topics

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3850 PART 20 Frontiers

cancer formation in mice, causally linking p53 mutations with cancer.

Normally, p53 functions as a transcription factor that suppresses the

transcription of genes involved in apoptosis resistance. While myriad

mutations in p53 have been described, some result in an alternate

conformation that interacts with different HSP70 chaperones within

the PN. Binding of the mutant p53 protein to these chaperones affects

the DNA binding property necessary for its tumor-suppressor function

and facilitates binding to other domains, resulting in changes in gene

expression that protect malignant cells from apoptosis.

■ STRONGLY ENHANCED AGGREGATION

PROPENSITY AND AMYLOID FORMATION

(ALZHEIMER’S DISEASE, PARKINSON’S

DISEASE, AMYOTROPHIC LATERAL

SCLEROSIS, HUNTINGTON’S DISEASE, TYPE 2

DIABETES MELLITUS)

In some individuals, native or mutant proteins include sequence motifs

that promote an alternate highly ordered aggregation state when the

cellular environment is altered and in aging. The most common of

these motifs are the beta-pleated sheets, which, when exposed to

the solvent environment of the cell, easily bind to one another in an

iterative process that can accommodate many thousands of molecules

that form insoluble cross-beta sheet amyloid species. Broadly, these

intracellular aggregates are classified as oligomers (2–24 molecules),

protofibrils (rods 4–11 nm wide and 200 nm long), and amyloid fibrils

with a similar width to protofibrils but microns in length. While the

formation of oligomers is thermodynamically unfavorable, polymerization is favorable, causing aggregates to seed slowly but grow exponentially. In some cases, for example, Huntington’s disease, familial

forms of Alzheimer’s disease, and ALS, aggregation is accelerated by

mutations. However, in many cases, the aggregates contain other cellular proteins that share biophysical properties of aggregation propensity

or reflect dysfunction in the PN that facilitates their seeding or propagation (see below). While in most instances, damage caused by protein

aggregates is localized to the cells in which they form, as occurs with

islet amyloid peptide in some patients with type 2 diabetes, amyloidogenic proteins associated with neurodegenerative diseases have been

shown to “spread” between cells. Damage to neurons by aggregates in

Alzheimer’s disease can elicit a local inflammatory response by resident immune cells in the brain, both of which contribute to pathology.

Much effort has been directed toward the detection of aggregates and

amyloid and the development of small molecules or antibodies that

block further growth or the enhancement of cellular activities of the

PN to suppress protein misfolding.

■ SECRETED AGGREGATED AND AMYLOID SPECIES

CAUSING SYSTEMIC AMYLOIDOSIS

In patients with systemic amyloidosis, the secretion of large amounts

of aggregation-prone proteins results in the deposition of aggregates in

many tissues. These proteins can include immunoglobulins secreted

from plasma cells in patients with systemic inflammation or multiple

myeloma or other aggregation-prone proteins including transthyretin.

Similar to other aggregate-induced diseases, mutations in transthyretin

that facilitate polymerization are associated with an increased risk of

developing systemic amyloidosis with advancing age. These aggregates

induce cellular toxicity, inflammation, and matrix reorganization that

interfere with function in an organ-specific manner. Deposition of

amyloid produces stiffness where there should be flexibility, creates

barriers where there should be free flow, and distorts size where there

should be fit. The stiffness is particularly damaging to the heart, lung,

and blood vessels and both smooth and skeletal muscle. The barrier

effect can result in malabsorption in the gastrointestinal tract and glomerular dysfunction, cardiac and peripheral nerve conduction defects,

and limitation of joint range of motion.

■ NATIVE PROTEINS PRONE TO AGGREGATE

WHEN THE CELLULAR ENVIRONMENT IS ALTERED

BY STRESS AND AGING

While well-defined genetic abnormalities have been essential in

elucidating the molecular mechanisms that underlie the formation

of protein aggregates and causally linking them to disease, many, if

not most, clinical diseases associated with the formation of protein

aggregates develop in patients without identified mutations. In these

patients, a decline in the chaperone and quality control mechanisms

of the PN allows exposure of aggregation-prone domains of normal

proteins to the solvent environment of the cell. Once seeded, these

protein aggregates can expand rapidly to induce local or systemic

injury. The decline in function of the PN that allows these aggregates

to form might develop gradually with advancing age or might occur

suddenly in response to an age-triggered biologic program, as occurs in

C. elegans.

■ INFECTIOUS DISEASES AND IMBALANCED CELL

STRESS RESPONSES IN AGING

A model in which the function of the PN is reduced in aging might

explain the disproportionate morbidity and mortality in older individuals exposed to systemic stress. While these stressors include infections, surgical or accidental trauma, sepsis, and myocardial infarction,

among others, pneumonia, the most common cause of death from an

infectious disease in the United States, provides an illustrative example.

As was evident during the COVID-19 pandemic, pneumonia morbidity and mortality disproportionately affect the elderly. Viral pneumonias, including those caused by influenza viruses and SAR-CoV-2, are

primarily localized to the lung, where they activate a local and systemic

inflammatory response and denude the alveolar lining. The resulting

hypoxemia and systemic inflammatory response injures distant organs

independent of viral injury. Impaired function of the PN during the

stress might allow seeding of tissues with toxic aggregates with longterm consequences. Repair of the damaged lung and distant organs

represents a major challenge to proteostasis that might be overcome

in younger individuals but fail in those who are older with poor stress

resilience. This loss of proteostasis resilience necessary to limit damage

and allow repair could explain clinical observations in pneumonia survivors who develop persistent lung injury, skeletal muscle dysfunction

impairing mobility, chronic kidney disease, cognitive dysfunction and

dementia, and an increased risk of ischemic cardiovascular events in

the year after hospital discharge.

■ FURTHER READING

Balch WE et al: Adapting proteostasis for disease intervention. Science

319:916, 2008.

Chandrahas VK et al: Coordinating organismal metabolism during

protein misfolding in the ER through the unfolded protein response.

Curr Top Microbiol Immunol 414:103, 2017.

Chiti F, Dobson CM: Protein misfolding, amyloid formation, and

human disease: A summary of progress over the last decade. Annu

Rev Biochem 86:27, 2017.

Eisele YS et al: Targeting protein aggregation for the treatment of

degenerative diseases. Nat Rev Drug Discov 14:759, 2015.

Labbadia J, Morimoto RI: The biology of proteostasis in aging and

disease. Annu Rev Biochem 84:435, 2015.

Levine B, Kroemer G: Biological functions of autophagy genes:

A disease perspective. Cell 176:11, 2019.

Mallucci GR et al: Developing therapies for neurodegenerative disorders: Insights from protein aggregation and cellular stress responses.

