What is HIV-Related Endocrinopathies?
By the end of 2018, approximately 37.9 million people were living with HIV, and 24.7 million of them had access to anti-retroviral therapy (ART). ART is a type of medication used to manage HIV. While HIV was once a very scary disease, effective ART has turned it into a manageable chronic condition. However, reducing the number of deaths related to HIV through ART has led to an increase in common health problems and conditions often seen in older individuals, many of which are related to the endocrine system.
The endocrine system is a network of glands in our bodies that produce hormones, which help to control many different bodily functions. People with HIV often experience problems with their endocrine system. These problems can be minor, showing no symptoms and only abnormal lab tests, or serious, involving a full failure of one the glands. Each part of the endocrine system can be affected. Even though many of these changes could be seen with any serious illness, some changes seem to be specific to HIV infection.
During the early years of the AIDS pandemic, the endocrine system problems seen in people with HIV were typically caused by opportunistic infections and HIV-related cancers affecting endocrine organs. Opportunistic infections are infections that take advantage of weak immune systems. However, with the widespread use of ART that has reduced the occurrence of the late symptoms of AIDS, more attention is now paid to endocrine system problems caused by the direct effects of HIV infection, the rebuilding of the immune system, and the use of ART.
What Causes HIV-Related Endocrinopathies?
Advanced HIV can cause thyroid dysfunction, similar to a different condition called euthyroid sick syndrome, which happens when the body is fighting a serious illness. It can result in low levels of certain thyroid hormones, but unlike euthyroid sick syndrome, advanced HIV doesn’t usually cause high levels of a hormone called reverse T3.
Many health conditions, such as cancers and invasive infections, can disrupt the function of the thyroid. For instance, Kaposi sarcoma and lymphoma can spread into the thyroid, causing it to swell or break down and often resulting in hypothyroidism, a condition where the thyroid doesn’t produce enough hormones. Certain infections, like Pneumocystis jiroveci and Cryptococcus neoformans, can invade the thyroid and cause inflammation that may result in either an overactive or underactive thyroid.
Some medications used to treat HIV and its associated infections can change how the body processes thyroid hormones. Certain drugs, like rifampin, phenytoin, ketoconazole, and ritonavir, can speed up the breakdown of these hormones. Some other drugs may disrupt the body’s immune system and lead to an autoimmune disorder that affects the thyroid.
Similarly, HIV can lead to adrenal gland dysfunction, causing a condition called adrenal insufficiency. This can occur when HIV attacks the adrenal gland or if the immune system mistakenly creates antibodies against the adrenal gland. People with HIV may also notice elevated levels of cortisol, a hormone that helps the body respond to stress, which has been linked to an increased production of certain proteins made by the immune system.
There is another condition HIV patients may experience, known as glucocorticoid resistance. Symptoms include weakness, weight loss, and changes to skin color. These are due to high cortisol levels and a reduced responsiveness to cortisol.
Bone disorders like osteoporosis can also occur in people with HIV due to constant inflammation in the body. HIV poses unique factors that put these individuals at a higher risk for osteoporosis, which includes both conventional risks (like unhealthy lifestyle habits) and some specific to the condition (like being coinfected with hepatitis B or C). HIV treatments can also cause reduced bone density.
HIV can affect hormonal function in both men and women, which may result in gonadal dysfunction – a condition that affects sexual development and fertility. Men with HIV often have lower testosterone levels, leading to a particular type of gonadal dysfunction known as secondary hypogonadism, which is often caused by a combination of multiple factors including chronic illness, weight loss, and direct infection of the hormonal control centers in the brain. Women with HIV can also undergo certain hormonal changes that can potentially lead to irregular menstruation or even early menopause.
HIV can also lead to several metabolic dysfunctions, such as “wasting,” where there is an involuntary loss of body weight and cellular mass. Prior to advanced treatments for HIV, “wasting” was one of the most common AIDS-defining conditions. In some cases, HIV can also lead to an imbalance in the body’s fat distribution, disruption of glucose regulation (leading to diabetes), and abnormal blood lipid levels.
