A healthy immune system is a very important part of maintaining one's health and well-being. The immune system is important for protection against infections, cancer surveillance, and maintaining a healthy balance for most bodily functions. A compromised immune system or inadequate immune response may lead to serious infections because of the inability of the immune system to respond to, or contain, the infection (see table 1). Certain viral infections can directly suppress the immune system, the most dramatic example of which is HIV. However, it is becoming evident that a number of viruses can substantially and adversely affect the immune response through several different mechanisms, not the least of which is through the contributory role of growth hormone deficiency.

Premise

Statistics show complex diseases including chronic illness have been steadily on the rise for over a century. Deaths from infectious disease from 1980 to 1992 are up 58%, making it the #3 cause of death. If we exclude HIV, all other infectious diseases have risen by a total of 22%. Despite overall gains in life expectancy, today many adult men and woman face the possibility of succumbing to a myriad of symptoms that characterize chronic diseases such as Chronic Fatigue Syndrome (CFS), Fibromyalgia Syndrome (FMS), Irritable Bowel Syndrome (IBS), autoimmune disease such as Systemic Lupus Erethematosus (SLE), sinusitis, bronchitis, and psychiatric disorders.

The onset of chronic illness begins with inflammation, immune system dysfunction, and a hypercoagulation state leading to anoxia and dysfunction. At times, only one part of the body may be affected, while at other times the entire body - including the HPA Axis (hypothalamus-pituitary adrenal axis) - will be involved.

The portals of entry for chronic illness include the respiratory tract, periodontal pathology, the gastrointestinal (GI) tract, and/or trauma. Onset may be acute or chronic, achieving a cumulative effect on the adrenals, GI tract, respiratory tract, urinary tract, and liver, hormones, thyroid, immune system and CNS function.

A New Reference Point for Understanding the Role of Growth Hormone Deficiency in Chronic Illness

Making a Diagnosis

The evaluation of the chronically ill patient is a great challenge to the clinician, researcher and health care professional. It requires a broad and interpretative view of disease, a psychosocial sensitivity, astuteness to mental health disorders, as well as formulating a good ongoing relationship with the patient to promote his/her openmindedness in assessing all possible medical considerations.

Many - if not all - of the following factors contribute to the etiology and disease process of many chronic illnesses.

• Psychiatric disorders
• Defect in immune system, such as allergies
• Infections - bacterial, viral, fungal, parasitic
• Coagulation cascade defect
• Environmental toxins
• Trauma, accidents, surgery
• Stress - physical and emotional
• Growth Hormone Deficiency (GHD)
• Genetic defects

Proper diagnosis and effective treatment of chronic illness necessitates that the physician understands the interrelationship between infections, coagulation defect, toxins, trauma, stress, and growth hormone deficiency.

My clinical experience with chronically ill patients has led me to establish the following working definition that is characterized by a series of specific biological processes (Figure 1):

Figure 1. Activation of Coagulation in CFS/FMS/Chronic Illness: Immune System Activation of Clotting

 

Table 1. Components of the Immune System Implicated in Chronic Disease

Humoral Immunity	Cell-mediated Immunity (CMI)	Phagocytic cells	Natural Killer (NK) Cells	Cytokines
Antibodies formed by B lymphocytes with the help of T cells after contact of an antigen develops into antibodies producing plasma cells or memory B cells that bind to antigens. Humoral immunity is important for certain types of bacteria and some viruses.	Responsible for recognition of invading organisms and activation of various "killing cells" that eradicate infection. Involves T helper cells (CD4 cells), cytotoxic T-cells (CD cells), and many cytokines. CMI is important for many viruses, some bacteria, and fungus invaders.	Including the cell types of neutrophils and macrophages, responsible for engulfing, digesting, and killing infecting organisms. Phagocytic cells fight bacteria and some fungus infections, as well as parasites.	First line of defense that can quickly kill invaders, without having to be specifically primed ahead of time. NK cells are involved in elimination of viral infections and cancer.	Chemicals produced by immune cells in order to communicate and orchestrate the attack against unwanted infections and altered cells. Cytokines can act on other immune cells, especially cells that are proximally located.