Ann Rev Cell Dev Biol 36:165, 2020.

Song J et al: Quality control of the mitochondrial proteome. Nat Rev

Mol Cell Biol 22:54, 2020.

3851 Novel Approaches to Diseases of Unknown Etiology CHAPTER 492

information, i.e., patients and their families, health care providers,

government health care agencies, insurers, epidemiologists, genetic

counselors, pharmacologists, biologists, etc. As an example, a diagnosis

of Parkinson’s disease in an adult is based on the progressive emergence

of signs and symptoms of bradykinesia, rigidity, asymmetric rest tremor,

and postural instability (clinical diagnosis), which are typically responsive to the administration of L-dopa (a therapeutic response biomarker).

Together, these are cardinal features of striatonigral degeneration (a

mechanistic diagnosis), a process associated with neuronal α-synuclein

deposition and Lewy body pathology (histopathologic diagnosis) often

based on a genetic susceptibility conferred by mutations in genes such

as synuclein (SYNCA, a molecular diagnosis) and likely influenced by

environmental exposures (e.g., manganese or other neurotoxins).

With ongoing advancements in medical science and technology,

the standard for what constitutes a reasonable diagnosis continues to

evolve toward higher levels of specificity. Efforts to adopt the principles of precision medicine include a growing emphasis on the context

of disease within the genetic repertoire, environment, social factors,

medical history, nutrition, and the microbiome of any given individual. Examples include cancer susceptibility, genetically determined

idiosyncratic reactions to medications, and unique pathogen susceptibilities in patients with certain immune deficiencies.

■ UNDIAGNOSED RARE DISEASES

Most undiagnosed diseases are rare. While individual rare diseases have

a low prevalence by definition, they are numerous in aggregate. It is

estimated that >6000 rare diseases affect millions of people throughout

the world. Many rare diseases have a genetic basis and onset in childhood. As the cloud of uncertainty inherent in the undiagnosed disease

state is removed, new disease-specific counseling, therapies, resources,

community engagement, and advocacy opportunities become possible.

■ THE EFFECT OF THE UNDIAGNOSED

DISEASE STATE ON THE PATIENT

Patients with an undiagnosed disease are frequently driven to understand the basic nature of their ailment (what, when, where, how, etc.).

Individuals, families, physicians, and society, however, might have a

wide range of tolerance to the uncertainties associated with the undiagnosed disease state. Being undiagnosed has profound detrimental

effects. Patients can go undiagnosed for decades, leading to personal

and family uncertainty, high levels of stress, decreased productivity,

limited accessibility to disease-specific counseling and resources,

decreased quality of life, and excess utilization of medical services.

APPROACH TO CHALLENGING DISEASES

OF UNKNOWN ETIOLOGY

Approaches to a patient with an undiagnosed disease can be separated

into two categories. The first is a new assessment by a consultant, new

provider, or diagnostic referral center. The second is periodic reassessment by an existing provider for a patient who remains undiagnosed.

■ COMPREHENSIVE DATA COLLECTION

A potentially time consuming but critical initial step is the aggregation

of all available medical data. Essential records are listed in Table 492-2.

TABLE 492-1 Factors Contributing to the Presence of an

Undiagnosed Disease

FACTOR EXAMPLE

Misleading information False-negative and false-positive test results

Rare disorder Many inherited disorders have only been

identified in a few individuals. For example,

sialuria, a well-understood disorder of sialic

acid metabolism, has been reported in

10 individuals (OMIM 269921).

Unusual causes of common

diseases, including atypical

course of illness

Insulin-dependent diabetes mellitus may be

the presenting feature for the relatively rare

autoimmune polyendocrinopathy syndrome,

type I (OMIM 240300).

Presence of multiple disorders

(blended phenotypes)

For an example, see PubMed ID 24863970.

Lack of characteristic

symptoms of known disease

Diseases are commonly ascertained via

cardinal signs or symptoms leading to

incomplete ascertainment of all possible

disease presentations. For instance, not

all persons with Marfan’s syndrome are

tall relative to other family members. For

progressive diseases, pathognomic signs

and symptoms may be missing in early stages

of disease.

New disease No prior knowledge or record of such disease

Incorrect affected status

assignments in family history

A heritable disorder may be inappropriately

excluded if family history information is

incorrect.

Primary disease manifestations

obscured by other factors

Maladaptive behavior, medication effects, and

secondary disease manifestations may obscure

signs and symptoms of a primary disorder.

Disease not expected in region

or population

Cystic fibrosis in persons of African ancestry,

sickle cell disease in persons of northern

European ancestry; infectious agents with

marked geographical incidence patterns

Diseases thought to be

eradicated

Poliomyelitis

Diseases occurring in

unexpected time of life

Parkinson’s disease in children, lysosomal

storage disease in adults

Malingering Feigned disease features intended to achieve

secondary gain (Munchausen syndrome)

Rare disease mechanisms Transmitted or sporadic prion disease, unusual

zoonotic diseases

Abbreviation: OMIM, Online Mendelian Inheritance in Man.

TABLE 492-2 Essential Records for Undiagnosed Disease Patients

1. Any narrative summaries that detail the course of the illness

2. Copies of original test results with names, dates, testing circumstances,

normal ranges, and test facility information

3. Electronic copies of imaging studies

4. Consultation notes

5. Hospitalization intake and discharge summaries

6. Accurate family history accounts and family relations

Optional but potentially useful records include:

1. Photographs and/or videos of disease manifestations

2. Longitudinal data (growth charts, symptom logs, serial lab measurements)

3. Data or specimens that could be reanalyzed, including pathology specimens

and genomic sequencing of raw data

THE UNDIAGNOSED DISEASE STATE

The term disease, etymologically meaning “lack of ease” or the presence

of discomfort, is defined as an abnormal state that negatively affects the

structure or function of all or part of an organism and that is not due

to any immediate external injury. When referring to a person experiencing a disease, the word patient is used in its original, meaning “the

one who endures suffering.” These terms are well suited when referring

to patients with undiagnosed diseases. A patient with an undiagnosed

disease is one for whom a medical diagnosis is not discerned after reasonable efforts utilizing established methods and procedures. Multiple

factors may contribute to a failure to reach a diagnosis (Table 492-1).

Patients who are affected by an undiagnosed disease for a protracted

period of time can be said to be in an undiagnosed disease state.

■ THE MEANING AND CONTEXT OF A DIAGNOSIS

A diagnosis often entails hierarchical levels of information specificity with varying levels of relevance to the users (consumers) of such

492 Novel Approaches to

Diseases of Unknown Etiology

David Adams, Camilo Toro, Joseph Loscalzo

3852 PART 20 Frontiers

The overall goal of data collection is a full understanding of the

course of the disease and a verification of critical data elements used

for diagnostic decision-making. Incorrect or partial second-hand

accounts of prior test results contribute substantively to incorrect or

missed diagnoses.

