Primary aldosteronism: an update

 

Here's an update on this topic recently published in Cardiology in Review.

The original Conn syndrome was described in 1956 as a case report of a young woman with hypertension and severe hypokalemia who was found to have an adrenal adenoma and was cured after adrenalectomy. Subsequently we've found that primary aldosteronism is much more common than previously thought. It's certainly not a rare cause of secondary hypertension but it is markedly under-diagnosed.

The mechanism of action of aldosterone is described in the paper thusly:

Aldosterone, which is synthesized in the adrenal zona glomerulosa, acts primarily at the renal collecting tubule where it binds to mineralocorticoid receptors leading to an increased number of open epithelial sodium channels (ENaC) in the luminal membrane4 and increased Na-K-ATPase expression.5 Reabsorbed sodium leaves the luminal cell via the Na-K-ATPase pump. Subsequent intraluminal electronegativity triggers potassium secretion through membrane potassium channels. Additionally, aldosterone has been found to act at the second part of the distal convoluted tubule, where both the thiazide-sensitive sodium chloride cotransporter and ENaC are expressed. By regulating the function of these transporters, aldosterone is thought to have effects on sodium and chloride balance and blood pressure (BP) control.6

Hypokalemia is characteristic but only a minority of patients exhibit it at presentation.

Regarding the different etiologies, again, from the paper:

The most common cause of primary hyperaldosteronism is bilateral idiopathic hyperplasia (IHA), accounting for 60% of cases. An aldosterone-producing adenoma (APA) is seen in 30%, primary (unilateral) adrenal hyperplasia in 2%, aldosterone-producing adrenocortical carcinoma in less than 1%, familial hyperaldosteronism (FH) type 1 (glucocorticoid-remediable) in less than 1%, FH type 2 (APA or IHA) in less than 6%, and FH type 3 (germline KCNJ5 mutations) in less than 1%.9 Although germline mutations of KCNJ5 are quite rare, causing FH type 3 PA, somatic mutations of KCNJ5 are relatively common, and in one study was seen in 38% of patients with APA. These mutations are believed to increase expression of CYP11B2, the aldosterone synthase gene.10Glucocorticoid-remediable aldosteronism, which is inherited as an autosomal dominant trait, usually presents in childhood with moderate to severe hypertension. The pathophysiology involves ectopically synthesized aldosterone in the zona fasciculata under adrenocorticotropin control.

Patients with primary hyperaldosteronism have a higher cardiovascular risk then do those with comparable degrees of essential hypertension. This is believed to be due to direct extrarenal damaging effects of of aldosterone such as endothelial damage and myocardial fibrosis.

The two big questions are who should be screened and how to work it up. Guidelines are fairly aggressive in their recommendations for screening. They are covered in the paper. In brief, things that should trigger a workup include severity of hypertension (levels persistently exceeding 150 / 100), resistant hypertension which could be translated to mean failure to control the hypertension on 3 drugs or essentially any patient who is on four drugs even if controlled and hypokalemia whether spontaneous or diuretic associated. Additional candidates would include those with family history, those with early onset, and those with an adrenal incidentaloma. In addition those with sleep apnea are candidates. There is a somewhat poorly understood connection between sleep apnea and hyperaldosteronism.

It has been estimated that if these criteria or fully applied around 50% of hypertensive patients in primary care would be candidates for screening. This is straight out of of the Endocrine Society guidelines. This may seem like over testing and will certainly rule out the disorder in a substantial number of patients but it is promulgated in guidelines and published recommendations due to a substantially under-diagnosed disease burden.

Diagnosis starts with simultaneous measurement of renin and aldosterone. The renin measurement can either be plasma renin activity or renin concentration. Preferably these are done in the morning, seated for 5 to 15 minutes. The patient should be potassium and sodium replete and have diuretics discontinued. Unless the aldosterone to renin ratio is very high or spontaneous hypokalemia is observed further confirmatory testing is likely to be necessary followed by testing for the etiology of hyperaldosteronism. This includes ruling out glucocorticoid responsive hyperaldosteronism. Imaging is generally required followed often by adrenal vein sampling. Once one is past the initial screening test help from an endocrinologist or hypertension specialist might be warranted.

