Adipsia: Understanding the Absence of Thirst

Thirst serves as one of the most fundamental homeostatic drives in mammalian biology, ensuring fluid balance, cardiovascular stability, and cellular integrity. When this protective biological alarm fails entirely, the resulting condition—known clinically as adipsia—presents a profound physiological challenge capable of precipitating severe, life-threatening hyperosmolality. This comprehensive academic guide provides an exhaustive clinical and neurobiological overview of adipsia, analyzing its underlying neuroanatomy, diagnostic evaluation, and complex management pathways.

Adipsia

1. Concise Definition

Adipsia is a severe physiological and neurological disorder characterized by the complete absence of thirst and a corresponding failure to drink water, even in the presence of life-threatening hyperosmolality and cellular dehydration. Unlike transient disinterest in fluids, true adipsia represents a structural or functional disruption within the central osmoregulatory networks of the brain, particularly involving the anterior hypothalamus and lamina terminalis.

In individuals with adipsia, the physiological signals that ordinarily trigger fluid-seeking behaviors—such as elevated effective plasma osmolality, hypovolemia, and elevated circulating levels of angiotensin II—fail to register consciously or stimulate behavioral action. Consequently, patients do not experience dry mouth, craving for liquids, or the conscious imperative to consume fluids. Without structured, external behavioral interventions or scheduled fluid intake protocols, adipsia leads inexorably to extreme hypernatremia, renal failure, lethargy, encephalopathy, seizures, coma, and eventual death.

Clinically, adipsia is distinguished from hypodipsia, which represents an attenuated or elevated threshold of thirst perception rather than a complete absence. While hypodipsic individuals drink inadequate volumes or only respond when dehydration becomes exceptionally severe, adipsic individuals demonstrate a total detachment between systemic hydrational status and the perception of thirst, maintaining an absence of thirst sensation across all osmolar physiological gradients.

2. Etymology & Linguistic Origin

The term adipsia derives directly from classical Greek roots, constructed through the combination of the privative prefix a- (ἀ-), meaning “without,” “lacking,” or “absence of,” and the nominal root dipsa (δίψα), signifying “thirst.” The suffix -ia (-ία) is an abstract noun-forming element frequently utilized in classical medical Latin and Greek to designate a pathological condition, bodily state, or clinical disease.

Linguistically, the term mirrors parallel pathophysiological nomenclature such as aphasia (absence of speech) or anorexia (absence of appetite). In historical medical literature, early Greek and Roman physicians used related cognates to describe states of abnormal hydration, though precise clinical usage defining the pathological loss of thirst emerged during the nineteenth century as experimental physiologists began localizing vegetative regulatory centers within the central nervous system. The term was formally integrated into modern neurological and endocrinological lexicons following early twentieth-century ablation experiments in animal models and clinical case reports of hypothalamic damage.

3. Pronunciation & Grammatical Form

Pronunciation: Phonetically transcribed in the International Phonetic Alphabet (IPA) as /eɪˈdɪp.si.ə/ or /əˈdɪp.si.ə/. The stress falls primarily on the second syllable: ay-DIP-see-uh or uh-DIP-see-uh.

Grammatical Form:

• Part of Speech: Uncountable noun.
• Adjectival Form: Adipsic (/eɪˈdɪp.sɪk/), referring to an organism, behavior, or physiological state characterized by the absence of thirst (e.g., “an adipsic patient,” “adipsic hypernatremia”).
• Synonymous / Variant Stems: Occasionally paired with pathological modifiers, such as adipsic diabetes insipidus or neurogenic adipsia.
• Syntactic Usage: It functions predominantly as a diagnostic label, a subject, or an object describing a neurological symptom or syndrome within physiological, pediatric, endocrinological, and neurosurgical contexts.

4. Detailed Conceptual Explanation

To comprehend the pathophysiology of adipsia, one must first delineate the standard neurobiology of fluid homeostasis. Under normal conditions, systemic hydration is defended through two interconnected systems: the neuroendocrine secretion of arginine vasopressin (AVP, also termed antidiuretic hormone) by the neurohypophysis, and the conscious behavioral drive of thirst. Both mechanisms are governed by specialized osmoreceptor neurons clustered in the circumventricular organs of the lamina terminalis, specifically the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO).