Analysis of the collected data allows for reconstruction of the

process by which previous disease presentation, diagnostic thought

processes, and test interpretation led to the current understanding of a

patient’s illness. Unintentional obfuscation of the history and findings

can result from missing records, incomplete recall by the patient and

fragmentation, and propagation of information (and misinformation)

in the medical record. Optimally, the presence and character of key

features of the illness will be reinforced by perspectives derived from

multiple evaluations.

■ VALIDATION OF SUBJECTIVE AND

OBJECTIVE FINDINGS

Teasing apart the layers of a patient’s presentation often uncovers a

variety of adaptive (and maladaptive) coping strategies. Some are

idiosyncratic to the disease state (e.g., sun avoidance in a patient with

xeroderma pigmentosum), whereas others are driven by psychosocial factors and could become primary drivers of the phenotype. It is

important to consider, however, that patients believed to have “functional” or “somatoform” disorders, e.g., nonepileptic events (pseudo

seizures), frequently have concurrent bona fide epileptic events. Careful consideration of clinical phenomenology and associated findings on

physical examination and ancillary investigations may provide clarity,

affirmation, and effective redirection. Distinct clinical, radiographic,

and laboratory abnormalities provide entry points to the generation

of a differential diagnosis and could become effective biomarkers of

disease progression and response to interventions.

Testing Strategies and New Technology The historical exclusion of a diagnostic hypothesis may be based on testing that is no longer state of the art. For example, congenital disorders of glycosylation

(CDG) were historically diagnosed using transferrin isoelectric focusing. It was subsequently found that the diagnosis of many CDG types

required mass spectrometric and molecular approaches. The initial

assessment of a patient with an undiagnosed disease should include

a reassessment of the diagnostic logic and data used in past decisionmaking. In the absence of concrete diagnostic leads, the use of broad

scope screening tools may prove beneficial in generating meaningful

diagnostic hypotheses (Table 492-3). In some cases, newer testing

options may be difficult to obtain and/or be costly. Prior probability of

disease and available resources will factor in determining whether new

diagnostic testing is practical.

Molecular Approaches, Including Genomics The availability

and variety of clinical molecular modalities have transformed diagnostic testing in many settings. These advances have arisen from both

testing scope, e.g., exome-wide, genome-wide, and transcriptome (RNA

sequencing [RNA-Seq]) sequencing, and new medical knowledge, e.g.,

new disease-gene associations and molecular interaction networking

(network medicine). Complementary screening tools, such as metabolomics, show diagnostic promise, particularly when combined with

sequencing data to generate a fuller picture of disease manifestations.

Simultaneous consideration of multiple data types can provide a means

of appreciating overlapping and reinforcing evidence, with the potential

to inform both hypothesis-driven and agnostic approaches to diagnosis.

HYPOTHESIS-DRIVEN MOLECULAR TESTING Hypothesis-driven testing implies that a defined set of heritable (or potentially heritable) disorders is the principal impetus for testing. Selection of a targeted gene

sequencing panel, possibly augmented with structural variant detection technologies, may allow for improved sensitivity, lower cost, and

fewer unrelated (secondary) findings relative to full exome or genome

sequencing studies. In the setting of an initial undiagnosed disease

evaluation, prior sequencing panels may not include recently discovered genes. Testing with an updated panel or targeted sequencing of a

newer gene is an option for consideration. In some cases, sequencing

panels are generated by selective reporting of relevant genes within an

exome data set. In such cases, it may be possible to expand the analyses

to new genes of interest without additional sequencing.

AGNOSTIC MOLECULAR TESTING Agnostic testing typically uses data

from exome or genome sequencing and considers all possible diagnoses, even those with a low pretest probability of being present. This

approach can also generate hypotheses for potentially new disease-gene

associations. Analysis of the sequencing data typically includes an unrestricted search throughout the entire human genome or exome space.

DNA sequence variants with potential medical relevance are identified

first by bioinformatic characteristics, including known association with

disease, predicted importance for protein function, interspecies conservation, population frequency, and an evolving list of other factors. The

list of candidate variants is then subject to expert review (i.e., curation).

The interpretation of test results in this setting is highly influenced by

both the adequacy of communication between the clinical and testing

teams and the information content of the data sources used to annotate

each of the thousands of variants generated in the course of sequencing.

There is a rapid proliferation of new testing platforms and analytical

tools with the potential to contribute to solving undiagnosed diseases,

but it remains challenging to judge their broad utility. While awaiting

for systematic validation and practice standards, novel techniques may

be considered in special cases where a diagnostic hypothesis is closely

TABLE 492-3 Clinically Available Tests with Notable Utility for

Undiagnosed Cases

TEST TARGET PHENOTYPES RATIONALE

Single nucleotide

polymorphism microarray

and/or karyotype

Dysmorphic features,

cognitive impairment,

neurodevelopmental

disorders

Genomic structure

abnormalities may

be missed by other

testing

Exome or genome

sequencing

Any undiagnosed disease

that is chronic and not

clearly acquired

Tests a broad

range of potentially

unconsidered

diagnostic entities

Lysosomal storage

diseases (LSDs),

molecular or enzymatic

tests. urine organic

acids, urinary

glycosaminoglycans

(GAGs), oxysterols

Progressive neurologic

disorders, psychiatric

disorders

Some LSDs have

nonspecific

presentations, and

adult-onset cases are

often missed

Congenital disorders

of glycosylation, Apo

CIII and N-glycan mass

spectrometry

Pediatric-onset disorders,

cognitive impairment,

neurologic phenotypes

Large group of

disorders; phenotypes

for many still being

characterized.

Biochemical disorders,

ammonia, serum polyols,

urine purines and

pyrimidines, plasma

amino acids, very-longchain fatty acids

Neurologic phenotypes,

especially with waxing and

waning course, selective

speech involvement or

patients with unusual selfselected diets

Metabolic disorders

may have nonspecific

symptoms, and adultonset cases are often

missed

Mitochondrial sequencing

and mitochondrial

depletion studies;

biochemical screening

with serum lactate, blood

pyruvate, plasma amino

acids, and GDF-15

Complex multisystem

disorders with

neurometabolic, endocrine,

and gastrointestinal

symptoms, muscle

dysfunction, and waxing

and waning or progressive

course

Large group of

disorders with

a wide range of

presentations; yield is

improved by studies in

affected tissue (e.g.,

liver or muscle)

Cerebrospinal fluid

(CSF) studies including

amino acids (AAs),

lactate, pterins,

methyltetrahydrofolate

(MTHF), or special CSF

flow studies

Synthetic neurotransmitter

defects in patients with

unexplained fluctuating

encephalopathy/movement

disorders or patients with

atypical neuroinflammatory

syndromes

Patterns of profiles

point to particular

enzymatic deficits

in neurotransmitter

synthesis or

characterization of

unique immunologic

profiles of

inflammatory central

nervous system

diseases

3853 Novel Approaches to Diseases of Unknown Etiology CHAPTER 492

aligned with the type of data generated by a specific testing strategy

(Table 492-4).

