Cushing's syndrome (CS) is a multifaceted clinical condition arising from prolonged exposure to excessive levels of cortisol. This hormonal imbalance can stem from various sources, including the prolonged intake of synthetic corticosteroids (exogenous CS) or the overproduction of cortisol or adrenocorticotropic hormone (ACTH) within the body (endogenous CS). Cushing's disease (CD), a specific subtype of CS, is characterized by hypercortisolism caused by a pituitary tumor. Hypercortisolism is found to cause many metabolic abnormalities including hypertension, hyperlipidemia, impaired glucose tolerance, and central adiposity. Given the array of metabolic disturbances associated with CS, dietary interventions have emerged as a promising adjunctive strategy to manage the condition. Specifically, the role of protein intake and ketogenic diets has garnered attention in recent years.
Understanding Cushing's Syndrome and Its Metabolic Impact
Cushing’s syndrome (CS) is a rare disorder of hypercortisolism related to exposure to high levels of cortisol (>20 mcg/dL between 0600-0800 or >10 mcg/dL after 1600) for an extended period. CS affects 10 to 15 people per million and is more common among those with diabetes, hypertension, and obesity. The metabolic derangements associated with CS include visceral obesity, elevated blood pressure, dyslipidemia, type II diabetes mellitus (T2DM) and insulin resistance. CS physical exam findings include round face, dorsal fat pad, central obesity, abdominal striae, acne, and ecchymosis. Other symptoms associated with CS include low libido, headache, change in menses, depression and lethargy. The most common features of CS are weight gain, which is found in 82% of cases, and hypertension, which is found in 50-85% of cases.
CS can be caused by exogenous glucocorticoids, known as iatrogenic CS, ectopic ACTH secretion (EAS) from sources like a small cell lung cancer or adrenal adenoma, known as EAS CS, or excess production of ACTH from a pituitary tumor, known as CD. In CD, ACTH subsequently causes increased production of cortisol from the adrenal glands. CD accounts for 80-85% of endogenous cases of CS. Other conditions including alcoholism, depression, severe obesity, bulimia and anorexia nervosa can lead to a Cushing-like state, although are not considered true CS.
Ketogenic Diets: A Potential Therapeutic Approach
The low-carbohydrate diet approach and, notably, the very low-calorie ketogenic diet (VLCKD) have several therapeutic applications, improving many metabolic disorders, including diabetes mellitus, obesity, arterial hypertension, insulin resistance and dyslipidaemia, as strongly supported by evidence.
A LC diet is a general term for diets which lower the total carbohydrates consumed per day. A ketogenic diet is a subtype of LC that is described as having even fewer carbohydrates, typically less than 30 g/day. By reducing carbohydrate intake and thus limiting insulin production, the body achieves ketosis by producing an elevated number of ketones including β-hydroxybutyric acid, acetoacetic acid, and acetone, in the blood. A carnivore diet, a specific type of a ketogenic diet, is defined as mainly eating animal food such as meat, poultry, eggs and fish. Contrarily, a standard American diet (SAD) is defined as a diet high in processed foods, carbs, added sugars, refined fats, and highly processed dairy products. There are several therapeutic applications for LC diets that are currently supported by strong evidence. These include weight loss, cardiovascular disease, T2DM, and epilepsy.
Read also: Dietary Guidelines for Dogs with Cushing's
Mechanisms of Ketogenesis
Reduction in exogenous glucose intake and reduction in the insulin/glucagon ratio result in reduced inhibition of lipolysis in adipose tissue. This leads to increased levels of free fatty acids circulating and to greater beta oxidation of fatty acids, with the formation of ketone bodies at the liver level and, to a lesser extent, at the renal level. Blood sugar levels are maintained in a physiological range thanks to liver function, both through mobilization from the hepatic glycogen reserve and through the process of gluconeogenesis.
Ketone bodies are used by many tissues, including those of the heart, kidney, skeletal muscle and central nervous system. In physiological conditions, Acetyl-CoA can be combined with oxaloacetate that is obtained by glycolytic processes. A VLCKD is associated with a slowed glycolysis, which results in the use of oxaloacetate for neoglucogenesis, while the Acetyl-CoA obtained from the beta oxidation of fatty acids is used for the production of ketone bodies. The VLCKD diet is the model with the greatest availability of Acetyl-CoA.