Thyroid acropachy: an unusual complication of Graves disease

From a recent published case report and mini-review:

The pathogenesis of acropachy is unknown, except for the anatomic location, in that it is probably similar to that of pretibial myxedema. It appears that TRAb molecules bind to the TSH receptors of fibroblasts present in the periosteum region and trigger an inflammatory response, producing cell proliferation and glycosaminoglycan deposition (7,8). The musculoskeletal manifestation is almost never seen without the remaining components of the triad of orbitopathy, dermopathy, and acropachy (9,10). Some studies suggest smoking is a predisposing factor for acropachy in GD patients (9).

In most cases, acropachy is asymptomatic, but the main clinical manifestations are digital clubbing, skin tightness with or without digital clubbing and usually with small-joint pain (in severe cases), soft tissue edema, and reactional periosteum, and skin alterations in fingers and nails may also be present (7). The disorder mostly affects the metacarpus phalangeal and proximal interphalangeal regions in the upper and lower limbs, especially the ankles and metatarsal phalangeal joints (11).

ICU or stepdown for your DKA patient?

From a recent study:

Highlights

In some centers, all Diabetic Ketoacidosis (DKA) patients are admitted to ICU.

No difference in in-hospital mortality was found between DKA patients admitted to step-down units or ICU.

DKA patients admitted to step-down units had significantly lower costs than those admitted to ICU.

Hospitals should preferentially consider monitoring of DKA patients in step-down units.

Abstract

Purpose

There is wide variation in the utilization of Intensive Care Unit (ICU) beds for treatment and monitoring of adult patients with Diabetic Ketoacidosis (DKA). We sought to compare the outcomes and hospital costs of adult DKA patients admitted to ICUs as compared to those admitted to step-down units.

Materials and methods

We included consecutive adult patients from two hospitals with a diagnosis of DKA. Patients were either admitted to the ICU, or a step-down unit, which has a nurse-to-patient ratio of 2:1, but does not have capability for mechanical ventilation or administration of vasoactive agents. The primary outcome was in-hospital mortality.

Results

We included 872 patients in the analysis. 71 (8.1%) were admitted to ICU, while 801 (91.9%) were admitted to a step-down unit. We found no difference in in-hospital mortality between patients admitted to the ICU and those admitted to the step-down unit (adjusted odds ratio [OR]: 1.14, 95% confidence interval [CI]: 0.87–2.64). Mean total hospital costs were significantly higher for patients admitted to the ICU ($20,428 vs. $6484, P less than 0.001).

Conclusions

Adult DKA patients admitted to a step-down unit had comparable in-hospital mortality and lower hospital costs as compared to those admitted to the ICU.

The cholesterol hypothesis is alive again!

From a recent paper in JAMA:

Key Points

Question Is consuming dietary cholesterol or eggs associated with incident cardiovascular disease (CVD) and all-cause mortality?

Findings Among 29 615 adults pooled from 6 prospective cohort studies in the United States with a median follow-up of 17.5 years, each additional 300 mg of dietary cholesterol consumed per day was significantly associated with higher risk of incident CVD (adjusted hazard ratio [HR], 1.17; adjusted absolute risk difference [ARD], 3.24%) and all-cause mortality (adjusted HR, 1.18; adjusted ARD, 4.43%), and each additional half an egg consumed per day was significantly associated with higher risk of incident CVD (adjusted HR, 1.06; adjusted ARD, 1.11%) and all-cause mortality (adjusted HR, 1.08; adjusted ARD, 1.93%).

Meaning Among US adults, higher consumption of dietary cholesterol or eggs was significantly associated with higher risk of incident CVD and all-cause mortality in a dose-response manner.

This paper has been wildly overhyped. It’s new data but concludes nothing we didn’t already know: cholesterol matters. The real problem is, so do a lot of other things. Those who would hype this finding lack an appreciation of the concept of population attributable risk.

Do you really need a TSH receptor antibody test to distinguish Grave’s disease from other forms of hyperthyroidism?

In this study clinical assessment alone was poor.

Testosterone replacement associated with better cardiovascular outcomes

Will a randomized controlled trial some day blow this out of the water like we saw in the case of ERT?