Because the OVLT and SFO reside outside the blood-brain barrier, their specialized primary sensory neurons are uniquely positioned to monitor minute fluctuations in systemic sodium concentration and effective blood osmolality. When dehydration raises plasma osmolality above the standard threshold (typically 280 to 285 mOsm/kg), these osmosensitive cells shrink mechanically due to osmotic water movement. This mechanotransductive deformation opens stretch-inactivated cation channels, causing neuronal depolarization. Signals are subsequently transmitted along efferent pathways to the median preoptic nucleus (MnPO), which coordinates homeostatic autonomic outflow and projects rostrally to the anterior cingulate cortex and the insular cortex, generating the conscious sensation of thirst.

In genuine adipsia, this complex afferent pathway or its cortical integration is damaged. The disruption can arise from structural destruction of the lamina terminalis, vascular infarction, congenital dysgenesis, granulomatous infiltration, or mechanical compression caused by suprasellar neoplasms such as craniopharyngiomas or anterior communicating artery aneurysms. When these osmoreceptive networks are obliterated, the brain remains blind to systemic hypertonicity. Plasma osmolality may climb beyond 320 to 350 mOsm/kg—levels that would induce overwhelming, unendurable thirst in a healthy person—yet the individual feels no thirst whatsoever.

The conceptual scope of adipsia must also be delineated from psychogenic or deliberate fluid restriction. An individual fasting or refusing liquids due to a psychiatric condition (such as catatonia or delusional depression) perceives thirst at a somatic level but suppresses or fails to act upon the urge due to affective or cognitive disturbances. In contrast, pure organic adipsia is an absolute interoceptive failure: the afferent conscious sensation of thirst is absent. The patient can drink fluid if commanded or reminded to do so, but without external prompting, they will never spontaneously seek liquid, irrespective of severe mucosal drying, hypovolemic orthostasis, or critically elevated serum sodium levels.

5. Historical Development

The systematic exploration of thirst mechanisms and their pathological absence began in the mid-twentieth century through pioneering neurophysiological investigations. Historically, dehydration and polyuria were well documented, but thirst was frequently viewed merely as a local peripheral sensation originating from dryness of the pharyngeal mucosa—a hypothesis championed by Walter Cannon in the early twentieth century. This peripheral theory was challenged by classic ablation experiments performed in animals during the 1940s and 1950s.

In the early 1950s, Swedish physiologist Bengt Andersson performed landmark experiments demonstrating that microinjections of hypertonic saline into the anterior hypothalamus of goats elicited immediate, ravenous drinking behavior, whereas electrical stimulation of these discrete areas drove animals to drink enormous quantities of water. Conversely, bilateral electrolytic lesions placed in these circumscribed hypothalamic loci abolished spontaneous drinking, producing the first experimentally created models of animal adipsia. Andersson’s work conclusively proved that thirst is orchestrated centrally within the hypothalamus rather than peripherally in the oral cavity.

In the late 1960s and 1970s, endocrinologist Gary L. Robertson and colleagues formalized the clinical, osmometric classification of osmoregulatory syndromes in human patients. Robertson developed precise radioimmunoassays for arginine vasopressin and correlated circulating hormone titers directly with plasma osmolality during hypertonic saline infusions. Through this rigorous quantitative methodology, Robertson identified human patients presenting with idiopathic or post-surgical chronic hypernatremia who exhibited a total dissociation between plasma sodium concentrations and vasopressin release, coupled with complete absence of thirst. Robertson classified this spectrum, identifying Type A through Type D osmoregulatory defects, solidifying “adipsic hypernatremia” as an identifiable clinical entity distinct from classic central diabetes insipidus.

6. Theoretical Foundations

The study of adipsia is grounded in the cybernetic framework of homeostatic drive and interoceptive predictive coding. Homeostasis, formalized by Walter Cannon following Claude Bernard’s conception of the milieu intérieur, posits that vital systems maintain physiological variables within narrow, life-sustaining boundaries via negative feedback loops. Thirst operates as a prime homeostatic drive: deviations from an internal set point initiate an aversive motivational state (thirst) that drives specific corrective behaviors (drinking) until the perturbation is restored.

