Grant Liddle

Grant Winder Liddle (1921-1989) portrait

Grant Winder Liddle (1921-1989) was an American endocrinologist

Liddle was a transformative figure in 20th-century endocrinology, renowned for his elegant use of physiologic testing to dissect complex hormonal syndromes. His career was defined by methodical clinical investigation, diagnostic innovation, and mentorship. At Vanderbilt University, he established one of the premier endocrine programs in the United States, training over 70 fellows, many of whom became national leaders in academic medicine.

Liddle’s clinical acumen led to the discovery of Liddle syndrome (1963), a rare hereditary form of hypertension due to constitutive sodium reabsorption in the distal nephron. He developed the dexamethasone suppression test, a cornerstone in the diagnosis of Cushing syndrome, and was the first to characterise ectopic ACTH secretion as a paraneoplastic phenomenon. His application of the metyrapone test to assess pituitary reserve offered one of the earliest dynamic endocrine assays. He also clarified the dual secretion of ACTH and β-lipotropin from the pituitary, expanding understanding of proopiomelanocortin (POMC) derivatives and their regulatory mechanisms.

Liddle’s investigations into hormonal regulation of renal sodium transport, initiated during his NIH tenure with Fred Bartter, identified sodium retention in Cushing syndrome and pseudohyperaldosteronism. Beyond his scientific contributions, Liddle’s leadership at Vanderbilt helped shape modern American endocrinology. He fostered a rigorous, inquisitive culture that blended clinical care with bench-to-bedside research, leaving a legacy as both an innovator and mentor.

Biographical Timeline
  • 1921 – Born June 27 in American Fork, Utah, USA; son of Parley Heber Liddle, a draughtsman. Third-generation descendant of Mormon pioneers.
  • 1939–1943 – Attended the University of Utah; graduated BS in 1943 as valedictorian and member of Phi Beta Kappa.
  • 1943–1948 – Attended UCSF School of Medicine; graduated MD in 1948. Awarded the Gold Headed Cane; served as senior class president. Served in the United States Army during World War II (1943-1946)
  • 1948–1951 – Internship and residency at UCSF. Research fellow in the Metabolic Research Unit under Leslie Bennett and Peter Forsham.
  • 1953–1956 – Clinical associate in the Section on Clinical Endocrinology, National Heart Institute, NIH; worked with Frederic Bartter (1914–1983).
  • 1956 – Joined Vanderbilt University School of Medicine as Director of the Endocrine Service in the Department of Medicine. Appointed full professor of medicine at Vanderbilt (1961)
  • 1963 – Described the familial hypertensive disorder later known as Liddle syndrome, characterised by early-onset hypertension, hypokalaemia, and low renin and aldosterone levels.
  • 1960s–1970s – Developed the dexamethasone suppression test and metyrapone test; coined the term “ectopic hormone secretion” in relation to paraneoplastic endocrine syndromes.
  • 1968–1983 – Chairman of the Department of Medicine at Vanderbilt
  • 1971 – Received the Endocrine Society’s first Distinguished Leadership Award.
  • 1977 – Received the American College of Physicians’ John Phillips Memorial Award.
  • 1981 – Elected to the United States National Academy of Sciences.
  • 1983 – Suffered a stroke while driving; sustained serious injuries and stepped down as department chair.
  • 1989 – Died June 29 in Nashville, Tennessee, aged 68.
Medical Eponyms
Liddle Syndrome (1963)

Liddle syndrome, also called pseudohyperaldosteronism, is a rare autosomal dominant disorder of salt handling that results in early-onset, resistant hypertension, hypokalemia, and metabolic alkalosis. It is pathophysiologically characterized by low plasma renin activity and suppressed aldosterone secretion—mimicking mineralocorticoid excess. The syndrome arises from mutations in the epithelial sodium channel (ENaC) of the distal nephron, leading to constitutive sodium reabsorption. Treatment with ENaC inhibitors like amiloride is effective; mineralocorticoid antagonists are ineffective.