What to do with subclinical hyperthyroidism

From a recent concise review:

Subclinical hyperthyroidism is defined by a low or undetectable serum thyroid-stimulating hormone level, with normal free thyroxine and total or free triiodothyronine levels. It can be caused by increased endogenous production of thyroid hormone (e.g., in Graves disease, toxic nodular goiter, or transient thyroiditis), by administration of thyroid hormone to treat malignant thyroid disease, or by unintentional excessive replacement therapy. The prevalence of subclinical hyperthyroidism in the general population is about 1% to 2%; however, it may be higher in iodine-deficient areas. The rate of progression to overt hyperthyroidism is higher in persons with thyroid-stimulating hormone levels less than 0.1 mIU per L than in persons with low but detectable thyroid-stimulating hormone levels. Subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation and heart failure in older adults, increased cardiovascular and all-cause mortality, and decreased bone mineral density and increased bone fracture risk in postmenopausal women. However, the effectiveness of treatment in preventing these conditions is unclear. A possible association between subclinical hyperthyroidism and quality-of-life parameters and cognition is controversial. The U.S. Preventive Services Task Force found insufficient evidence to assess the balance of benefits and harms of screening for thyroid dysfunction in asymptomatic persons. The American Thyroid Association and the American Association of Clinical Endocrinologists recommend treating patients with thyroid-stimulating hormone levels less than 0.1 mIU per L if they are older than 65 years or have comorbidities such as heart disease or osteoporosis.

Testosterone and cardiovascular health

From a recent review:

Testosterone (T) has a number of important effects on the cardiovascular system. In men, T levels begin to decrease after age 40, and this decrease has been associated with an increase in all-cause mortality and cardiovascular (CV) risk. Low T levels in men may increase their risk of developing coronary artery disease (CAD), metabolic syndrome, and type 2 diabetes. Reduced T levels in men with congestive heart failure (CHF) portends a poor prognosis and is associated with increased mortality. Studies have reported a reduced CV risk with higher endogenous T concentration, improvement of known CV risk factors with T therapy, and reduced mortality in T-deficient men who underwent T replacement therapy versus untreated men. Testosterone replacement therapy (TRT) has been shown to improve myocardial ischemia in men with CAD, improve exercise capacity in patients with CHF, and improve serum glucose levels, HbA1c, and insulin resistance in men with diabetes and prediabetes. There are no large long-term, placebo-controlled, randomized clinical trials to provide definitive conclusions about TRT and CV risk. However, there currently is no credible evidence that T therapy increases CV risk and substantial evidence that it does not. In fact, existing data suggests that T therapy may offer CV benefits to men.

Autoimmune thyroid disease

Free full text review. From the conclusion:

The management of autoimmune thyroid disease continues to be revised by new research which includes the identification of new entities, such as IgG4-related thyroid disease and new drug-induced forms of thyroid disease; the development of novel small molecules capable of influencing mechanisms of autoimmunity; and more detailed knowledge of the risks versus benefits of thyroxine therapy in subclinical hypothyroidism.

Adrenal crisis

Nuts, bolts and a lot of pearls here.

Renin-aldosterone profiling for all hypertensives? Have we come full circle?

Decades ago John Laragh popularized renin profiling for the evaluation of hypertensive patients. But due to limited availability of testing in community practice and a shift in the way population based research was applied to the treatment of hypertension it fell out of favor. More recently interest has resurfaced. In a recent issue of JACC there is a paper on the prevalence and clinical characteristics of primary aldosteronism. From the paper:

Background Despite being widely recognized as the most common form of secondary hypertension, among the general hypertensive population the true prevalence of primary aldosteronism (PA) and its main subtypes, aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH), remains a matter of debate.

Objectives This study sought to determine the prevalence and clinical phenotype of PA in a large cohort of unselected patients with hypertension, consecutively referred to our hypertension unit, by 19 general practitioners from Torino, Italy.

Methods Following withdrawal from all interfering medications, patients were screened for PA using the ratio of serum aldosterone to plasma renin activity. PA was diagnosed according to Endocrine Society guidelines. The diagnosis was confirmed or excluded by an intravenous saline infusion test or captopril challenge test and subtype differentiation was performed by adrenal computed tomography scanning and adrenal vein sampling, using strict criteria to define successful cannulation and lateralization of aldosterone production.

Results A total of 1,672 primary care patients with hypertension (569 newly diagnosed and 1,103 patients already diagnosed with arterial hypertension) were included in the study. A total of 99 patients (5.9%) were diagnosed with PA and conclusive subtype differentiation by adrenal vein sampling was made in 91 patients (27 patients with an APA and 64 patients with BAH). The overall prevalence of PA increased with the severity of hypertension, from 3.9% in stage 1 hypertension to 11.8% in stage 3 hypertension. Patients with PA more frequently displayed target organ damage and cardiovascular events compared with those without PA, independent of confounding variables.