Modern neurocomputational models have refined this understanding by incorporating principles of allostasis and predictive regulation. Researchers have demonstrated that the lamina terminalis does not merely respond reactively to osmotic shifts; it computes prospective hydrational changes. For instance, cold water contacting receptors in the oral cavity and oropharynx triggers an immediate, presystemic cessation of firing in thirst neurons in the SFO and OVLT long before the consumed fluid is absorbed across the intestinal epithelium into the bloodstream. This predictive inhibition prevents overdrinking and osmotic shock.

In theoretical frameworks of adipsia, this entire cybernetic apparatus fails due to neural circuitry degradation. Adipsia represents an interruption along the interoceptive axis that translates visceral state detection into motivational salience. Within Antonio Damasio’s somatic marker framework or A.D. (Bud) Craig’s neuroanatomical model of interoception, internal bodily states are projected to the posterior and anterior insular cortices to generate subjective emotional and motivational states. When hypothalamic and circumventricular nuclei fail to send signals rostrally, or when pathways connecting the limbic system and insular cortex are severed, the physiological imperative is never translated into subjective awareness, leaving the organism without the internal motivation to seek hydration.

7. Key Components, Types & Dimensions

Adipsia is not a homogenous presentation; it encompasses varied clinical configurations based on neuroanatomical etiology, concurrent endocrinopathies, and the degree of osmoreceptor destruction:

• Congenital vs. Acquired Adipsia: Congenital forms arise from developmental malformations of the midline forebrain, including holoprosencephaly, septo-optic dysplasia (de Morsier syndrome), or agenesis of the corpus callosum with associated hypothalamic dysgenesis. Acquired adipsia occurs secondary to acute structural insults, such as head trauma, neurosurgical resection of suprasellar tumors, subarachnoid hemorrhage, or inflammatory conditions.
• Adipsic Diabetes Insipidus (ADI): The most complex and hazardous clinical subtype, wherein patients lack both the conscious sensation of thirst and the neurohypophyseal capacity to synthesize or secrete arginine vasopressin. Consequently, these individuals lose massive quantities of dilute urine while remaining entirely unmotivated to drink, leading to rapid, life-threatening hypernatremic dehydration unless treated with exogenous vasopressin analogs and strict fluid schedules.
• Adipsia with Preserved Vasopressin Secretion: A rarer phenotype in which the osmoreceptors controlling thirst are selectively destroyed, but the sub-populations of osmoreceptive neurons regulating vasopressin secretion in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) remain partially intact. In such patients, the kidneys can still concentrate urine during hyperosmolality, yet the subjective drive to consume fluids remains absent.
• Reset Osmostat (Hypodipsia vs. Adipsia): A related dimension in which the osmotic threshold for thirst is reset upward to an abnormally high plateau. The individual experiences no thirst within the normal physiological range (280–295 mOsm/kg), developing mild thirst only when plasma osmolality reaches high thresholds (e.g., >310 mOsm/kg). True adipsia represents the end-stage anchor of this continuum, where the threshold is effectively infinite.
• Secondary / Psychogenic Adipsia: A functional cessation of water intake observed in profound psychiatric illness, including severe catatonia, end-stage dementia, or severe neurological motor apraxia, where the primary osmoreceptor apparatus remains physically intact but executive or motivational access is blocked.

8. Examples & Illustrative Cases

The clinical manifestations of adipsia are best understood through real-world medical scenarios that illustrate its presentation, diagnostic challenges, and management dilemmas:

Case Illustration 1: Post-Surgical Resection of Craniopharyngioma. A 24-year-old patient underwent a transbasal surgical excision of a large retrochiasmatic craniopharyngioma. Following surgery, the patient exhibited polyuria with high urine output (exceeding 6 liters daily) with low urine osmolality (85 mOsm/kg), confirming central diabetes insipidus. Desmopressin (DDAVP) was initiated. However, despite a documented serum sodium level rising to 168 mmol/L and serum osmolality reaching 345 mOsm/kg, the patient repeatedly denied experiencing thirst, describing their mouth as comfortable and consistently refusing offered fluids. Without scheduled oral water intake and carefully managed parenteral hypotonic infusions, the patient experienced hypernatremic delirium. This presentation prompted a permanent diagnosis of adipsic diabetes insipidus, requiring lifelong fixed-volume fluid prescription coupled with daily body weight tracking.