■ PERIODIC REEVALUATION

The cornerstone for the care of a patient in an undiagnosed disease

state is a plan for periodic reevaluation until a diagnosis is achieved.

The Undiagnosed Diseases Network, a 10-year National Institutes of

Health–sponsored national program specifically designed to evaluate undiagnosed patients (with several international counterparts),

reported a diagnostic rate of ~30%. This finding illustrates the fact that

many affected individuals remain in an undiagnosed state for a protracted period of time. For a medical provider, the care of an undiagnosed patient includes a program for symptomatic care, support related

to the undiagnosed state itself, and plans for a regular reevaluation

strategy seeking new insights into the diagnosis by following its time

trajectory. Reevaluation is guided by emerging knowledge in the field,

disease progression, and the development of new signs and symptoms.

The appearance of a similar disease in a sibling or close relative may

provide critical insight. Communication with the patient is an essential component. Many individuals with an undiagnosed disease report

feeling abandoned by their providers once diagnostic ideas have been

exhausted. Providers themselves may feel discouraged in being unable

to provide a diagnosis. The institution and discussion of a well-defined

plan for periodic reassessment and communication can help reinforce

the patient-provider relationship and set reasonable expectations.

Reevaluation of Differential Diagnosis The key to success for a

planned reevaluation visit is preparation. The problem and differential

diagnosis lists should be subject to careful, evidence-based review. New

or resolved clinical features may add or remove diagnostic considerations. The passage of time may result in the emergence of distinct new

phenotypic manifestations that serve as new clues in the formulation of

a definite diagnosis. Special consideration should be given to the effects

of reaching maturity and aging. The establishment of a phenotype as

being static versus progressive has prognostic value. Careful documentation of the rationale for including or excluding individual disorders

will streamline the process for both future reevaluations and the need

for consultants. Concurrent development of common diseases should

be thoughtfully considered as a possible component of the primary

undiagnosed condition. For example, insulin-dependent diabetes mellitus could be a feature of the rare autoimmune polyendocrinopathy

associated with mutations in the autoimmune regulator gene AIRE.

New Literature Keeping abreast of current literature is an important and challenging activity for all medical providers as the body of

medical knowledge continues to grow exponentially. For undiagnosed

diseases, newly reported disorders and disease-gene associations are an

important source of diagnostic resolution. Literature search tools such

as PubMed can be augmented by online resources that connect clinical

signs and symptoms (phenotypes) to disorders. For instance, using the

search terms “cardiomyopathy arthropathy diabetes hyperpigmentation” in the Online Mendelian Inheritance in Man website (https://

omim.org) produces a list of disorders that includes hemochromatosis.

In the context of an undiagnosed disease, this type of phenotypedriven approach can be used to search for new, relevant publications

and disorders. Tools that automate such searches continue to be developed in both open-source and commercial settings. The success of

these approaches is augmented by iterative application, ideally as part

of formal, periodic reevaluation of the undiagnosed patient.

■ GENOMICS

The use of medical testing based on the determination of DNA

sequence and structure (sometimes referred to as molecular testing)

has proliferated in recent years. A wide variety of approaches are available to the clinician, from single-gene sequencing to exome or genome

sequencing. Many reviews of this topic are available (see Adams and

Eng, 2018, in “Further Reading”). Consultation with colleagues trained

in genetics can be useful when developing an optimal testing approach.

In some cases, genetic testing results may already exist in the medical record during the initial evaluation of an undiagnosed patient. This

is increasingly true for younger patients; exome and genome sequencing are being used earlier, and with increasing frequency, for complex

diagnostic challenges. Reanalysis of previously obtained exome and

genome data should start with consideration of both the age and quality of the study and the reported patient phenotype at the time of the

study report. For sequence results generated in a clinical laboratory,

a discussion between the provider and the laboratory director often

answers important questions about recommended next steps. The discussion should touch on how technologic advances have affected the

utility of the older data and whether the laboratory offers reanalysis

of the data. At a minimum, the provider, the testing laboratory, or an

identified subspecialist should review previously reported DNA variants of unknown significance considering interval reports about the

gene in question. More advanced reanalysis strategies are emerging and

may be offered by the testing laboratory.

Some laboratories offer release of raw DNA sequencing data to

their patients on request. The utility of raw data varies and depends on

the identification of bioinformatics collaborators willing to reanalyze

the data. Sequencing data obtained as part of a research study may

not be suitable for clinical diagnostic purposes. In practice, raw and

research-generated sequencing data are most useful when a collaborating researcher can be identified.

When considering a new sequencing test, the inclusion of the parents and siblings of the proband has the potential to provide enormous

value in some situations. Discussion of an optimal approach with an

expert colleague or the testing laboratory is encouraged.

■ EXPOSOME

In many cases, a detailed occupational and environmental exposure history should be obtained. Some rare disease phenotypes are

pathognomonic of specific toxicant exposures (e.g., mesothelioma

TABLE 492-4 Emerging or Special Testing Strategies and Related

Diagnostic Questions

TESTING STRATEGY RELATED DIAGNOSTIC QUESTION

AVAILABLE

CLINICALLYa

Transcriptomics,

RNA-Seq

Relevance of splice, regulatory, and

other noncoding variants; correlated

changes in gene expression within

pathways

Metabolomics Hypothesis generation via

nontargeted approaches, correlated

pathway changes, correlation with

molecular findings

Yes

Epigenetics Diseases known or suspected to be

caused by methylation or parent-oforigin effects

Some

Transcriptional

profiling

Search for profile particular

to certain disease states, e.g.,

interferon inducible genes panels

(interferon signature) in certain

autoinflammatory disorders

Some

Specialized, diseasespecific testing

Prion-related diseases, metabolic

diseases, and many other assays

Some

Functional validation Model organisms, cell biology, and

other approaches to validating

a hypothesized gene-disease

association

Metagenomics Search for molecular fingerprints

of other organisms (e.g., infectious

agents) within human samples

Yes

Long-read

sequencing

technology

Accurate resolution of lowcomplexity regions of the human

genome (repeat expansion disorders)

and complex genome structural

rearrangements

Deep sequencing Accurate resolution of low levels of

mosaicism

Some

Available clinical tests are often a small subset of approaches available via

research collaboration. Clinical testing offerings are evolving rapidly and should be

reassessed periodically.