Risk Factors and Frequency for HIV-Related Endocrinopathies
Patients with HIV tend to experience various types of dysfunction and disorders more frequently than the general population. Their experiences can range from thyroid and adrenal dysfunction, bone disorders, and hormonal imbalances, to problems with growth hormones and the metabolism. Let’s look at each of these more closely:
- Thyroid Dysfunction: Overt thyroid dysfunction affects 1-3% of patients with HIV, the same as the general population. However, the less noticeable, or “subclinical” thyroid dysfunction, affects up to 12% of HIV patients.
- Adrenal Dysfunction: Prior to the introduction of antiretroviral therapy (ART), adrenal insufficiency was found in 5-10% of individuals with HIV. Today, this rate is lower but varies by population and geographic area.
- Bone Disorders: People with HIV are 6.7 times more likely to have issues with their bone mineral density, and 3.7 times more likely to have osteoporosis. In fact, their risk of fractures is almost 35-68% higher than the general population, and tends to happen about 10 years earlier.
- Gonadal Dysfunction: Before ART was introduced, over two-thirds of men with HIV experienced symptoms of hypogonadism, such as low testosterone levels. Nowadays, estimates range around 13-40%. Women with low CD4 counts might experience amenorrhea and anovulation (up to 50% of cases).
- Growth Hormone Deficiency: Research indicates that approximately 30% of all HIV patients show signs indicating a deficiency in growth hormones. This rate is reduced to 15% if using smaller measurements.
- Metabolic Dysfunction: Prior to ART, about 30% of people with HIV showed signs of tissue wasting and weight loss. Even with ART, weight loss continues to be seen in almost 20% of patients. Body fat distribution abnormalities occur in 10-80% of individuals, but this varies by study.
- Glucose Intolerance and Diabetes: Diabetes is estimated to affect 10.3% of individuals with HIV in the United States as per findings from 2009-2010. This figure goes up to 14.1% when adjusted for factors common in the general population.
- Lipid Abnormalities: A study found that 54% of HIV patients aged over 70 had dyslipidemia, and 23% had cardiovascular disease. Protease inhibitors, a type of medication, have been associated with dyslipidemia in 28% to 80% of patients taking the medication.
Signs and Symptoms of HIV-Related Endocrinopathies
Thyroid dysfunction is a condition where the thyroid gland doesn’t work properly. It can be subclinical, meaning you may not notice any symptoms, or it can be overt, causing multiple symptoms. Overt thyroid dysfunction includes hypothyroidism, where you might have dry skin, feel cold, be constipated, and feel tired. On the other hand, hyperthyroidism can make you intolerant to heat, anxious, and experience rapid heart rate or tremors. Additionally, muscle weakness, changes in menstrual cycles, and a swollen gland at the base of your neck could indicate any type of thyroid dysfunction.
Adrenal dysfunction is another condition where the adrenal glands don’t work properly. Chronic adrenal insufficiency results in symptoms like unexplained fatigue, nausea, abdominal discomfort, weight loss, amenorrhea and the darkening of the skin. On the other hand, acute adrenal insufficiency, or adrenal crisis, typically comes on quickly with symptoms like severe low blood pressure, low blood sugar, fever, confusion, or coma.
Hyperactivity of the adrenal gland, also known as Cushing syndrome, may present with weight gain, excess hair fall, bruising easily, weakened muscles, depression or reduced desire for sex. These patients may also have a large round face, abdomen and neck fat, thin skin or weak proximal muscles.
Osteoporosis is a bone-related disorder where one’s bones become weak and brittle, which might not cause any symptoms until a bone fracture occurs from a mild trauma such as a fall. These fractures commonly occur in the forearm or hip. If someone has decreased height, a stooped posture, or midline back pain, they may have a compressed spinal bone due to osteoporosis.