Case Illustration 2: Anterior Communicating Artery (ACoA) Aneurysm Rupture. A 52-year-old patient experienced a severe subarachnoid hemorrhage secondary to the rupture of an ACoA aneurysm, requiring endovascular coil embolization. During neuro-intensive care recovery, the patient stabilized hemodynamically but was noted to be uncharacteristically apathetic toward nutrition and hydration. Over a period of four days, the patient’s sodium levels steadily rose to 158 mmol/L. When given a glass of water, the patient drank politely but never initiated drinking independently or expressed a desire for liquids. Subsequent MRI confirmed bilateral microvascular infarction of the anterior commissure, the column of the fornix, and the lamina terminalis, destroying the osmosensing nuclei and resulting in permanent organic adipsia.

9. Measurement & Assessment

Because thirst is an internal, subjective experience, its measurement and the diagnostic verification of adipsia require systematic osmometric challenge testing correlated with subjective visual analog scales and biochemical monitoring:

• Hypertonic Saline Infusion Test: The gold standard diagnostic protocol. A standardized infusion of 3% or 5% sodium chloride is administered intravenously at a regulated rate (e.g., 0.1 mL/kg/min) to elevate serum sodium and osmolality in a controlled setting. Throughout the infusion, serum sodium, plasma osmolality, and plasma vasopressin are sampled every 15 to 30 minutes, while the patient rates their subjective thirst level on a calibrated Visual Analog Scale (VAS) ranging from 0 (“no thirst at all”) to 10 (“the most intense thirst imaginable”). In healthy individuals, thirst increases progressively once plasma osmolality crosses approximately 285–290 mOsm/kg. In patients with true adipsia, the thirst VAS score remains flat at zero despite marked hyperosmolality.
• Water Deprivation Test: Under strict inpatient supervision, fluids are withheld to assess whether endogenous dehydration triggers thirst and concentrated urine. If serum osmolality climbs beyond 300 mOsm/kg without eliciting subjective thirst, adipsia or profound hypodipsia is confirmed. The test must be terminated if body weight drops by more than 3–5% or if severe hypernatremia develops.
• Biochemical Profiling: Routine diagnostic markers include serum electrolytes (specifically hypernatremia, with sodium often exceeding 150–170 mmol/L), serum osmolality, blood urea nitrogen, creatinine, paired urine osmolality, and urine specific gravity.
• Neuroimaging: High-resolution magnetic resonance imaging (MRI) of the brain and pituitary-hypothalamic axis is essential. Clinicians evaluate T1, T2, and thin-cut coronal dynamic sequences through the sella turcica and anterior third ventricle to identify structural lesions, tumors, surgical resections, infarcts, or midline malformations in the lamina terminalis and adjacent circumventricular organs.

10. Applications & Practical Significance

The clinical and operational management of adipsia represents one of the most demanding tasks in clinical endocrinology, neurology, and nursing care. Because the patient cannot rely on internal biological signals, physiological stability must be maintained through conscious, external behavioral regulation.

The Fixed Fluid Prescription: Patients with adipsia must adhere to a strict, daily fluid balance protocol. Clinicians calculate baseline maintenance requirements based on body surface area or weight (typically 1.5 to 2.5 liters daily under temperate conditions), taking into account insensible losses from respiration and perspiration, as well as urine output. Patients are instructed to drink fixed volumes of water at specified intervals throughout the day regardless of how they feel, treating fluid intake like an oral medication.

Body Weight Monitoring: Because environmental temperatures, physical activity, and illness alter water loss unpredictably, fixed fluid prescriptions can lead to either dehydration or fluid overload. Therefore, daily morning weight measurements provide the most reliable surrogate marker of fluid balance. A sudden weight drop of 1 kilogram reflects an acute deficit of approximately one liter of free water, instructing the patient to drink an additional liter of fluid over that day. Conversely, acute weight gain warns of water retention and the risk of hyponatremia, which can be fatal if the patient is simultaneously taking fixed doses of desmopressin.

Multidisciplinary Care Coordination: The management of adipsia requires seamless coordination among endocrinologists, primary care physicians, dietitians, clinical neuropsychologists, and family caregivers. In pediatric populations or individuals with cognitive impairments, the responsibility for administering scheduled fluids rests entirely with parents or trained caregivers, who must remain vigilant for signs of dehydration, heat exhaustion, or acute electrolyte imbalances.

