations. Lesions in the middle fossa can lead to aphasia and motor deficits, while lesion in the posterior fossa can lead to cranial nerve deficits or coma.