1963 – Original Description by Liddle, Bledsoe and Coppage who published “A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion.”

We describe a familial disorder in which several members developed severe hypertension, hypokalemia, and metabolic alkalosis. These features mimic primary aldosteronism, yet plasma aldosterone concentrations were negligible. The condition was inherited in a dominant fashion, and did not respond to adrenalectomy.

This paper identified a familial disorder of renal sodium handling unresponsive to usual therapies for hyperaldosteronism. Liddle proposed a primary defect in sodium transport in the distal nephron before molecular techniques could confirm it.

1995 – Genetic Confirmation by Hansson JH et al. in Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Identified mutations in the SCNN1G gene encoding the γ-subunit of ENaC, resulting in impaired degradation and persistent activity of sodium channels. This study provided molecular confirmation of Liddle’s 1963 hypothesis.

1990s–2000s – Further mutations identified in SCNN1B and SCNN1A. Affected ENaC subunits fail to interact with ubiquitin ligase Nedd4 due to PY motif mutations, preventing internalization and degradation.

Treatment refinement – Amiloride and triamterene, which directly block ENaC, became the mainstay of therapy. Spironolactone is ineffective due to aldosterone independence.

2010s–2020s – Expanded phenotypic spectrum recognized. Some patients present normokalaemic or late in adulthood. Over 30 distinct mutations now documented across more than 70 families worldwide.

Summary

Liddle syndrome affects the collecting duct, where a gain-of-function mutation in the epithelial sodium channel (ENaC) leads to constitutive sodium reabsorption. This results in sodium retention, hypokalaemia, metabolic alkalosis, suppressed renin, and low aldosterone, producing a phenotype that mimics mineralocorticoid excess despite absent hormonal overproduction.

Comparative Context:

Comparison of Bartter, Gitelman and Liddle syndromes

Key Medical Contributions
Suppression Tests and Cushing Syndrome

The dexamethasone suppression test (DST), introduced by Liddle in 1960, revolutionized the diagnostic approach to Cushing syndrome. The test exploits the feedback inhibition of ACTH secretion by exogenous glucocorticoids. In healthy individuals, dexamethasone suppresses cortisol secretion via ACTH suppression. In Cushing syndrome, suppression patterns help differentiate pituitary adenomas (Cushing disease), adrenal tumors, and ectopic ACTH secretion.

1960 – Original description by Liddle in Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing’s syndrome. This established a practical method for functional subclassification of hypercortisolism prior to the advent of imaging or immunoassays. Liddle’s protocol involved measuring urinary free cortisol (or metabolites) after administering dexamethasone over several days.

The administration of dexamethasone in low and high doses permits the classification of Cushing’s syndrome based on the pituitary-adrenal feedback responsiveness. In Cushing disease, suppression of urinary 17-hydroxycorticosteroids is partial; in adrenal tumors and non-pituitary ACTH-producing tumors, suppression is absent.

Liddle, 1960

1960s–1980s – The DST became a cornerstone of endocrine diagnostics. The low-dose DST is used to confirm Cushing syndrome and the high-dose DST differentiates Cushing disease (partial suppression) from ectopic ACTH or adrenal causes (no suppression).

Modifications – Plasma cortisol replaced urinary measures and overnight DST protocols (1 mg) have become standard for screening. Limitations include false positives in depression, alcoholism, and stress and false negatives in mild or cyclic Cushing’s.

Paraneoplastic Syndromes and Ectopic Hormone Secretion

Liddle was a pioneer in identifying the endocrine manifestations of malignancy, particularly through his work on the ectopic ACTH syndrome, a form of Cushing syndrome caused by non-pituitary tumours secreting ACTH. He is credited with coining the term “ectopic hormone secretion”, which has since become foundational in clinical endocrinology.

1962 – Liddle and colleagues first proposed that non-endocrine tumours could produce biologically active ACTH, describing cases of Cushing syndrome not attributable to pituitary or adrenal disease.