11. Research & Empirical Evidence

Modern neuroscience continues to expand our understanding of the cellular and genetic architecture underlying thirst and its absence. Contemporary optogenetic and chemogenetic studies, primarily spearheaded by researchers such as Charles Zuker and Yuki Oka at the California Institute of Technology and Columbia University, have uncovered distinct neural circuits within the subfornical organ and the median preoptic nucleus that control thirst.

In murine models, researchers identified that distinct populations of excitatory glutamatergic neurons within the SFO (SFO^GLUT) drive water consumption, whereas inhibitory GABAergic neurons (SFO^GABA) suppress it. Optogenetic activation of SFO^GLUT neurons triggers immediate, voracious drinking in fully hydrated mice, whereas optical silencing of these same neurons completely abolishes drinking behavior in severely dehydrated animals, generating an acute, optogenetically induced model of transient adipsia. These investigations confirm that adipsia is not a diffuse cerebral impairment, but can be induced by the targeted inactivation of specific, genetically distinct neural subpopulations.

Clinical outcome registries and cohort analyses, such as historical reviews from major neurosurgical and pituitary centers (e.g., Crowely et al., 2007; Eisenberg et al., 2013), highlight the substantial morbidity associated with adipsic diabetes insipidus following craniopharyngioma resection. These studies demonstrate that patients suffering from combined adipsia and central diabetes insipidus exhibit significantly higher rates of hospital readmission, venous thromboembolism, pulmonary embolism, permanent cognitive decline, and long-term mortality compared to patients with isolated central diabetes insipidus who retain intact thirst mechanisms. This dramatic divergence underscores the protective value of intact thirst perception in human survival.

12. Cultural & Cross-Cultural Considerations

While the underlying neurobiology of adipsia is universal across all human populations, the lived experience, recognition, and daily management of the disorder are influenced by cultural, geographic, and socioeconomic contexts. Environmental temperature and ambient humidity represent direct physical challenges: patients with adipsia who reside in arid, tropical, or seasonally extreme climates face far higher risks of rapid dehydration, requiring localized adjustments to fluid prescriptions.

Cultural dietary patterns also influence fluid management. Diets rich in high-water-content fruits, vegetables, and soups provide baseline hydration that can partially buffer inadequate voluntary drinking. In contrast, diets high in sodium, dry starches, or refined sugars increase obligatory renal solute loads, accelerating hyperosmolar states if scheduled water intake is missed.

Furthermore, cultural rituals centered on communal eating, drinking, and religious fasting (such as Ramadan, Yom Kippur, or Christian Lent) present substantial health risks for individuals with adipsia. Because patients feel no physiological distress when avoiding water, they may unknowingly enter dangerous states of hypertonicity if they participate in religious fasting without medical supervision. Clinical teams working in diverse cultural settings must provide culturally sensitive education, emphasizing to patients, families, and religious authorities that fluid intake for an adipsic individual is not an optional beverage preference, but an indispensable, life-preserving medical therapy.

13. Criticisms, Debates & Limitations

Despite significant advances in neuroendocrinology, several controversies and diagnostic limitations persist regarding adipsia and its management:

• Diagnostic Ambiguity: Distinguishing between complete adipsia, high-threshold hypodipsia, and executive dysfunction remains challenging. In individuals with frontal lobe damage or cognitive impairment following brain injury, fluid neglect is common. Determining whether an unmotivated patient lacks the raw interoceptive sensation of thirst or instead possesses intact sensation but lacks the executive ability to initiate drinking requires complex diagnostic testing that is rarely performed outside specialized academic centers.
• Safety Risks of the Hypertonic Saline Test: The standard diagnostic protocol—intravenous hypertonic saline challenge—carries clinical risks. In elderly patients or those with underlying cardiopulmonary disease, the rapid induction of acute hypertonicity can precipitate heart failure, hypertension, or pulmonary edema. As a result, many clinicians diagnose adipsia empirically through spontaneous electrolyte patterns and clinical history, bypassing formal quantitative testing.
• Desmopressin Dosing in Adipsic Diabetes Insipidus: A major clinical dilemma is how best to dose desmopressin in the absence of thirst. In classic central diabetes insipidus, patients titrate their own fluid intake against their medication: when DDAVP wears off, polyuria returns, they become thirsty, drink water, and take their next dose. In adipsic patients, this protective feedback loop is gone. Fixed desmopressin administration coupled with scheduled water intake carries a high risk of accidental water intoxication (hyponatremia) if fluid intake exceeds output, or hypernatremic dehydration if fluid intake is missed. Clinicians continue to debate whether to allow periodic “breakthrough” polyuria before administering subsequent desmopressin doses or to maintain tight algorithmic control with daily laboratory testing.