• Chronic illness is a coagulation protein defect that leads to a hypercoagulation state when the patient is subjected to a pathogen, trauma, and/or toxins.
• Excess thrombin (IIa) generation converts fibrinogen to soluble fibrin monomer (SFM), causing fibrin (fibroid) deposition.
• Accumulation of fibrin on endothelial cell (EC) surfaces prevents oxygen and nutrients from entering tissues and cells, resulting with focal ischemia.
• Blood viscosity increases (slows) blood flow resulting in endocrine (HPA Axis) dysregulation, sleep disorder, central nervous system (CNS) dysfunction, decreased blood flow, fatigue, decrease in heart stroke volume, lowered blood pressure, lowered immune system function, and dysregulation of the adrenal glands.

Etiologies of Activation of Hypercoagulation State

At my clinic, we find that activation of the immune system and promotion of a hypercoagulation state are often prompted by viruses, toxins, bacteria, trauma, and vaccines (Table 2).

The immune system is the first-line defense against disease, and normal immune systems successfully manage the entry of pathogens, toxins, stress, etc.

Immunocompromised individuals are thus at increased susceptibility because:

• The immune system activates cytokines and endotoxins. An example of this is when a person has the flu, experiencing malaise, cognitive dysfunction, fever, etc. The infection activates the immune system, which then activates clotting. The end result is the accumulation of soluble fibrin monomer deposits (SFM), leading to anoxia.
• Infections actively release cytokines and chemokines, causing pain and discomfort. For most of us, this is a temporary infection response but in immunocompromised people the recovery is sometimes protracted.
• One in five people have a protein defect that creates clotting problems, resulting with an inability to clean up the SFM. As a result, fibrinoid deposits develop and lead to anoxia and disease.

Figure 2: Pro-inflammatory Cytokines - Possible Mechanism of Activation for Growth Hormone Deficiency

 

Stress - the way in which we react (mentally, emotionally, and physically) to life's demands - creates a number of physiological effects.

Stress is often responsible for fatigue (and an increased demand for nutrients), as well as an increase in the adrenaline-causing platelets to stick together - resulting with decreasing oxygen to the medulla region of the adrenal. This is what I refer to as a "hypercoagulation state."

Destruction of endothelial cells (that line capillaries), occurring over 15 to 20 years, causes chronic illness. At my practice, we observe these patients have anxiety: they express feeling as if they have not been getting enough oxygen, thereby creating depression, anxiety, pain and neuropathy. We evaluate these patients for viruses, bacteria, toxins, trauma, and history of vaccines.

Individuals diagnosed with SFM and chronic inflammation may present as having the antiphosphyolipid antibody syndrome (APS) with the EC as the disease target. These patients have a hypercoagulable state, which is demonstrated by increased makers of coagulation activation and increased blood viscosity due to the generation of SFM.

The CFS/FMS, chronically ill process is triggered by a variety of pathogens (Table 2). As a result:

• The offending pathogen mediates immune system activation that induces antibodies that cross-react with the EC protective proteins BGPI and Annexin V.
• These antibodies dislodge the protective protein from EC surface exposing phosphatidylserine (PS) on the EC surface in the capillary bed.
• Through a process of interaction, this results in thrombin generation leading to SFM formation.
• The SFM causes increased viscosity and is precipitated out on the EC as fibrin (fibroid) deposits. This increases ischemia, blocking nutrients and oxygen delivery in the microcirculation .

Table 2. Immune System/Hypercoagulation Activators

Virus	Toxin	Bacteria	Trauma	Vaccine
Human HerpesVirus (HHV-6)	Mercury	Mycoplasma	Injury	Anthrax
Epstein-Barr Virus	Cadmium	Chlamydia	Loss	Polio
Measles	Arsenic	Staphylococcus	Surgery	Measles
Cytomegalovirus (CMV)	Silver	Nanobacteria	Emotion
Chicken Pox	Lead	Beta Strep
Stealth virus	Other environmental exposures	Klebsiella Pneumoniae
Coxsackie

Note: There is not a clot, as observed in D-Dimer formation that causes thrombosis in cardiovascular disease resulting in acute blockage.

Growth Hormone Deficiency and the Chronically Ill

Growth Hormone Deficiency (GHD) (Table 3) occurs in patients with pituitary tumors, trauma, and post-surgically, comprising approximately 50% of the total etiology of GHD. I submit that the remaining 50% is associated with chronic inflammatory diseases, characterized by immune system dysregulation, adrenal dysregulation and hypercoagulation state.

The GHD symptom complex can occur after a chronic illness and has been studied extensively in relation to CFS, FMS, rheumatoid arthritis, and other diseases. The concept of anoxia caused by the immune system activation of coagulation with infection cytokine excess and vasculitis contributes to the decline and dysregulation of HPA axis.