3854 PART 20 Frontiers

and asbestos exposure, clear cell adenocarcinoma of the vagina and

intrauterine diethylstilbestrol (DES) exposure, chloracne and exposure

to halogenated aromatic hydrocarbons). For the most part, however,

chemical toxicant exposures do not produce unique phenotypes.

Rather, chemical exposures operate in conjunction with lifestyle

factors (e.g., smoking, alcohol intake, and nutritional status), differential host susceptibility (determined by age, sex, comorbidities,

genetics, etc.), and nonchemical stressors (e.g., psychosocial stress)

to produce (1) common, readily diagnosed medical diseases (e.g.,

asthma); (2) unusual or nonspecific phenotypes (e.g., erethism and

metallic mercury exposure); or (3) atypical presentations of otherwise

well-characterized disease states, initially considered an undiagnosed

disease (e.g., manganese-induced parkinsonism). The nonspecificity

typical of chemical-induced disease risk is further complicated by lack

of exposure biomarkers for many common environmental toxicants

(e.g., volatile organics), the short half-life of some contaminants (e.g.,

arsenic), and the possibility of decades long latency between exposure

and disease onset (e.g., chemical carcinogenesis or dietary exposures

to specific biochemical risk factors for atherothrombosis). In addition,

we live in an era in which new chemicals are introduced into consumer

products and the environment at a pace well beyond our capacity to

characterize their toxicity. Within this context, one of the most powerful tools for ascertaining chemical-related disease risk is a systematic

exposure history. Although there are no standardized instruments for

this purpose, there are published guidelines to implement exposure

assessments (Goldman and Peters, 1981; see “Further Reading” below).

These include a multistep approach to exposure assessment including

a job history; a review of exposures at work and at home or via hobbies

and recreation; ascertainment of any temporal relationship of symptoms or disease onset to work, home, or recreational activities; and the

food frequency questionnaire. If this screening identifies a potential

exposure or exposures of concern with respect to patient symptoms

and phenotype, a second step of evaluation involves a more detailed

history to identify specific suspect agents, options for quantitative

environmental exposure assessment (e.g., household tap water sampling, review of workplace Material Safety Data Sheets [MSDSs]) and

biomonitoring, and etiologic plausibility for at least some aspects of the

patient’s phenotype.

The traditional approach to focused external exposure assessment

proposed above does not, however, provide an integrated, quantitative

measure of all exposures over the life course, an exposure characterization of particular interest for the risk of chronic diseases such as cancer

or atherothrombosis. The exposome has been proposed as a promising

means for capturing the totality of human exposure over a lifetime (analogous to the totality of genetic exposure assessed via genomic analyses),

including not only external chemical or dietary/foodome (Barabasi

et al., 2020; see “Further Reading” below) exposures but also internal (e.g.,

metabolic, hormonal, microbiome) influences and psychosocial factors.

However, techniques for measuring the exposome are in relatively early

stages of development, are limited by the substantial variability in human

exposure experience, and have not yet been designed to capture complex

combinations commonly encountered in environmental or occupational

exposure settings (Peters et al., 2012; Wild, 2012; Brunekreef 2013;

Barabasi et al., 2020; see “Further Reading” below). This important element of assessing patients with undiagnosed disease is, however, evolving rapidly and offers the promise of becoming a more formal part of the

evaluation of many patients with undiagnosed disease.

■ ENGAGEMENT OF RESEARCH APPROACHES

Establishing a research collaboration for a patient with undiagnosed disease can be both challenging and rewarding. Time and effort resources

are likely to limit this approach to a subset of patients with particularly

compelling clinical presentations and a strong hypothesis about disease

causation. The process must include early and detailed communication

with the patient. Several approaches may be considered.

Leveraging Phenotypic and Genotypic Similarities For a

patient with a rare or undiagnosed disease and distinct presenting features, finding similarly affected individuals adds substantial benefits.

It can encourage research, provide a community for affected patients,

and improve the chances of finding commonalities in pathogenesis

and therapeutic strategies. Phenotypic aggregation may also allow the

patient to connect with consortia invested in related medical presentations. Examples include organizations dedicated to the study of related

diseases such as leukodystrophies, autoinflammatory disorders, and

even undiagnosed diseases, NORD, the National Organization for Rare

Disorders (rarediseases.org) can be a useful starting point. The Office

of Rare Disease Research within the National Center for Advancing

Translational Science supports consortia under the Rare Disease Clinical Research Network program. Building patient cohorts may also be

based on specific biological mechanisms or pathways, for example, the

United Mitochondrial Disease Foundation.

Data Sharing The proliferation of DNA sequencing technology and

the subsequent generation of many DNA variants of unknown clinical

significance have prompted the creation of data-sharing resources specifically designed to match similar cases submitted by clinicians and

researchers around the world. For example, a clinical exome report

may identify variants in a gene with a potential but unproven relationship to the patient’s presenting illness. The clinician could enter the

gene name into a gene-matching database, and if the same gene name

had been already entered by a different submitter, the database would

flag a match and send contact information to both submitters. The

matching procedure has the potential to identify additional cases of

an ultrarare or newly described condition, while avoiding the sharing

of the patient’s personal health information. Embellishments of this

approach involve inclusion of phenotypic features, data entry by families, and specific details of sequence variants. Example systems include

GeneMatcher, PhenomeCentral, and DECIPHER.

Collaboration Collaborations around undiagnosed disease

patients may take many forms. Studies focusing on related medical

conditions can sometimes be identified using the https://clinicaltrials.

gov website, which lists many U.S. and non-U.S. clinical studies. Databases of clinical information (e.g., this textbook, GeneReviews) can

be used to identify subject matter experts for related conditions. Such

experts can be queried about ongoing studies. In some cases, a willingness to work with consenting families to provide biological specimens

can open additional avenues for collaboration.

■ CHALLENGES

Data Portability Obtaining specimens, data, and records for a

chronically undiagnosed patient can be time-consuming and challenging. Families may be charged fees for obtaining copies of old studies.

Although continuing advances in record access are occurring, families

should be encouraged to collect and maintain an updated collection

of medical records. These should include copies of consultation notes,

original laboratory results, and radiology studies (the latter preferably

in electronic form). These record collections are useful for consultation, second opinions, and transitions between primary providers.

Managing Illness Behaviors, Expectations, and Secondary

Manifestations Patients with undiagnosed diseases may present

in any stage of the grieving process. Coping with uncertainty, loss of

abilities, work, relationships, autonomy, and financial security compound the primary manifestation of the disease. Patients may have a

wide range of expectations about the possible benefits of achieving a

diagnosis, including successful therapy. Patients of reproductive age

may find that their greatest uncertainty surrounds the potential heritability of their disorder, its effects on future reproductive decisions, and

the potential risk it may represent to their children and living relatives.