Hypogonadism is a condition in both men and women with decreased functioning of the sex glands. Male symptoms include erectile dysfunction, weight loss, low energy, decreased sexual desire and, less frequently, depression and cognitive dysfunction. Females tend to experience weight loss, fatigue, low mood, and a decreased sex drive. Both sexes may suffer from fractures occurring from mild trauma due to early onset osteoporosis caused by hypogonadism.
Growth Hormone Deficiency is a condition where insufficient growth hormone is produced. In children, symptoms include slow growth, delayed bone age, short stature, an increased weight-to-height ratio, and failure to thrive. Adults mainly have increased fat accumulation, decreased muscle mass, reduced energy, and loss of well-being.
AIDS-wasting syndrome is a condition where people living with AIDS experience sudden weight loss, muscle weakness, and generally poor health. Symptoms include loss of appetite, difficulty swallowing, pain while swallowing, loose stool, and a history of fungal or viral infections. The physical examination may reveal signs of weight loss, wasting, sunken temples, and thin skin. They may also have decreased sexual desire and erectile dysfunction.
Lipoatrophy and Lipohypertrophy are two conditions in association with HIV where there’s a mal-distribution of fat in the body. Lipoatrophy is the loss of fat from certain areas like the face and limbs. Facial lipoatrophy results in concave cheeks and visible facial muscles. Lipohypertrophy, by contrast, is an abnormal accumulation of fat in certain body parts like the back of the neck, the fat pads above the collarbone and the neck, as well as gynecomastia. Central obesity due to fat accumulation can also occur with disproportionate fat accumulation inside the abdomen.
Diabetes is a common metabolic dysfunction where the body does not properly handle glucose. People with diabetes may have increased urine output and thirst, visual disturbances, and symptoms of sensory nerve damage like numbness and tingling. Long-standing untreated diabetes can lead to significant weight loss. Elevated lipids (fats in the blood), often go unnoticed until detected in lab tests.
Testing for HIV-Related Endocrinopathies
To evaluate thyroid function, doctors usually measure certain hormones in the blood: thyroid stimulating hormone (TSH), and T4 and T3. Primary hypothyroidism is when your TSH is high and your T4 is low, while primary hyperthyroidism is when your TSH is low and your T4 or T3 is high. However, these aren’t reliable for diagnosing central or secondary hypothyroidism – here, diagnosis is made if T4 is low in the right clinical context. An autoimmune form of this condition may be suggested by high levels of thyroid autoantibodies. It’s also important to consider the levels of thyroxine-binding globulin (TBG), which correlate with CD4 lymphocyte counts when interpreting T4 and T3 levels.
If a patient shows signs of hyperthyroidism but a diagnosis can’t be confirmed, radioactive iodine uptake testing may be of help. Increased iodine uptake could signal Graves disease, while reduced or no uptake may help identify thyroiditis – a condition where the thyroid gland, located in the neck, gets inflamed.
Adrenal insufficiency or underactive adrenal glands are tough to diagnose in patients with HIV, as the symptoms often overlap with those of the HIV infection itself. If a patient has lower salt, higher potassium, and lower blood sugar levels, adrenal insufficiency may be present. While HIV can cause the cortisol levels to be increased, lower levels may indicate adrenal insufficiency. Imaging techniques can be useful to examine the adrenal glands for tumoral or infectious involvements.
Doctors recommend routine assessments to check for osteoporosis risk factors in people with HIV. This may include measuring vitamin D levels annually and scanning bone mineral density of women after menopause, men over 50, and patients having other risk factors for osteoporosis. Regular screenings are essential for patients with osteopenia (lower bone density than normal) and treatment should be considered for patients diagnosed with osteoporosis.
Low testosterone levels can indicate gonadal dysfunction in men. This should ideally be tested in the morning when the patient is fasting, as levels usually drop later in the day and post meals. Low testosterone levels associated with low or “inappropriately normal” gonadotropin levels hint at dysfunction of hypothalamus or pituitary glands. However, high gonadotropin levels indicate primary testicular dysfunction or hypogonadism.
Growth hormone deficiency can be identified with GH response to provocative testing. Imaging techniques are useful when hypertrophic or hypothalamic injury or disease is present and tests show GH deficiency.