Phases of a VLCKD
Generally, a VLCKD includes six phases. In Phase 1, patients are educated to eat high-biological-value protein preparations five times a day and vegetables with a low glycemic index. Meal preparations contain 18 g of proteins, 4 g of carbohydrates and 3 g of fats. In Phase 2, a portion of natural proteins, including meat/egg/fish, can be introduced at lunch or dinner combined with a protein preparation. In Phase 3, a second portion of natural protein is added in place of the protein preparation. After, a low-carbohydrate diet with a daily calorie intake ranging from 1200 to 1500 Kcal/day is started. Carbohydrates are gradually reintroduced. First, foods with a lower glycemic index are introduced, including fruit and milk products (Phase 4), followed by moderate glycemic index food such as legumes (Phase 5) and high glycemic index ones (bread, pasta and cereals-Phase 6).
VLCKD in Cushing's Disease Patients: A Clinical Evaluation
A very low-calorie ketogenic diet (VLCKD) is associated with improvement of metabolic and cardiovascular disorders. One study aimed to evaluate the effects of a VLCKD in patients with Cushing’s disease (CD) as adjunctive therapy to treatment for the primary disease. The study evaluated clinical, hormonal and metabolic parameters in 15 patients with CD and 15 controls at baseline after 1 week and 3 weeks of VLCKD and, further, after 2 weeks of a low-carbohydrate ketogenic diet (LCKD).
Key Findings
After 5 weeks of diet, a significant decrease in BMI (p = 0.002), waist circumference (WC) (p = 0.024), systolic blood pressure (p = 0.015), diastolic blood pressure (p = 0.005), ACTH (p = 0.026), cortisone (p = 0.025), total cholesterol (p = 0.006), LDL cholesterol (p = 0.017), triglycerides (p = 0.016) and alkaline phosphatase (p = 0.008) and a significant increase in HDL cholesterol (p = 0.017), vitamin D (p = 0.015) and oral disposition index (oDI) (p = 0.004) was observed in the CD patients. A significant decrease in BMI (p = 0.003), WC (p = 0.002), systolic blood pressure (p = 0.025), diastolic (p = 0.007) blood pressure and total cholesterol (p = 0.026) and an increase in HDL cholesterol (p = 0.001) and oDI (p < 0.001) was observed in controls.
Read also: Understanding Cushing's and Weight
Study Protocol
Patients with CD were all pharmacologically treated for the primary disease. Ten were treated with a pituitary-directed drug, pasireotide, and five with an adrenal-directed drug, metyrapone. After enrolment, patients with CD and controls were instructed to follow a nutrition plan of VLCKD for 3 weeks followed by 2 weeks of LCKD. Among patients with CD, 9 out of 15 had diabetes mellitus, 6 were on metformin treatment and 3 were on GLP-1 receptor agonists which were suspended 1 week before the start of VLCKD protocol. In total, 7 out of 15 had arterial hypertension and were pharmacologically treated with ACE inhibitors. After, a 2-week LCKD plan was prescribed consisting of three replacement meals, one conventional protein meal and two portions of low glycemic index vegetables for lunch and dinner for a total of about 820 Kcal/day.
Assessment of Clinical and Biochemical Parameters
Both in patients with CD and in controls, at baseline (time 0) and after 1 week and 3 weeks of VLCKD and a further 2 weeks of LCKD (after a total time of 5 weeks), clinical parameters (BMI, waist circumference and systolic and diastolic blood pressure), hormonal parameters (urinary free cortisol (UFC) on 24 h urine collection, late night salivary cortisol at 11 pm, serum cortisol at 8 am, serum ACTH at 8 am, serum cortisone, serum 17hydroxyprogesterone (17OHP), androstenedione and DHEAS) and metabolic parameters (fasting glucose and insulin; total, HDL and LDL cholesterol; triglycerides, glutamic oxaloacetate transaminase (GOT); glutamic piruvate transaminase (GPT); alkaline phosphatase; gammaGT; blood count; creatinine; sodium; potassium; calcium; phosphorus; parathyroid hormone; vitamin D and C-reactive protein) were evaluated. In addition, glycated hemoglobin (HbA1c) was measured only at baseline and an oral glucose tolerance test (OGTT) with evaluation of serum glucose and insulin at baseline and after (30-60-90-120 min) administration of 75 g of glucose was performed. Matsuda insulin sensitivity index (ISI-Matsuda), the oDI (oral disposition index) and the area under the curves of insulin (AUC2-h insulinemia) and glucose (AUC2-h glycemia) at baseline and after 5 weeks, both in patients with CD and controls were further calculated.
