Hematological, metabolic and endocrine complications

Author(s): Stephen R. Lebduska, MD, Bhargav Mudda, MD

Originally published:09/20/2014

Last updated:09/20/2014

1. DISEASE/DISORDER:

Definition

Injuries to the central nervous system (CNS), both within the brain and the spinal cord, trigger a cascade of events which alter the normal homestatic function of the neuro-endocrine system. These systems regulate cellular nutrition, energy consumption, oxygenation, and waste removal, which in turn control tissue growth and repair. Subsequently, these changes impact normal organ system functions that lead to various hematological, metabolic, and endocrine complications. Some complications such as osteoporosis after CNS injury are also covered elsewhere separately as a specific topic.

Etiology

Hematological, metabolic, and endocrine complications can result from traumatic brain injury (TBI) and spinal cord injury (SCI), as well as non-traumatic disorders involving the brain or spinal cord.

Epidemiology including risk factors and primary prevention

Immobilization hypercalcemia occurs in approximately 10-23% of patients with SCI. As many as 50% of patients with SCI will sustain osteoporotic or low impact fractures at some point post injury.1Studies have shown a 52.3% incidence of mild anemia in patients with traumatic spinal cord injury.2Also in patients with SCI, over one-third of persons will have low HDL, which is a known risk factor for cardiovascular disease. Studies have also reported rates of diabetes from 13% to 22% in patients with spinal cord injury or disorders.4

In TBI, studies have shown hormonal imbalances affect as many as 30-50% of patients after severe injury. In addition, up to an 80% incidence of gonadotropin deficiency in the acute phase after TBI can be seen.3Specific hormonal deficiencies include 18% incidence of growth hormone deficiency, 16% incidence of corticotropin deficiency, and 40% incidence of vasopressin abnormalities. Approximately 25% of long-term survivors of TBI show deficiencies of one or more of the hypothalamic-pituitary hormones.3

Patho-anatomy/physiology

The spectrum of acute and potentially life-threatening changes after brain injury and spinal cord injury vary widely, relating to the severity and level of injury. Anemia occurs acutely through blood loss from concurrent vascular trauma, and subacutely as a result of GI bleeding.2This is likely secondary to increased vagal tone, resulting in increased gastric secretions and diminished oral intake. Most remaining metabolic, endocrine and hematologic complications evolve over weeks and months post injury.

Damage to the pituitary or the hypothalamus results in impaired production of hormones produced and secreted by these glands.5The complications that arise from SCI can be attributed to the associated paralysis with diminished weight bearing, loss of sympathetic control, and loss of muscular action, which disrupts essential mechanisms. These include a disruption in circulation and transport of blood constituents, nutrients, hormones and cellular metabolites that may normally act as stimulators or feedback inhibitors of glandular and organ function.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Hormone imbalances:

Condition Hormones affected Commonly Associated Disease
Hormone deficiencies due to damage to pituitary or hypothalamus Thyroid Stimulating Hormone (TSH)

Insulin-like Growth Factor (IGF-1)

Growth Hormone (GH)

Follicle Stimulating Hormone (FSH)

Luteinizing Hormone (LH)

Adrenocorticotropic Hormone (ACTH)

Antidiuretic Hormone (ADH)

Hypothyroidism

Dwarfism, growth defects (in children)

Hypogonadism

Sex hormone deficiency

Corticosteroid deficiency

Diabetes Insipidus

Hormone excess seen in brain injury Antidiuretic Hormone (ADH) Syndrome of Inappropriate ADH

Commonly encountered electrolyte disorders in patients with TBI or SCI include:

  1. Hypercalcemia: Immobilization after SCI results in increased osteoclastic activity, causing bone resoprption and transient hypercalciuria for up to 18 months after injury. If the rate of resorption is extremely high (commonly in adolescents), or there is co-existing renal impairment, hypercalcemia results.4
  2. Serum sodium (Na+) abnormalities: Hyponatremia after TBI is due to SIADH which is often a self-limiting disease. This along with cerebral salt-wasting syndrome is often associated with TBI and subarachnoid hemmorrhage (SAH). By contrast, TBI can also result in Diabetes Insipidus (DI) which occurs from a failure of ADH release leading to hyponatremia. Severe hyponatremia may occur acutely after SCI as a result of impaired sympathetic influence on the renin-angiotensin response to acute injury. Furthermore, post-TBI, ACTH deficiency results in decreased secretion of corticosteoids from the adrenal glands and decreased sodium retention by the kidneys. Paralysis also causes overall reduction in blood pressure, which in turn increases secretion of ADH, resulting in hyponatremia. Impaired secretion of ADH results in increasing plasma sodium concentrations.3,6
  3. TBI and SCI are both associated with hypercoagulopathy which predisposes patients to thromboembolic events.
  4. Impaired glucose tolerance, higher risk of diabetes mellitus (DM) and hyperlipidemia have been associated with SCI.

Specific secondary or associated conditions and complications

  1. Anemia occurs in patients with chronic SCI due to a combination of etiologies, including chronic inflammation (from recurrent decubitus ulcers, urinary tract infections, etc), acute and chronic blood loss, and folic acid deficiency.2
  2. Impaired glucose tolerance.
  3. Diabetes Mellitus Type 2.
  4. Renal calculi (due to hypercalcemia).
  5. Osteoporosis, resulting in increased incidence of lower extremity and spinal fractures below the neurologic level of injury.
  6. Testosterone deficiency.
  7. Hyperlipidemia.
  8. Cardiovascular disease (due to adrenergic dysfunction, poor diet, and physical inactivity). Patients with SCI have increased prevalence of low levels of HDL compared to the general population.7,8
  9. Venous thrombo-embolism, (Risk diminishes with time, and generally not significantly higher than in general population after 1 year post-injury).

2. ESSENTIALS OF ASSESSMENT

History

Proper history taking is essential in the diagnosis and management of potential complications. An inventory of new and chronic complaints helps to elucidate evolving complications. Key information to elicit from patients is:

  1. Pre- and post-injury medical and surgical history.
  2. Medication history and current medications.
  3. Polyuria, polydipsia.
  4. New onset shortness of breath, dizziness or headaches.
  5. New onset neurological symptoms, including pain or weakness above or below neurologic level of injury.
  6. New onset of extremity swelling, warmth or erythema.
  7. Worsening fatigue.
  8. Recent weight gain or weight loss.
  9. Change in stool color or blood in stools.
  10. Loss of libido.
  11. Worsening fatigue and anorexia.
  12. Apathy.
  13. History of fragility fractures.

Physical examination

In addtion to other aspects of the general physical and neurological examination pertinent to the underlying CNS condition, it is important to assess and document findings related to specific metabolic and endocrine complications such as weight and Body Mass Index (BMI) calculation, presence of gynecomastia, testicular atrophy, or decreased pubic and axillary hair.

Laboratory studies

Conditions Routine Tests Ordered
Electrolyte Abnormalities
  • Basic metabolic panel (BMP), with serum Magnesium and Phosphate levels.
  • Serum osmolality (osm), urine osm, urine sodium (Na), urine potassium (K) and urine chloride (Cl)
  • Serum calcium and total protein
Anemia
  • Complete blood count (CBC) includes (Hemoglobin, Hematocrit, red blood cell (RBC) count, RBC indices), iron panel, peripheral blood smear (if indicated)
  • Stool guiac
  • Folate level
Metabolic Abnormalities
  • Glycosylated hemoglobinA1C (HbA1c) measurements
  • Fasting plasma glucose (FPG), or 2 -hour 75 g Oral glucose tolerance test
  • Lipid panel
  • BMP, Serum Calcium, Albumin, Vitamin D level
Hormonal Abnormalities
  • Thyroid stimulating hormone (TSH), Free T4
  • Dexamethasone Suppression test
  • Serum parathyroid (PTH) level
  • Serum testosterone