These factors may be equally or more disabling than the primary illness

and require an individualized and multidisciplinary approach.

CONCLUSION

Chronically undiagnosed diseases present a complex challenge to

patients, medical providers, and society at large. Development of a

comprehensive plan for evaluation, reevaluation, and support requires

a substantial investment of time and effort (Fig. 492-1).

3855 Novel Approaches to Diseases of Unknown Etiology CHAPTER 492

Consultative assessment

Comprehensive review and

re-evaluation of evidence

for prior conclusions

Testing to validate key

results and evaluate new

diagnostic hypotheses

Review new records, signs,

symptoms, and

environmental history

Consider new literature and

availability of new or

updated testing strategies

Consider hypothesisgenerating tests including

genomic sequencing

DIAGNOSIS?

Document reasoning and

supporting evidence

Yes No

Consider collaboration to

explore hypotheses

Work with patient to define

concrete follow-up plan

Reformulate differential

diagnosis

Iterative assessment

No diagnosis after

comprehensive evaluation

Symptomatic care,

consider empiric treatments

FIGURE 492-1 Approach to the patient with an undiagnosed disease.

Achieving an accurate diagnosis removes at least one level of uncertainty and allows for disease-specific counseling, therapies, resources,

community engagement, and advocacy opportunities otherwise not

afforded to undiagnosed patients.

■ FURTHER READING

Adams DR, Eng CM: Next-generation sequencing to diagnose suspected genetic disorders. N Engl J Med 379:1353, 2018.

Barabasi AL et al: The unmapped chemical complexity of our diet.

Nat Food 1:33, 2020.

Brunekreef B: Commentary: Exposure science, the exposome, and

public health. Environ Mol Mutagen 54:596, 2013.

Goldman RH, Peters JM: The occupational and environmental

health history. JAMA 246:2831, 1981.

Lee CE et al: Rare genetic diseases: Nature’s experiments on human

development. iScience 23:101123, 2020.

Peters A et al: Understanding the link between environmental exposures and health: Does the exposome promise too much? J Epidemiol

Community Health 66:103, 2012.

Splinter K et al: Effect of genetic diagnosis on patients with previously

undiagnosed disease. N Engl J Med 379:2131, 2018.

Wild CP: The exposome: From concept to utility. Review. Int J Epidemiol

41:24, 2012.

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Index

in intestinal ischemia, 2507

in intestinal obstruction, 2510

in malabsorption disorders, 2468t

mechanisms of, 108, 109t

in pancreatic cancer, 658

in pancreatitis, 111, 111t, 2659, 2666–2667, 2668

in pelvic inflammatory disease, 1087

in peptic ulcer disease, 2441

in peritonitis, 1054–1055, 2516

referred, 109t, 110

Abdominal paracentesis, 323, 324, 489

Abdominal reflexes, 3281

Abdominal wall disorders, 110

Abdominojugular reflex, 1817, 1937

Abducens nerve, 3279

Abducens nerve palsy, 230, V3

Abducens nerve paresis, 229

Abduction and external rotation test, 2112

Abemaciclib, 513t, 548t, 552, 613t, 624

Aβ (amyloid beta)

in AD, 3302, 3370–3372, 3372f, 3373f

circadian fluctuations in accumulation of, 3809

in neurodegenerative diseases, 3298–3299, 3299t,

3422

in protein aggregation and cell death, 3297, 3297f

as therapeutic target, 3374, 3375

Aβ amyloidosis, 878

Aβ antibodies, 3375

Aβ fibers, 91

Abetalipoproteinemia (acanthocytosis, BassenKornzweig syndrome)

clinical features of, 304, 3139t, 3145

genetic considerations in, 3145, 3145t, 3426

pathophysiology of, 2463, 3145, 3426

peripheral blood smear in, 425, 428f

retinitis pigmentosa, 227

treatment of, 2532

vitamin D deficiency in, 2531

Aβ2

M amyloidosis, 878, 878t, 883. See also

Amyloidosis

Aβ/tau protein, 191t, 193–194

Aβ vaccine, 3375

ABI (ankle-brachial index), 2076, 2108

Abiotrophia spp., 1028, 1196

Abiraterone, 544, 687, 687f, 688

ABL1 gene mutations, 820–821

Ablation

alcohol septal, A11

catheter-based. See Catheter-based ablation

with stereotactic radiation, 1923, 1923f

ABL gene mutations, 500t, 501

ABO RBC blood group system, 884, 887, 887t

Abortion, 1304, 1353, 1443, 3037

Abortive infection, 1457

ABPA. See Allergic bronchopulmonary

aspergillosis (ABPA)

Abruptio placenta, 3763

Abscess

anorectal, 2504–2505, 2504f

brain. See Brain abscess

epidural. See Epidural abscess

head and neck, 254–255

intraabdominal. See Intraabdominal abscess/

infections

periapical, 256

peritonsillar, 255, 1351

perivalvular, 1024

retropharyngeal, 255

submandibular, 255

subperiosteal, 251

tuboovarian, 1342, 1342f, 1353

Abscopal effect, 463

Absence seizures, 3306–3307, 3315f

Absent (vanishing) testis syndrome, 3002

Absolute risk reduction, 29

Absorption

of antibacterial drugs, 1150

of carbohydrates, 2460

disorders of. See Malabsorption disorders

of drugs, 466, 1150

of lipids, 2459–2460, 2460f, 2460t

luminal phase, 2458, 2460

overview of, 2459

post-mucosal, 2458, 2466

of proteins, 2460

small intestinal mucosal phase, 2458, 2462

Absorption spectrum, 417

Abstract thought, assessment of, 3279

Abulia, 183, 3327, 3327f

ABVD regimen, 853–854

ACA (Affordable Care Act), 44

Acalabrutinib, 513t, 544, 545t, 839, 850, 877

Acalculia, 198

Acamprosate, 2626, 3562

Acanthamoeba spp., 1718, S12

Acanthamoeba spp. infections

clinical features of, 1719

chronic meningitis, 1114t

keratitis, 220, 1698, 1699t, 1719

meningoencephalitis, 1097, 1719

seizures, 1699t

diagnosis of, 1719, 1719f, S12

epidemiology of, 1718, S12

invasive, 1698

treatment of, 1719

Acanthocytes, 425, 428f

Acanthocytosis. See Abetalipoproteinemia

Acantholysis, 400

Acanthosis, 2119f, 2696t

Acanthosis nigricans

anti-insulin receptor antibodies in, 2996

in diabetes mellitus, 3101, 3126

disorders associated with, 390, 599, A5,

A15

hyperpigmentation in, 390, A5

in metabolic syndrome, 3154

in obesity, 3086

Acarbose, 2452, 3110t

Accelerated idioventricular rhythm (AIVR), 1910f,

1917, 1917f, 2063, A8

Accelerated junctional rhythm, 1896, 2063

Accessory pathways (APs)