Adverse Events
All patients included in the study completed the protocol. Some adverse events were registered: 10 patients with CD and 11 controls experienced acetonemic breath and headache; 3 patients with CD and 2 controls experienced hunger; 9 patients with CD and 10 controls experienced constipation.
Impact on Cortisol and ACTH Levels
Analyzing in detail patients with CD, after 5 weeks of ketogenic diet, a decrease in ACTH in 12 out of 15 patients, a decrease in UFC in 10 out of 15 patients, a decrease in salivary cortisol in 6 out of 15 and a decrease in cortisol after 1 mg of DST in 4 out of 15 patients was observed. By contrast, in controls, a decrease in ACTH in 12 out of 15 patients, a decrease in UFC in 6 out of 15, a decrease in cortisol after 1 mg of DST in 4 out of 15 and a decrease in serum cortisol in 5 out of 15 after 5 weeks of diet was observed.
The Role of Cortisone and Vitamin D
The study revealed no changes in serum and urinary cortisol levels and ACTH levels, while a significant increase in cortisone serum levels was observed in patients with CD. It also showed that patients with CS had lower vitamin D levels compared to healthy controls, with significant improvement after a VLCKD.
Read also: Diet and Ogilvie Syndrome
Influence of 11β-HSD1 Enzyme
An interesting role in obesity is played by the enzyme 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which is involved in conversion of inactive cortisone into active cortisol; it was observed that this activity could change after weight loss. Other studies reported unchanged serum cortisol, cortisone and urinary steroid levels and decreased 11β-HSD1 after weight loss.
Comparison with Other Dietary Interventions
Interestingly, the effects of fasting, a very low-calorie diet (VLCD) and a low-calorie diet (LCD) on serum cortisol levels were evaluated by a metanalysis. This meta-analysis excluded studies based on salivary or urinary cortisol levels in order to prevent heterogeneity of the studies. Short-term calorie restriction was reported to be associated with an increase in cortisol values, while a VLCD and LCD had no long-term effects on serum cortisol values and were less stressful than fasting. In contrast, other findings reported a significant increase in cortisol levels after high-protein and high-fat meals, the time of observation was limited to a single meal, and it is difficult to speculate whether the cortisol response could change after chronic assumption of high-protein and high-fat meals.
Impact of Cortisol-Lowering Drugs
The study also evaluated patients with CD regarding pharmacological treatment for the primary disease. Cortisol-lowering drugs could impact on the results of a lack of change on serum, salivary and urinary cortisol values. However, a control group of healthy people was also evaluated and no significant changes in cortisol values, supporting the hypothesis that a ketogenic diet does not have a relevant effect on cortisol values.
Benefits of Nutritional Intervention in CD
Nutritional intervention may be a mainstay for the treatment of CD that is able to improve metabolic complications of CD when combined with the treatment of the primary disease. Indeed, a VLCKD reduces visceral fat and decreases appetite, resulting in weight loss. It reduces lipogenesis, increases lipolysis and decreases glucose and insulin levels, improving insulin sensitivity and glycemic control in patients with type 2 diabetes mellitus and gonadal function in women with PCOS. In addition, the natriuretic effect of ketone bodies results in a reduction in blood pressure values. Controlled ketogenesis is one of the mechanisms of action of inhibitors of renal sodium-glucose co-transporter type 2 (SGLT2-inhibitors), which, beyond causing natriuresis and glycosuria, promote a shift towards ketogenesis resulting in a 38% decrease in cardiovascular mortality. Further, a VLCKD improves inflammation, reducing TNF-alpha, PAI-1, IL-6, IL-8 and MCP-1, which are strongly involved in the pathophysiology of cardiovascular diseases and obesity.