Patients with HIV or AIDS wasting syndromes should be evaluated thoroughly, after which imaging studies may be needed to check for infections and hormone deficiencies.
Diagnosis of lipodystrophy (abnormal body fat distribution) is mainly clinical; tests for fat measurement are limited to research settings. Patients should be routinely checked for lipodystrophy at each clinic visit and those diagnosed should be assessed for metabolic abnormalities.
Patients with HIV should have their fasting blood glucose and glycated hemoglobin (HbA1c) measured before and 3 months after starting antiretroviral therapy (ART). However, HbA1c might underestimate diabetes in this population, thus a cutoff at 5.8% may be more appropriate.
Patients with HIV and dyslipidemia (high cholesterol) should get their lipid levels checked routinely. High levels can increase risk of heart disease and death due to heart disease. It’s also important to evaluate any history of heart disease, eating habits, physical activity, history of smoking, diabetes, BMI, and waist circumference.
Treatment Options for HIV-Related Endocrinopathies
When a person with HIV experiences thyroid dysfunction, the treatment approach is typically the same as for those without HIV. Hypothyroidism, the underactivity of the thyroid gland, is usually managed with levothyroxine supplements. Graves disease, an autoimmune disease that causes the overproduction of thyroid hormones, can be treated with medications, radioactive iodine therapy, or surgery. Sometimes, the dosage of levothyroxine needs to be increased in patients who are taking other medications that speed up thyroid hormone clearance. Also, if thyroid dysfunction is caused by cancerous or other infectious diseases, treating these diseases may help normalize the condition.
Treating adrenal insufficiency can be life-saving for individuals with HIV, but it needs to be correctly diagnosed, as unnecessary treatment can lead to other health issues. Treatment often involves hydrocortisone, and patients should monitor for signs of overdose like excessive weight gain and high blood pressure. Around times of stress or when taking certain medications, the dose of hydrocortisone may need to be increased.
For bone disorders and osteoporosis, patients with HIV who don’t get enough calcium in their diet may need supplements. Vitamin D may also be needed to maintain healthy bones. Some HIV medications can cause bone loss, so a medication switch may be beneficial in these cases. For severe osteoporosis, a group of drugs called bisphosphonates might be recommended.
For men with low testosterone levels and symptoms of hypogonadism, testosterone replacement therapy may be an option. This can improve sexual function, muscle mass, mood, and bone density. Women with premature menopause or long menstruation gaps could benefit from hormone replacement therapy to combat fast bone mineral density loss.
Growth hormone deficiency is usually managed through a combination of hormone replacement and treating the underlying disease. The use of growth hormone replacement in patients whose deficiency started in adulthood should be carefully considered due to the high costs and modest benefits.
For metabolic disorders, the strategy often involves diagnosing and treating any infectious diseases, addressing hormonal imbalances and improving overall calorie intake. Appetite stimulants can be considered for aiding weight gain. Testosterone replacement therapy or anabolic steroids may be useful for increasing muscle mass in cases of significant weight loss.
People with HIV may develop fat loss or gain in specific parts of their body. For fat loss, replacing certain HIV medications with others can sometimes help. Fat gain can usually be managed with a healthy diet and exercise. Medication-wise, metformin can help but should be avoided if there is coincident fat loss.
Managing diabetes in those with HIV is similar to managing it in the general population. It involves lifestyle changes, dietary management, weight reduction, and medications. For high cholesterol levels, statins are often the first line of treatment. However, choice must carefully be considered due to potential interactions with HIV medications.
What else can HIV-Related Endocrinopathies be?
In people with HIV, issues with the thyroid could potentially be due to several conditions like lack of iodine, autoimmune diseases, and various inflammations or disorders of the thyroid gland.
Additionally, when a person with HIV is diagnosed with adrenal insufficiency, other possible causes should be considered, especially those involving the pituitary gland or hypothalamus. These may include diseases or processes such as tumors, infections, and inflammatory disorders.