arrhythmias associated with, 1896

characteristics of, 1896

in preexcited tachycardias, 1897, 1898f

treatment of, 1897–1898

in Wolff-Parkinson-White syndrome. See WolffParkinson-White syndrome

AA amyloidosis, 882

clinical features of, 878t, 882, 2335t, 2336t

diagnosis of, 879f, 2345

etiology of, 882

incidence of, 882

pathogenesis of, 2345

treatment of, 882, 2345

AAG (autoimmune autonomic ganglionopathy), 3434

AAS abuse. See Anabolic-androgenic steroid (AAS)

abuse

AAT. See α1

-Antitrypsin (AAT)

AAV (adeno-associated virus), 644, 3415, 3685t, 3688

AAV-LPL, 3688

Abacavir

adverse effects of

genetic considerations in, 409, 1555, 1573

in HIV infection, 1573, 1587t

hypersensitivity, 412, 1573. See also Druginduced hypersensitivity syndrome

(DIHS)

genetic variations in response to, 477t, 478, 479

for HIV infection, 1587t

molecular structure of, 1590f

resistance to, 1592f

Abaloparatide, 3207–3208

A band, of sarcomere, 1803–1804

Abatacept, 2707t, 2762t, 2763, 2784, 2808, 2812

ABAT deficiency, 3269t

ABCA1 deficiency (Tangier disease), 1816, 3139t,

3146, 3487

ABCB1, 475t, 478

ABCB6 gene mutations, 396, 779t, 781

ABCD1 gene mutations, 3293, 3414t

ABCD2

score, 3344, 3344t

ABCDE rule, 580, A5

ABCG5/G8 gene mutations, 3141

ABCG5/G8 hemitransporter, 2641

Abciximab

actions of, 925f, 927–928

adverse effects of, 905–906, 905t, 928

discontinuation before lumbar puncture, S9

dosage of, 928

genetic variations in response to, 922t

indications for, 928

in PCI, 2066

pharmacology of, 928t

Abdomen

paradoxical movement of, 266

physical examination of, 321–322, 1816

swelling/distention of, 321, 322f, 2510. See also

Ascites

Abdominal aortic aneurysm. See Aortic aneurysm,

abdominal

Abdominal pain, 108

in acute intermittent porphyria, 3243

in appendicitis, 2514, 2514t

approach to the patient, 108t, 111–112

differential diagnosis of, 111t, 2382–2383, 2382t

in Fabry disease, 3258

history in, 111

in IBS, 2490

imaging in, 112

in immunocompromised patients, 110

Page numbers in bold indicate the start of the main discussion of the topic. Page numbers followed by “f ” or “t” refer to the page location of figures and tables,

respectively. Location entries starting with “A”(Atlases), “S” (Supplemental chapters), or “V” (Video chapters) indicate online-only chapter numbers; this content

available to all Harrison’s readers at www.accessmedicine.com/harrisons. Index entries that end with a “v” represent book page numbers where video content is

referenced.

INDEX

I-2 Accidents, 73t

ACD gene mutations, 3682t

ACE. See Angiotensin-converting enzyme (ACE)

ACE2, 3796

Acebutolol, 2040t, 3591t

ACE inhibitors. See Angiotensin-converting

enzyme (ACE) inhibitors

Acephalgic migraine, 3325, 3357

Aceruloplasminemia, 2533, 3232

Acetaminophen

for acute otitis media, 250

adverse effects of

hepatotoxicity, 472, 2586t, 2588, 2589f, A13

metabolic acidosis, 363

nephrotoxicity, 94

thrombocytopenia, 905t

for back pain, 123, 125

drug interactions of, 540t, 1400, 2861t

metabolism of, 2588

for migraine, 3362t

for osteoarthritis, 2861, 2861t

for osteoarthritis in older adults, 3747

overdosage/poisoning with, 2588–2589

for pain, 78, 78f, 94–96, 95t

as premedication for rituximab, 575

for prevention of acute mountain sickness, 3619

for SLE-related pain, 2746

for spinal stenosis, 121

for tension-type headache, 3365

for upper respiratory infection, 249

Acetaminophen-aspirin-caffeine, 3361, 3362t

Acetanilide, 784t

Acetazolamide

actions of, 2291

for acute angle-closure glaucoma, 221

adverse effects of, 340, 366–367, 410, 2281, 3619

for altitude illness, 3618, 3618t, 3620, 3621

for episodic ataxia, 3425

for heart failure, 1946t

for hyperkalemic periodic paralysis, 3530

for hypokalemic periodic paralysis, 3530

for metabolic alkalosis, 366

for paroxysmal symptoms in MS, 3474

for pseudotumor cerebri, 224

for raised CSF pressure headache, 116

for salicylate-induced acidosis, 362

for tumoral calcinosis, 3217

for uric acid nephropathy, 3252

Acetoacetate, 360

Acetylcholine (ACh), 288, 297, 3427

Acetylcholine receptor (AChR)

in congenital myasthenic syndromes, 3511–3512,

3512t

in myasthenia gravis, 2696t, 2735, 3509–3510, 3511

Acetylcholine receptor (AChR) antibodies, 729t

Acetylcholinesterase (AChE), 3511, 3512t

Acetylcholinesterase (AChE) inhibitors

for gastroparesis, 293, 294t

nerve agents as, S4

overdosage/poisoning with, 3592t

for snakebite treatment, 3599, 3601t

Acetyl-CoA, 3793

N-Acetylglutamate synthase deficiency, 3270t,

3273

N-Acetyltransferase, 467t

Achalasia, 2427

chronic, esophageal cancer and, 626

clinical features of, 2427

diagnosis of, 2427, 2427f

differential diagnosis of, 2427

dysphagia in, 289

LES relaxation impairment in, 2427, 2428f

subtypes of, 2428f

treatment of, 2396, 2397f, 2427–2428

Achilles bursitis, 2878

Achondrodysplasia, 3216, 3646

Achondroplasia, 3228

AChR. See Acetylcholine receptor (AChR)