Study Limitations
The current study shows some limitations. First, the number of patients with CD included in the study is quite low, even though CD is rare. Second, the duration of the study is brief. Third, the pharmacological treatment of CD was different among the patients. Fourth, the overall nutritional risk of an enduring implementation of this dietary protocol were not evaluated. However, the study, to our knowledge, is the first one which evaluates the usefulness of nutritional intervention in patients with CD, analyzing the effects on serum and urinary cortisol levels, beyond anthropometric, metabolic and insulin sensitivity parameters, not only in patients with CD but also in a control group.
A Case Report: Low-Carb Diet and Cushing's Disease
Literature shows that many of the symptoms of hypercortisolism can improve with a low carb (LC) diet, which consists of consuming <30 g of total carbohydrates per day. In one case report, a patient with CD who presented with obesity, hypertension, striae and bruising, initially improved some of his symptoms by implementing a LC diet. Despite strict adherence, his symptoms of insulin resistance and hypertension persisted. This case report also highlights that when patients are unable to overcome hormonal pathology, clinicians should not blame patients for lack of adherence to a diet, but instead understand the need to evaluate for complex pathology.
Patient History and Dietary Changes
A male patient in his thirties, of Asian descent, had a past medical history of easy bruising, central obesity, headaches, hematuria, and hypertension and past family medical history of hypertension in his father and brother. In 2015, he was at his heaviest weight of 179 lbs. with a body mass index (BMI) of 28 kg/m2, placing him in the overweight category (25.0-29.9 kg/m2). At that time the patient reported he was following a SAD diet and was active throughout the day. The patient stated he ate a diet of vegetables, fruits and carbohydrates, but he was not able to lose weight. The patient stated that he switched to a LC diet, to address weight gain and hyperglycemia, and he reported that he lost approximately 35 lbs. in 1.5 years. The patient described his LC diet as eating green leafy vegetables, low carb fruits, fish, poultry, beef and dairy products. The patient then later switched to a carnivore diet. He noted despite aggressively adhering to his diet, that his weight-loss had plateaued, although his waist circumference continued to decrease.
Metabolic Markers and Hospital Admission
The patient’s blood glucose levels decreased overtime despite impaired glucose metabolism being a known side effect of hypercortisolism. The patient’s high-density lipoprotein (HDL) remained in a healthy range (40-59 mg/dL) and his triglycerides stayed in an optimal range (<100 mg/dL), despite dyslipidemia being a complication of CD. Despite strict adherence to his diet and initial improvement in his weight, his blood pressure and his blood sugar levels, in October of 2021 the patient was admitted to the hospital for hypertensive urgency, with a blood pressure of 216/155. His complaints at the time were unexplained ecchymosis, hematuria and significant headaches that were resistant to Excedrin (acetaminophen-aspirin-caffeine) use.
Diagnosis of Cushing's Disease
Given the persistent symptoms, despite his significant change in diet and weight loss, a hormonal etiology was suspected. The patient was seen in-person, in our office, in March of 2022. On the physical exam, moon facies and prominent abdominal striae were noted. Several screening tests for Cushing’s syndrome were ordered. Based on screening tests and significant physical exam findings, the patient was referred to endocrinology for a low dose dexamethasone suppression test (DST). The low dose DST and midnight salivary cortisol were both positive indicating hypercortisolism. To begin determining the source of hypercortisolism, the plasma ACTH was evaluated. The MRI revealed a 4 mm heterogeneous lesion in the central pituitary gland which is suspicious of a cystic microadenoma. To confirm that a pituitary tumor was the cause of the patient’s increased cortisol, the patient was sent for inferior petrosal sinus sampling (IPSS). The ratios confirmed that the hypercortisolism was due to the pituitary tumor.