In cases of patients with HIV who present with a bone fracture, it’s important to rule out other conditions like cancer, fibrous dysplasia, and other bony lesions. They could also be dealing with secondary osteoporosis due to other conditions, which would require targeted treatment.
Sexual dysfunction and other symptoms of low testosterone in men could be due to a number of factors beyond hypogonadism. These include psychological problems related to HIV, fear of HIV transmission, drug use, body image issues in the context of AIDS-related weight loss, and issues with fat distribution.
A deficiency in growth hormone can be triggered by multiple disorders affecting the pituitary gland and hypothalamus. Potential causes could be tumors, infections, surgeries, accidents, and genetic abnormalities.
Various conditions can cause significant weight loss, including: gastrointestinal disorders like celiac disease, hormonal diseases like hyperthyroidism and adrenal insufficiency, advanced heart and kidney diseases, alcohol and substance use disorders, and cancer.
It’s also important to consider conditions that cause weight gain when diagnosing lipohypertrophy. These can include physical inactivity with excess calorie intake, hormonal issues, and potential side effects from certain medications.
In cases of diabetes mellitus, disorders or medications unrelated to HIV could be the cause. Prolonged use of antipsychotics, glucocorticoids, and thiazides can lead to glucose intolerance.
For people with severe hyperlipidemia and a strong family history of hyperlipidemia or early onset heart disease, consider familial syndromes. Other secondary causes of high lipid levels include diabetes mellitus, obesity, excessive alcohol consumption, hypothyroidism, and the usage of certain medications.
What to expect with HIV-Related Endocrinopathies
Thyroid Dysfunction
If treated correctly, people living with HIV have the same chances of recovering from thyroid dysfunction as those without HIV.
Adrenal Dysfunction
For HIV patients, treating adrenal insufficiency—when the adrenal glands don’t produce enough hormones—could be life-saving. But unnecessary treatment might worsen existing infections, increasing the risk of illness and even death. Adrenal insufficiency is usually a result of opportunistic infections or growth of abnormal tissue (neoplasia), and its presence often marks an advanced stage of AIDS.
Bone Disorders and Osteoporosis
Patients infected with HIV experience fragility fractures—when a bone breaks from a fall from standing height or less—about 10 years earlier than the general population. Transitioning to an HIV medicine plan that’s easier on the bones can slow down bone loss. However, it’s unclear if this also decreases the number of fractures. When treating osteoporosis in HIV-infected patients with medication that slows down or stops bone loss (bisphosphonates), a similar improvement in bone strength is seen to that in the general population. But it’s not yet known if this treatment can effectively decrease the number of fractures.
Gonadal Dysfunction
Hypogonadism—when a person’s sex glands produce little to no hormones—in an HIV individual not on ART (antiretroviral therapy used to manage HIV) can signify advanced AIDS and a poor overall outcome. The outlook can change depending on the root cause of hypogonadism. Secondary hypogonadism—which arises from issues involving the pituitary gland and is often due to abnormal tissue growth or infection—may have a worse outcome than most primary hypogonadism instances. However, testosterone replacement therapy can positively influence the quality of life by improving sexual function, mood, muscle mass and strength, and bone strength.
Growth Hormone Deficiency
In general, providing growth hormone (GH) to patients genuinely deficient in it can result in increased muscle mass, decreased fat, and enhanced quality of life. It has been found to strengthen bones in men, but not women, for unclear reasons. GH has differing effects on cholesterol levels, and the impact on the heart is mixed. However, research on its effect on overall survival chances is lacking.
Patients with GH deficiency due to a disease of the pituitary gland (hypopituitarism) face an elevated risk of dying from various causes even with hormone replacement. There’s no current research on the treatment of HIV individuals with GH deficiency and hormone replacement.
Metabolic Dysfunction
HIV- and AIDS-Wasting Syndromes
In patients suffering from wasting syndromes—a significant and unintentional weight loss—the amount of weight lost directly impacts their death risk. Even after the introduction of ART significantly cut the overall HIV-related death rate, HIV-related wasting continues to be an issue. Even on ART, losing more than 10% of body weight increases the mortality risk four to six times.