Table 3. Manifestations of Adult Growth Hormone Deficiency (GHD)

Disturbed lipid pattern	Decreased exercise capacity
Abnormal body composition	Defective sweat secretion & thermoregulation
Excess weight and central adiposity	Increased tone in the sympathetic nervous system
Impaired glucose homeostasis	Decreased bone mineral content
Impaired fibrinolysis	Decreased activity in osteoclast precursor and proliferation and differentiation of osteoclasts
Impaired cardiac functioning	Problems with sleep quality
Reduction in arterial distensibility (esp. carotid artery in women)	Decreased social contact and stiffness
Low nitric oxide levels, contributing to atherosclerosis	Significantly more health issues than others of sex/age
Premature atherosclerosis
Major risk factor in CHF and heart disease and premature death

There are several similarities between the symptoms in fibromyalgia and GHD, and the two conditions are somewhat interrelated (Table 4). A working definition of fibromyaligia (Figure 2) is that infection releases toxins, causing liver cells to produce cytokines including interleukin-6 (IL-6).

Table 4. FMS/GHD At a Glance

GH deficiency occurs 30% of patients in some studies	Muscle Weakness
GH treatment shows significant improvements in trigger points	Fatigue-low energy
Low IGF-1 levels in FMS	Decrease Exercise capacity
Disturbed circadian rhythm of cortisol	Social isolation
Response to GH took 6 months and patient experienced global improvement	Poor general health
Central pain state: up regulation of N-methyl-D-asparate (NMDA) receptor at spinal synapse	Cold intolerance
Dysregulation of substance P	Impaired cognition
Sleep disturbance abnormal stage 3 & 4 (when GH is not secreting)	Dysthymia Decrease in body mass Reduced IGF-1 Decrease in 24 hr GH secretion Response to GH treatment

The cytokines interact with nerves that travel to the brain which signals down the spinal cord, causing amplified pain signals.

Three cytokines, IL-1, IL-6, and IL-8, cause severe widespread pain, fatigue and disturbed sleep. IL-6 is related to fatigue and impaired concentration. TNF alpha activates hypothalamus corticotrophin releasing hormones (CRH) and releases IL-1 that does not stimulate the pituitary or adrenal glands.

Treatment of GHD should only be initiated once infections are cleared, as acute infection can be detrimental. It is my clinical experience that treatment of GHD has minimal risks. In actuality, for chronically ill patients, GHD replacement therapy imparts great psychological, psychosocial and cardiovascular health benefits. The treatment adds greatly to quality of life and to maintaining a healthy life style. Benefits of growth hormone replacement therapy may include:

• Reduction in body fat mass
• Increase in lean body mass
• Increase in total body water
• Oppose the action of insulin on adipocytes
• Increase in fat mobilization by hydrolysis of triglycerides into glycerol and free fatty acids
• Stimulate fatty acid transportation from adipose tissue to the liver
• Inhibit FFA re-esterification by adipocytes
• Increase whole protein synthesis for the first month then returning toward baseline with a new steady state
• Increase body nitrogen and total body potassium
• Antinatriumic effects - salt and water retention GH and IGF-1 (synthesized in the heart) are expressed in the heart. Rate is based on maturation, neural differentiation, neuro-potential and energy metabolism (mitochrondial)
• Increase in oxygen consumption and cardiac output
• Increase in B-endorphins in cerebrospinal fluid, which may improve psychological well-being (IGF-1 receptors are located in all regions of the brain, and GH receptors are located in the choroid plexus, hypothalamus, pituitary, and hippocampus)
• Increase in net conversion of cortisol to cortisones, by inhibiting the activity of HB- HSD Type I
• For thyroid, T4 replacement shows no change in GH function
• There is a reciprocal relationship between cortisol and GH secretion
• Reduce coronary and cerebrovascular disease
• Reduce premature deaths
• Reduce osteoporosis
• Increase quality of life, which reduces depression, fatigue and pain

In summary, growth hormone deficiency (GHD) needs to be evaluated in patients who, after the primary etiology is diagnosed and treated, still exhibit symptoms of other illness. Based on my clinical experiences, patients who exhibit symptoms of chronic infections, osteoporosis, cardiovascular disease, dementia (depression), and a hypercoagulation state all need to be evaluated for growth hormone deficiency.