1965 – Liddle published The ectopic ACTH syndrome describing its biochemical features and emphasizing that tumours of non-endocrine origin, particularly small cell lung carcinoma and bronchial carcinoid, could secrete ACTH, leading to hypercortisolism resistant to pituitary-directed treatments.

Liddle’s framework helped establish other paraneoplastic syndromes (e.g. SIADH, hypercalcaemia of malignancy) under the umbrella of ectopic hormone secretion.

Circadian Rhythms and the HPA Axis (1966)

Liddle made seminal contributions to the understanding of circadian and activity-related regulation of adrenal hormone secretion. His work dismantled the idea of an immutable “adrenal cycle,” showing that rhythms in cortisol and aldosterone secretion were heavily influenced by external behaviours especially sleep-wake patterns and posture, rather than by intrinsic biological clocks alone.

1966 – In his Jeremiah Metzger Lecture, Liddle demonstrated that cortisol secretion follows a robust daily rhythm, with peak levels around 8 a.m. and a trough by midnight, closely mirroring plasma ACTH.

When subjects adopted a non-circadian sleep-wake schedule (e.g. 4 hours sleep/8 hours awake), cortisol rhythms adapted, showing two daily peaks instead of one: “The ease with which the plasma 17-OHCS [cortisol] were shifted from one to two cycles per day would suggest that the cyclic regulation of ACTH-cortisol secretion is dependent upon the sleep-wake cycle rather than some inborn mechanism.”

Aldosterone secretion, in contrast, was driven largely by posture via renin stimulation, not ACTH: “The circadian rhythm in aldosterone secretion vanished when subjects were kept recumbent… Posture appears more important than ACTH in determining aldosterone rhythmicity.”

Key Experimental Contributions:

  • ACTH suppression via dexamethasone abolished cortisol rhythmicity but not aldosterone rhythm (unless posture was also fixed).
  • Posture reversal (e.g. being upright at night) reversed the aldosterone rhythm.
  • Sleep-wake cycle manipulation (rather than light exposure) rescheduled ACTH and cortisol rhythms.
Metyrapone Test and Pituitary Reserve (1959)

Liddle and colleagues introduced the metyrapone test (then using the trade name Metopirone or SU-4885) as a novel functional assay to evaluate pituitary ACTH reserve. By inhibiting cortisol synthesis at the 11β-hydroxylase step, metyrapone provokes a compensatory rise in ACTH if the pituitary is intact. This response was used to assess the integrity of the HPA axis and distinguish between primary and secondary adrenal insufficiency.

In this 60-patient study, Liddle’s group demonstrated that failure to increase 11-deoxycortisol following metyrapone indicated impaired pituitary ACTH secretion, while patients with intact pituitary function showed robust precursor steroid accumulation.

Key Features of the Test:

  • Drug used: SU-4885 (metyrapone), a reversible inhibitor of 11β-hydroxylase (CYP11B1)
  • Biochemical effect: Cortisol falls → ACTH rises (if pituitary is functional) → 11-deoxycortisol and compound S increase
  • Clinical interpretation:
    • Normal pituitary: ↑ ACTH → ↑ 11-deoxycortisol
    • Pituitary insufficiency: Blunted ACTH → little/no increase in precursors

Later adaptations refined the protocol into a single-dose metyrapone test, using midnight administration and morning blood sampling for cortisol and 11-deoxycortisol. The test remains a useful diagnostic tool for confirming secondary adrenal insufficiency and evaluating HPA recovery post-glucocorticoid therapy.

Major Publications
References

Biography

Eponymous terms

Eponym

the person behind the name

more eponyms…

Physician in training. German translator and lover of medical history.

BA MA (Oxon) MBChB (Edin) FACEM FFSEM. Emergency physician, Sir Charles Gairdner Hospital. Passion for rugby; medical history; medical education; and asynchronous learning #FOAMed evangelist. Co-founder and CTO of Life in the Fast lane | On Call: Principles and Protocol 4e| Eponyms | Books |

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