14. Related Terms & Distinctions

To avoid diagnostic errors, adipsia must be carefully differentiated from related physiological and clinical terms:

• Hypodipsia: Characterized by an abnormally diminished, but not entirely absent, sensation of thirst. Individuals with hypodipsia have an elevated osmotic threshold for thirst activation, but retain the ability to experience thirst when systemic dehydration becomes severe.
• Polydipsia: The exact clinical opposite of adipsia, defined as excessive, insatiable thirst. Polydipsia can be secondary to uncontrolled diabetes mellitus, classic diabetes insipidus, or psychogenic polydipsia (compulsive water drinking unrelated to osmotic signals).
• Diabetes Insipidus (Central / Cranial): A disorder caused by inadequate synthesis or secretion of vasopressin from the neurohypophysis, leading to large volumes of dilute urine (polyuria). Most patients with isolated diabetes insipidus have intact, highly active thirst (compensatory polydipsia) and maintain normal serum sodium if given access to water; adipsia only occurs if the thirst osmoreceptors are simultaneously destroyed.
• Anorexia: The loss of appetite or desire for food. While both adipsia and anorexia represent disruptions of nutritional homeostasis, they involve distinct hypothalamic regulatory systems, with anorexia primarily mediated by the arcuate nucleus, pro-opiomelanocortin (POMC), and neuropeptide Y (NPY) systems.
• Oligodipsia: A descriptive, occasionally used variant referring to infrequent fluid intake, which may arise from behavioral habits rather than organic neuroanatomical damage.

15. Summary & Key Takeaways

Adipsia is a severe, life-threatening disorder characterized by the complete absence of the thirst drive, arising from structural, congenital, or acquired damage to the central osmoregulatory networks within the anterior hypothalamus and lamina terminalis. Without conscious interoceptive feedback to guide fluid balance, adipsic individuals are vulnerable to acute hyperosmolar dehydration and severe hypernatremia.

Management requires shifting fluid regulation from automatic internal biological drives to structured external behavioral regimens. By pairing scheduled daily fluid intake with routine morning weight monitoring and careful electrolyte tracking, clinicians and patients can successfully manage the complications of adipsia, preventing hypernatremic crises and maintaining long-term physiological stability.

References

• Andersson, B. (1953). The effect of injections of hypertonic NaCl-solutions into different parts of the hypothalamus of goats. Acta Physiologica Scandinavica, 28(2-3), 188–201. https://doi.org/10.1111/j.1748-1716.1953.tb00969.x
• Baylis, P. H., & Thompson, C. J. (1988). Osmoregulation of vasopressin secretion and thirst in health and disease. Clinical Endocrinology, 29(5), 549–576. https://doi.org/10.1111/j.1365-2265.1988.tb03704.x
• Crowley, R. K., Sherlock, M., Agha, A., Smith, D., & Thompson, C. J. (2007). Clinical insights into adipsic diabetes insipidus. The Journal of Clinical Endocrinology & Metabolism, 92(3), 853–858. https://doi.org/10.1210/jc.2006-2005
• Eisenberg, A., Stern, N., & Gafni, R. (2013). Adipsic diabetes insipidus: A challenging condition. Pituitary, 16(4), 518–526. https://doi.org/10.1007/s11102-012-0448-4
• McKinley, M. J., & Johnson, A. K. (2004). The physiological regulation of thirst and fluid intake. Physiology & Behavior, 19(1), 1–19. https://doi.org/10.1152/physiol.00007.2004
• Oka, Y., Ye, M., & Zuker, C. S. (2015). Thirst driving and quenching circuits associated with the subfornical organ. Nature, 520(7547), 349–352. https://doi.org/10.1038/nature14108
• Robertson, G. L. (1995). Thirst and vasopressin function in normal and disordered states of water balance. The Journal of Laboratory and Clinical Medicine, 125(6), 674–679.