Imaging

  1. A non-enhanced computed tomogrophy (CT) scan of the head is the initial standard of brain imaging to properly aid all other workups. Magnetic resonance imaging (MRI) has shown to be at least 30% more sensitive than CT scan but the need to order imaging studies should always be made on a case-by-case basis. Both CT and MRI are used to detect extent of head injury and injury to the hypothalamus as well as the pituitary gland. Furthermore, CT scans can be helpful in indentifying certain skull fractures that are more likely to be associated with injury to hypothalamus-pituitary axis.
  2. For osteoporosis, dual-energy x-ray absorptiometry (DXA) scan is currently the best available clinical tool for the diagnosis of osteoporosis. Furthermore, monitoring of bone mineral density (BMD) over time has shown to be helpful in management of disease.
  3. Plain x-rays for suspected lower extremity fractures.

Early predictions of outcomes

Extent of brain injury, manifested in residual cognition and level of paralysis after injury are predictors of subsequent prognosis. The severity of TBI seems to be related to the likelihood of developing post-traumatic hypopituitarism. Adolescent and young adult males are more commonly affected by hypercalcemia in SCI than other populations.9

Environmental

  1. Optimization of the home setting for safe wheelchair mobility and tranfers can help safeguard osteopenic patients from potential low impact trauma.
  2. Adaptive devices to facilitate access to and compliance with medications.
  3. Adequate heating and air conditioning to minimize metabolic demand.
  4. Provision of facilities for aerobic exercise can help improve cardiovascular health.10

Social role and social support system

Education provided by health care professionals directly to patients and indirectly through training given to their caregivers for reinforcement of health maintenance strategies can aid in managing complications associated with SCI and TBI. For instance, diabetic teaching provided to the family and the patient has been shown to improve compliance.11

Professional Issues

Due to loss in neurologic feedback mechanisms, patients with SCI as well as patients with brain injury frequently remain asymptomatic in the face of evolving pathology. (Reduced or absent anginal symptoms, vague or blunted symptoms of renal calculi or appendicitis, lack of pain in the presence of large decubiti, etc.) Successfully achieving patient compliance with dietary, behavioral, exercise, and preventive regimens is frequently quite challenging for clinicians. Regular and accurate documentation of physical findings and patient education is crucial in achieving these objectives.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Treatment for the various conditions listed are as follows:

  1. Osteoporosis: Oral bisphosphonate antiresorptive therapy (Alendronate, Etidronate, Clodronate, Tiludronate) have been tried. Some studies have suggested Vitamin D supplementation may be protective against bone loss in SCI, although this needs further study.12
  2. Diabetes Mellitus: Strict glucose montioring. Oral agents (Metformin, Glipizide, etc), Insulin therapy (particularly for patients with long-standing disease, poor response to oral medications or noncompliance). Diet and lifestyle modification.13
  3. SIADH (Acute): Fluid restriction to 800 ml/day. Hydration with IV normal saline. Salt tablets in occassional cases.6
  4. Anemia: Iron supplementation (if iron deficiency anemia) or treat underlying condition; B12 supplementation in Vitamin B12 deficiency.14
  5. Testosterone replacement therapy has shown to increase lean tissue mass and energy expenditure in hypogonadal men.15
  6. Hyperlipidemia: Diet and lifestyle modification. Statin therapy.
  7. Renal Calculi due to Hypercalcemia: IV fluids (Acute managment), dietary modifications tailored to each individual patient depending on most likely cause of stone formation (uric acid stones, sturvite stones, etc).
  8. Diabetes Insipidus (DI): Desmopressin in Central DI

At different disease stages

Coordination of care

Lifelong care for patients with SCI and TBI after the acute management and initial rehabilitation requires collaboration between physiatrists, medical and surgical specialists and therapists. This care is most effectively coordinated by a physiatrist and a primary care physician who are in frequent contact and pursue a mutually derived plan of care. In general, a primary care approach to managing patients with SCI and SCD (spinal cord disorders) faciltates access to a larger team of clinicians who specialize in this care, and includes the physiatrist and the internist.

