Amyloidosis, characterized by the deposition of amyloid protein in an abnormal fibrillar form [1–3], involves a variety of uncommon and complex systemic diseases, the classification of which necessitates the timely identification of the specific molecular type of amyloid protein fibril involved [1]. More than 25 different types of proteins, and many additional variants, may cause amyloidosis [1]. It may occur as systemic, localized, systemic and localized, cerebral, or extracerebral disease [1]. There may be multiple organ involvement, with the kidney most commonly involved. Heart, lung, and liver involvement may also be found [1–3]. Systemic amyloidosis typically occurs as AL amyloidosis, also termed primary amyloidosis, which is derived from an immunoglobulin light chain or a light chain fragment; or may occur as AA amyloidosis, formerly termed secondary amyloidosis, which is associated with chronic inflammatory processes or chronic infections [1]. Hereditary amyloidoses, thought to be an underdiagnosed amyloidosis, may clinically mimic AL amyloidosis, and include, among others, amyloid derived from fibrinogen A alpha chain (Afib), amyloid derived from transthyretin (ATTR), amyloid derived from a mutant of lysozyme (ALys), and amyloidosis derived from apolipoprotein AI (AApo AI) [1]. More recently amyloidosis derived from leukocyte chemotactic factor-2 (ALect-2) was added to systemic amyloidosis [2]. There has recently been a “formidable evolution” of systemic amyloidoses treatments from one of entirely supportive disease management to one dependent upon the specific molecular type of amyloid protein involved, utilizing “quite diverse, radical, and aggressive treatments,” including chemotherapeutic regimens, some with stem cell rescue; stem cell transplantation; liver transplantation; and liver transplantation combined with heart or kidney transplantation [1]. Currently, treatments once only provided to younger patients are showing benefits in older adults, and research is ongoing [1]. These remarkable therapeutic advances for some specific types of amyloidosis depend upon early, specific, and accurate amyloidosis diagnosis in order to best ensure appropriate patient treatment and optimize prognosis [1]. Hence not only late diagnosis but also misdiagnosis of the amyloidosis-type consequently leading to the application of aggressive treatment is dangerous [1, 4].

Amyloidosis may mimic many other diseases and is frequently difficult to diagnose; patients present with variable and often general symptoms and progress variably in their disease courses [3]. In some cases other diseases mask amyloidosis’ sometimes subtle signs and symptoms. Because of these concerns, “it is imperative that the criteria for amyloid-type diagnoses be stringent” [1]. Diagnostic workup may not end with the diagnosis of amyloidosis; for example, kidney biopsy may be used in considering liver transplantation [1].

Pathology workup continues to evolve. Although Congo red stain is still considered the “gold standard” for amyloidosis, some other older methods have been eliminated. For example: “[i]t must be stressed that potassium permanganate stain currently has no role in amyloid typing” [1]. Further, diagnosing AL type and differentiating it from hereditary amyloidosis may be challenging [1]. Although immunohistochemical diagnosis of AA-type amyloidosis remains generally reliable, it may require the use of panels of immunostains, including repeat panels, for accurate diagnosis [1]. Electron microscopy and Western blotting may also need to be employed for diagnosis, as they have been shown to in some cases provide better diagnostic results than immunohistochemical staining [1]. In other cases, tandem mass spectrometry with laser microdissection has been successfully applied to amyloid typing [5]. When therapy was supportive, diagnosis did nothing to alter patient prognosis; however, diagnostic and therapeutic advances increase the potential for diagnostic delay or misdiagnosis, ultimately to the patients’ detriment, with consequentially increased physician risk of medical malpractice lawsuits.

Physician responsibility for timely and accurate amyloidosis diagnosis is now correspondingly greater. Delayed diagnosis, failure to diagnose, and misdiagnosis are the typical allegations in medical malpractice lawsuits, and due to the potential for serious injury where there is specific, effective therapy available, would likely be the alleged cause of action in cases of amyloidosis misdiagnosis or diagnostic delay [4, 6–8]. The potential for large damage awards exists, because damage allocation may include the cost of medical care, lost wages and income, loss of spousal companionship, potential permanent disfigurement, and pain and suffering [7].

While lawsuits for failure to diagnose, misdiagnosis, or delayed diagnosis of amyloidosis have not yet emerged in the legal literature, their likelihood is increasing, as discussed below. As such, it behooves physicians, both specialists in amyloidosis and nonspecialists, to better understand the basics of medical malpractice, including possible avenues for plaintiff claims and potential defenses.