Disorders of Glucose and Lipid Metabolism and Fat Distribution
HIV individuals are more likely to develop various metabolic abnormalities. These risks are due to the HIV virus itself, the natural progression of the disease, and the use of ART. These metabolic complications can increase the risk for plaque buildup in arteries, leading to potential heart-related issues. In one study, HIV individuals had a 50% higher heart attack risk than the non-HIV population over six years. ART has greatly improved the lifespan of HIV patients. However, an important life expectancy gap still exists between people with HIV and those without.
Possible Complications When Diagnosed with HIV-Related Endocrinopathies
Thyroid Dysfunction
If hypothyroidism isn’t managed correctly, it can cause a number of health issues like anemia, electrolyte abnormalities, high fat levels in the blood, high blood pressure, and a higher risk of heart disease. In severe and untreated cases, hypothyroidism can cause myxedema coma, a dangerous condition with symptoms related to a slowed metabolism in various organs.
On the other hand, if hyperthyroidism isn’t properly treated, it can lead to complications like abnormal heart rhythms, heart failure, and bone loss. Severely unchecked hyperthyroidism can cause a thyroid storm, a potentially fatal state often triggered by stress, illness, or surgery.
All forms of thyroid dysfunction can negatively impact menstruation, fertility, and the outcome of pregnancies.
Adrenal Dysfunction
Absence of proper treatment can make acute adrenal insufficiency lethal due to cardiovascular collapse. Chronic adrenal insufficiency involves weight loss and its related complications, as well as a lower overall quality of life. A condition called Cushing’s syndrome can increase the risk of high blood glucose levels, high blood pressure, high blood fat levels, bone loss, and heart disease.
Bone Disorders and Osteoporosis
The main health issue related to osteoporosis is bone breakage. Spinal fractures are the most common, followed by hip and forearm fractures. These fractures can cause considerable pain and disability, and can lower the quality of life while increasing the risk of death.
Gonadal Dysfunction
Meanwhile, hypogonadism can lead to sexual dysfunction, weight loss, reduced happiness, and poor quality of life. It can also cause bone loss, increase chances of fragile bones that can easily break, and higher death rates. Testosterone replacement therapy, used for treatment, may elevate heart disease risk in older men. It may also cause increased red blood cell count, increased bad cholesterol, worsened sleep apnea, and a higher risk for blood clots.
Growth Hormone Deficiency
Patients with this deficiency that started in childhood face a higher risk of short adult height. All patients with this issue face risks of reduced bone mineral density, fractures, decrease in lean muscle mass, and fat accumulation. They usually score lower on quality-of-life measures than their healthy peers.
Metabolic Dysfunction
HIV- and AIDS-Wasting Syndromes
These conditions increase mortality rates and risks for malnutrition, bone loss, and fractures. Affected patients frequently get lower health-related quality-of-life scores.
Disorders of Fat Distribution, Glucose, and Lipid Metabolism
Lipodystrophy involves fat metabolism issues, insulin resistance, chronic inflammation, and an elevated heart disease risk. Issues with body fat distribution can harm self-esteem and life quality.
Complications linked to diabetes are wide-ranging, including diseases affecting the brain’s blood vessels, heart disease, chronic kidney disease, peripheral vascular disease, and vision loss from diabetic retinopathy. Dyslipidemia heightens the risk for hardening of the arteries and related issues. Severe hypertriglyceridemia can cause inflammation of the pancreas.
Preventing HIV-Related Endocrinopathies
People living with HIV should be aware that they have a higher chance of developing hormonal disorders and heart disease. Even though HIV itself can increase these risks, usual risk factors like age, family history, and high blood pressure are still very important predictors of heart disease for people with HIV. Therefore, the best way to reduce the risk of heart disease involves making healthy lifestyle changes. These include quitting smoking, eating a balanced diet, exercising regularly, maintaining a healthy weight, and limiting alcohol consumption.