Patient & family education

Patient and family education should be geared with a goal-oriented approach to ensure that patients can deal with complications in the most effective manner. Common areas of focus include:

  1. Diabetic education
  2. Anticoagulation administration
  3. Clot prevention and management
  4. Insulin administration and glucose monitoring
  5. Diet and lifestyle modifications
  6. Monitoring wound and skin

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Practice pearls include:

  1. Assess for worsening fatigue and diminished functional endurance on a routine basis to evaluate for underlying anemia.
  2. Regularly monitor patient’s diet, lifestyle, weight, for possible glucose intolerance.
  3. Regular specific inquiry about patient mood, libido, menses and general perception of energy level may alert the clinician to evolving hormonal abnormality.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

NA

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

Although it appears clear that the rate of overall bone loss and subsequent evolution of osteoporosis in patients with SCI diminishes with time, this process does not appear to reach a steady state and efforts to prevent or even reverse bone density loss have been pursued for many years. The role for empiric use of bisphosphonates and duration of treatment remains controversial. Also, the role of receptor activator of nuclear factor of kappa B ligand inhibitors such as Densosumab in preventing and treating osteoporosis after SCI and TBI are not known. The overall benefit and optimal utilization of weight-bearing activities, and muscular action through functional electrical stimulations remains controversial.

REFERENCES

1. Battaglino RA, Lazzari AA, Garshick E, Morse LR. Spinal cord injury-induced osteoporosis: pathogethogenesis and emerging therapies.Curr Osteoporosis Rep. 2012; DOI 10.1007/s/11914-012-0117-0.

2. Perkash A, Brown M. Anemia in patients with traumatic spinal cord injury.Journal of American Paraplegic Society.1986;9(1-2):10-15.

3. Behan LA, Phillips J, Thompson CJ, Agha A. Neuroendocrine disorders after traumatic brain injury.J Neurol Neurosurg Psychiatry.2008;79(7):753-759.

4. LaVela, et al. Diabetes mellitus in individuals with spinal cord injury or disorder.J Spinal Cord Med. 2006;29(4):387-395.

5. Aimaretti G, Ghigo E. Traumatic brain injury and hypopituitarism.Scientific World Journal. 2005;5:777-781.

6. Hoorn EJ, van der Lubbe N, Zietse R. SIADH and hyponatraemia: why does it matter? NDT Plus. 2009;2:iii5-iii11.

7. Myers J, Lee M, Kiratli J. Cardiovascular disease in spinal cord injury: an overview of prevalence, risk, evaluation and management.Phys Med Rehabilitation.2007;86:142-152

8. Furlan JC, Fehlings M. Cardiovascular complications after acute spinal cord injury: pathophysiology, diagnosis, and nanagement.Neurosurg Focus. 2008:25(5):E13.

9. Maynard FM. Immobilization hypercalcemia following spinal cord injury.Arch Phys Med Rehabil. 1986;67(1):41-44.

10. Warburton DER, et al. Cardiovascular health and exercise following spinal cord injury. Spinal Cord Injury Rehabilitation Evidence, vs 4.0. Vancouver, Canada: 2012;1-43.

11.Arnour TA, Norris SK, Jack L, Zhang X, Fisher L. The effectiveness of family interventions in people with diabetes mellitus: a systematic review.Diabetic Medicine.2005;22:1295-1305. doi: 10.1111/j.1464-5491.2005.01618.x

12. Hochberg MC, Ross PD, Black D, et al. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group.Arthritis Rheum. 1999;42:1246.

13. American Diabetes Association. Standards of medical care in diabetes-2014.Diabetes Care. 2014;37(Suppl 1):S14.

14. Frisbie JH. Anemia and hypoalbuminemia of chronic spinal cord injury: prevalence and prognostic significance.Spinal Cord. 2010;48: 566-569.

15. Bauman WA, Cirnigliaro CM, La Fountaine MF, Jensen AM, Wecht JM, Kirshblum SC, Spungen AM. A small-scale clinical trial to determine the safety and efficacy of testosterone replacement therapy in hypogonadal men.Horm Metab Res. 2011;43(8):574-579.

Author Disclosure

Stephen R. Lebduska, MD
Nothing to Disclose

Bhargav Mudda, MD
Nothing to Disclose

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