Detailed examinations of the medical malpractice system can be found [6]. Briefly, a claim of failure to diagnose or delayed diagnosis is a claim of medical malpractice, which is an alleged tort. A tort is “damage, injury, or a wrongful act done willfully, negligently, or in circumstances involving strict liability, but not involving breach of contract, for which a civil suit can be brought” [9]. Medical malpractice tort allegations generally involve allegations of negligence [6]. Negligence is “[c]onduct which falls below the standard established by law for the protection of others against unreasonable risk of harm; it is a departure from the conduct expectable of a reasonably prudent person under like circumstances” [10]. To be held negligent, a physician must be found to have committed a medical error that rises to the level of a breach of duty of care to the patient, i.e., not met the standard of care required in caring for the patient [6]. Today’s “reasonable person” standard is determined by whether a physician “proceed[ed] with such reasonable caution as a prudent man would have exercised under such circumstances” [6, 11]. Unfortunately, what constitutes the medical malpractice standard of care in a courtroom has not been well settled; and currently, there are numerous definitions and explanations of “standard of care” in medical malpractice [6]. The standard of care may not be straightforward or easily determined [6, 12]. As Richard Epstein noted, “Everyone supports a standard of reasonable care, but everyone interprets it just a little bit differently” [6, 13]. Standard of care is frequently determined by the court from the testimony of expert witnesses [14]. The expert has an obligation of candor toward the court; however, “standards of care are routinely interpreted oppositely by expert witnesses…[and] both sides devote considerable effort to screening and disqualifying consultant experts whose views do not represent the ‘standard’ the attorney needs to make the case. The attorney is doing his or her job” [6, 15]. As such, expert witness shopping for “hired guns” often leads to a confusing “battle of the experts” [6].

Traditional tort theory requires that for a plaintiff to succeed in a medical malpractice lawsuit, a physician’s actions must be proved to “more likely than not” have caused the injury [16–18]. In other words, “[i]f the plaintiff had a 51% chance of survival, and the misdiagnosis reduced that chance to zero, the estate is awarded full wrongful death damages, but if the patient had only a 49% chance of survival, and the misdiagnosis reduced it to zero, the plaintiff receives nothing. Thus, whenever the chance of survival is less than even, the ‘all or nothing’ rule gives a ‘blanket release from liability for doctors and hospitals…regardless of how flagrant the negligence’” [17]. Claims of injustice from this “all-or-nothing approach” has led courts, and over the last two decades, to adopt the “loss-of-chance” doctrine, which views a person’s prospect for surviving a serious medical condition as something of value, “even if the possibility of recovery was less than even (i.e., less than a 50 % chance) prior to the physician’s allegedly tortuous conduct” [17, 19].

Courts are increasingly adopting the “loss-of-chance” doctrine in medical malpractice cases [20–27]. Courts that accept that a physician’s action would “more likely than not” caused a patient’s injury can hold physicians liable for patient injury [28]. Courts that accept less of an injury, i.e., a patient’s “loss of chance” of any clinical improvement or prolonged survival, can nonetheless impose liability [24]. Currently, “loss-of-chance” liability is accepted by approximately half the states, and the legal trend shows increasing acceptance, with five of seven state supreme courts accepting the doctrine [29]. The doctrine nonetheless is controversial [18, 30–35]. “One of the most debated issues involving the loss of chance is causation” [36]. “A majority of states adopting an exception for loss-of-chance plaintiffs have done so by relaxing the causation standard to less than the normal preponderance-of-the-evidence threshold. In applying a relaxed standard, “freed from its moorings” [21], these states provide a loss-of-chance plaintiff an opportunity to recover damages despite an inability to prove causation by a preponderance of the evidence. This is achieved by allowing the presentation of expert testimony to demonstrate that the plaintiff was either deprived of a ‘substantial possibility’ of survival or recovery or simply incurred an ‘increased risk’ of suffering the ultimate injury as a result of the defendant’s negligence” [36]. With today’s new diagnostic criteria, new diagnostic methods, and new therapies for patients with amyloidosis which are more specific to the exact type of fibril protein causing the amyloidosis, and for which early therapy yields a better prognosis, it is reasonable to imagine that “loss-of-chance” doctrine may be useful for plaintiffs who cannot show that the delayed diagnosis or misdiagnosis was more likely than not the proximate cause of the plaintiff’s injury.