Achromatopsia, 202, 218

Achromobacter xylosoxidans, 1248, 1248t

Acid anhydride exposure, 2171, 2171t

Acid-base disorders, 359, 359t, 360t, S1. See also

specific disorders

Acid-base homeostasis, 359

Acid-base nomogram, 359–360, 359f

Acidemia, 2659, 3268

Acid ethyl esters, 3142t

Acid-fast bacteria, S11

Acid fume exposure, 2171t

Acid maltase (acid α-glucosidase) deficiency. See

Pompe disease

Aciduria, orotic, 3253t, 3254

Acinetobacter spp., 1275

Acinetobacter spp. infections, 1275

antibiotic resistance in, 1135, 1168t, 1169, 1276,

1277–1278

bloodstream, 1277

in cancer patient, 558t, 559

clinical features of, 1276–1277

community-acquired, 1276

complications of, 1278

diagnosis of, 1275, S11

in disasters, 1276

epidemiology of, 1275–1276

etiology of, 1275

health care–associated, 1275–1276

infection control and prevention of, 1278–1279,

1278f

meningitis, 1277

pathogenesis of, 1276

pneumonia, 1276–1277

prognosis of, 1278

in returning war veterans, 1276, S6

skin and soft tissue, 1277

treatment of, 1156–1157t, 1277–1278, 1278t, S6

urinary tract, 1071, 1277

ventilator-associated pneumonia, 1017–1018,

1130

ACIP (Advisory Committee on Immunization

Practices), 982

Acitretin, 378, 378t, 384, 385t, 410

aCL (anticardiolipin), 2745, 2749t

Acneiform eruptions, 385–386, 387t

Acne rosacea, 382

clinical features of, 370t, 372f, 382, 382f, 386, A5

complications of, 383

differential diagnosis of, 385–386

treatment of, 383

Acne vulgaris, 381

clinical features of, 370t, 372f, 381–382, 382f,

395, A5

drugs exacerbating, 409

folliculitis in, 1035

pathophysiology of, 382

treatment of, 382

Acotiamide, 297

Acoustic neuroma. See Vestibular schwannoma

(acoustic neuroma)

Acoustic reflex, 245

Acoustic reflex decay, 245

Acral angiodermatitis, 398

Acral erythema, drug-induced, 410

Acrocephalopolysyndactyly (Pfeiffer’s syndrome),

3649

Acrochordon, 370t, 372f, 390

Acrocyanosis, 1815, 2113f, 2114

Acrodermatitis chronica atrophicans, 1428

Acrodermatitis enteropathica, 2532

Acrodysostosis, 3189–3190, 3189t

Acrolein exposure, 2171t

Acromegaly, 2912

clinical features of, 2912, 2913f, 3531

arthropathy, 2871

cutaneous, 390

hirsutism, 3039

hypertension, 2080

oral, 256–257

skeletal, A15

diagnosis of, 2912

etiology of, 2871, 2912, 2912t

familial, 2908

laboratory investigation of, 2904t, 2912

vs. pachydermoperiostosis, 3215–3216

paraneoplastic, 722t

treatment of, 2912–2914, 2914f

Acro-osteolysis, 2779, 2779f

Acropachy, thyroid, 2876, 2939f, 2940

Acroparesthesia, in Fabry disease, 3258

Acrylamide, 3495t

ActA, 1209

ACTA2 gene mutations, 3229t, A16

ACTH. See Adrenocorticotropic hormone (ACTH)

ACTHoma, 664t, 665

ACTH stimulation test, 2956

Actin, 1804, 1804f, 1957f, 2696t

Actinic cheilitis, 587, 587f

Actinic dermatitis, 422

Actinic keratosis

clinical features of, 371t, 372f, 587f, A5

conversion of, 587

malignant conversion of, 419

sun avoidance and, 491

treatment of, 418

Actinic prurigo, 421

Actinobacillus spp. See Aggregatibacter spp.

Actinomyces spp., 1340. See also Actinomycosis

Actinomyces-like organisms, 1342

Actinomycetoma, nocardial, 1338, 1338f, 1339,

1339t, 1340. See also Nocardia spp.

infections

Actinomycosis, 1340

clinical features of

abdominal, 1341–1342

CNS, 1113t, 1342

disseminated, 1342–1343

in dog-bite wound, 1124

hepatic-splenic, 1342, 1342f

musculoskeletal and soft tissue, 1342

oral-cervicofacial, 258t, 261, 1341, 1341f, 1354

pelvic, 1342, 1342f

thoracic, 1341, 1341f

diagnosis of, 1343, S11

epidemiology of, 1340

etiology of, 1340

pathogenesis of, 1341

treatment of, 1343–1344, 1343t

Action potentials, cardiac, 1806, 1866–1868, 1867f,

1869, 1874f

Action spectrum, 417

Activase. See Alteplase (rtPA)

Activated charcoal, 297, 3588, 3589, 3607

Activated partial thromboplastin time (aPTT)

causes of abnormal values, 456t

in coagulation disorders, 911, 911t, 912

coagulation factors tested in, 455, 455f, 911f

LA-PTT, 456

INDEX

for monitoring heparin therapy, 930 I-3

in preoperative testing, 456

prolonged, 456t

reagent composition of, 456

Active surveillance

in prostate cancer, 685–686

in testicular cancer, 691

Active transport, 2290

Activin, 2895

Acupressure, 294, 2386

Acupuncture, 126, 129, 3785t, 3787, 3788

Acustimulation, 2386

Acute brain failure. See Delirium

Acute cellular rejection, 1974, 2213

Acute chest syndrome, 760

Acute confusional state. See Delirium

Acute coronary syndromes

diagnosis of, 2053, 2053f

evaluation and management of, 2047f

global considerations in, 2052

hyperbaric oxygen therapy for, 3626t

myocardial infarction

non-ST-segment elevation. See Non-STsegment elevation acute coronary

syndrome (NSTE-ACS)

ST-segment elevation. See ST-segment

elevation myocardial infarction (STEMI)

PCI for, 2069. See also Percutaneous coronary

interventions (PCI)

pulmonary edema in, 2256

unstable angina, 100, 101t, 2046. See also NonST-segment elevation acute coronary

syndrome (NSTE-ACS)

venous thromboembolism and, 2093, 2094f

Acute disease- or injury-associated malnutrition,

2535

Acute disseminated encephalomyelitis (ADEM),

3476, A16

Acute febrile illness, 973

approach to the patient, 974

clinical presentations of, 974–980, 975t

diagnostic workup in, 974

history in, 974

physical examination in, 974

rashes associated with, A1

treatment of, 974, 975t

Acute febrile neutrophilic dermatosis. See Sweet

syndrome

Acute generalized eruptive/exanthematous

pustulosis (AGEP)

clinical features of, 138t, 386, 414, 414f, 416t, A1

differential diagnosis of, 143, 414

drugs associated with, 414, 416t

immune pathways of, 408t

Acute HIV syndrome, 1540, 1562, 1569f, 1569t.

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