Diagnostic Procedures for Cushing's Syndrome
When CS is suspected based on clinical findings, the use of exogenous steroids must first be excluded as it is the most common cause of hypercortisolism. If there is still concern for CS, there are three screening tests that can be done which are sensitive but not specific for hypercortisolism. The screening tests include: a 24-h UFC, 2 late night salivary cortisol tests, low dose (1 g) DST. The first step to determine the cause of hypercortisolism is to measure the plasma level of ACTH. Low values of ACTH < 5 pg/mL indicate the cause is likely ACTH-independent CS and imaging of the adrenal glands is warranted as there is a high suspicion of an adrenal adenoma. When the serum ACTH is elevated >/20 pg/mL it is likely an ACTH-dependent form of CS. To further evaluate an ACTH-dependent hypercortisolism, an MRI should be obtained as there is high suspicion that the elevated cortisol is coming from a pituitary adenoma. If there is a pituitary mass >6 mm there is a strong indication for the diagnosis of CD. If there is still a high suspicion of CD with an inconclusive MRI, a high dose DST (8 g) is done. Patients with CD should not respond and their ACTH and DHEA, a steroid precursor, should remain high. Similarly, CRH stimulation test is done and patients with CD should have an increase in ACTH and/or cortisol within 45 min of CRH being given. If the patient has a positive high-dose DST, CRH-stimulation test and an MRI with a pituitary tumor >6 mm no further testing is needed as it is likely the patient has CD. If either of those tests are abnormal, the MRI shows a pituitary tumor < 6 mm, or there is diagnostic ambiguity, the patient should undergo IPSS with ACTH measurements before and after the administration of CRH.
IPSS is the gold standard for determining the source of ACTH secretion and confirming CD. In this invasive procedure, ACTH, prolactin, and cortisol levels are sampled prior to CRH stimulation and after CRH stimulation. To confirm CD, a ratio of IPS:P is calculated for values prior to and after CRH stimulation. A peak ratio greater than 2.0 before CRH stimulation or a peak ratio greater than 3.0 after CRH stimulation is indicative of CD.
General Dietary Recommendations for Cushing's Syndrome
Cushing syndrome occurs due to abnormally high levels of cortisol, which is commonly related to steroid use. Symptoms include weight gain, thinning skin, fluid retention, and stretch marks, among others. Cushing syndrome may cause a wide range of symptoms, including: unintentional weight gain, fatty deposits, purple stretch marks, muscle weakness, edema, thinning skin, hyperhidrosis, skin injuries that are slow to heal, back pain, bone pain, acne, fatigue, increased number of infections, anxiety, irritability, depression, mood changes, hypertension, hyperglycemia, increased thirst, and increased urination.
According to Cindy Penaranda, a registered dietitian with Banner Health, fine-tuning your diet can help bring balance back to your health. Here are some dietary recommendations for someone who is living with Cushing syndrome:
Vitamin D: The sunshine vitamin is packed inside foods like fatty fish, mushrooms and some cereals.
Avoid sugary and processed foods: Too much cortisol can mess with your blood sugar, weight and eating habits, putting you at greater risk for insulin resistance (prediabetes) and diabetes. Avoid sugary and processed foods and snacks to keep your blood sugar and weight gain in check. Pick high-fiber foods rich in carbohydrates with lower glycemic levels.
Limit salt intake: High cortisol can play a sour note on your blood pressure, leading to hypertension. Skip the salty processed stuff and stick with natural choices like fresh fruits, veggies, eggs, lean meats like chicken and fish and homemade soups.
Consume enough protein: Sometimes, Cushing syndrome can make your muscles weaker. People with Cushing syndrome may have thinner arms and legs due to reduced muscle mass, Eating enough protein can help keep your muscles in good shape.
Stay hydrated: Don’t forget to drink plenty of water. Staying hydrated helps your body work better and prevents fluid buildup.
Treatment Options for Cushing's Syndrome
The overall goal of Cushing syndrome treatment is to lower the levels of cortisol in your body. Your treatment plan will depend on the underlying cause. If your condition is caused by taking steroid medications, a doctor will recommend lowering your dose or suggest an alternative nonsteroidal treatment. A doctor may also prescribe a medication to help manage cortisol levels. Some drugs decrease cortisol production in the adrenal glands or decrease ACTH production in the pituitary gland. Others block the effect of cortisol on your tissues. Examples of medications may include: ketoconazole (Nizoral), mitotane (Lysodren), metyrapone (Metopirone), pasireotide (Signifor), mifepristone (Korlym, Mifeprex) in those with type 2 diabetes or glucose intolerance.
For pituitary, endocrine, and adrenal tumors, the first-line treatment is surgical removal. If surgery doesn’t work or the cancer has spread, a healthcare professional may recommend other cancer treatments like radiation therapy or chemotherapy.