Conclusions Our results demonstrated that PA is a frequent cause of secondary hypertension, even in the general population of patients with hypertension, and indicates that most of these patients should be screened for PA.

An editorial in the same issue advocates for screening of all hypertensives.

There were some eye opening findings. Of the target organ complications cited above, LVH was seen in 54% of patients with PA vs 32% of those with essential hypertension (EH), microalbuminuria in 27% with PA vs 13% with EH and cardiovascular events in 15% with PA vs 6% with EH. Serum potassium was not a useful marker, as hypokalemia was seen in only 29% of those with PA.

Screening is not that difficult but what if the patient tests positive? That would lead to a lot of CT scans and invasive adrenal vein samplings. As the speaker in the audio file said, it’s something to think about the next time a patient with hypertension comes into your office.

Smart Mat technology can detect diabetic foot ulcers a month in advance

From a report in Diabetes Care. There were a lot of false positives.

RAI vs antithyroid drugs

This is from an evidence summary from AFP:

Radioactive iodine therapy and antithyroid medications produce similar health-related quality-of-life outcomes in patients with Graves disease. Radioactive iodine therapy is an appropriate choice for patients who prefer definitive treatment. Antithyroid medications are appropriate in patients attempting to avoid long-term thyroid hormone therapy and should be considered in those with increased risk of Graves ophthalmopathy, such as smokers.1 (Strength of Recommendation: B, based on inconsistent or limited-quality patient-oriented evidence.)

Pre admission oral corticosteroids and the risk of ARDS in septic patients

From a recent study:

Objectives: To determine the association between preadmission oral corticosteroid receipt and the development of acute respiratory distress syndrome in critically ill patients with sepsis.

Design: Retrospective observational study.

Setting: Medical, surgical, trauma, and cardiovascular ICUs of an academic medical center.

Patients: A total of 1,080 critically ill patients with sepsis.

Interventions: None.

Measurements and Main Results: The unadjusted occurrence rate of acute respiratory distress syndrome within 96 hours of ICU admission was 35% among patients who had received oral corticosteroids compared with 42% among those who had not (p = 0.107). In a multivariable analysis controlling for prespecified confounders, preadmission oral corticosteroids were associated with a lower incidence of acute respiratory distress syndrome in the 96 hours after ICU admission (odds ratio, 0.53; 95% CI, 0.33–0.84; p = 0.008), a finding that persisted in multiple sensitivity analyses. The median daily dose of oral corticosteroids among the 165 patients receiving oral corticosteroids, in prednisone equivalents, was 10 mg (interquartile range, 5–30 mg). Higher doses of preadmission oral corticosteroids were associated with a lower incidence of acute respiratory distress syndrome (odds ratio for 30 mg of prednisone compared with 5 mg 0.53; 95% CI, 0.32–0.86). In multivariable analyses, preadmission oral corticosteroids were not associated with in-hospital mortality (odds ratio, 1.41; 95% CI, 0.87–2.28; p = 0.164), ICU length of stay (odds ratio, 0.90; 95% CI, 0.63–1.30; p = 0.585), or ventilator-free days (odds ratio, 1.06; 95% CI, 0.71–1.57; p = 0.783).

Conclusions: Among ICU patients with sepsis, preadmission oral corticosteroids were independently associated with a lower incidence of early acute respiratory distress syndrome.

Should subclinical hyperthyroidism be treated? If so, when?

Here are some key points from the ATA guidelines:

When TSH is persistently less than 0.1 mU/L, treatment of SH is recommended in all individuals greater than or equal to 65 years of age; in patients with cardiac risk factors, heart disease or osteoporosis; in postmenopausal women who are not on estrogens or bisphosphonates; and in individuals with hyperthyroid symptoms…

When TSH is persistently less than 0.1 mU/L, treatment of SH should be considered in asymptomatic individuals less than 65 years of age without the risk factors listed in Recommendation 73...

When TSH is persistently below the lower limit of normal but greater than or equal to 0.1 mU/L, treatment of SH should be considered in individuals greater than or equal to 65 years of age and in patients with cardiac disease, osteoporosis, or symptoms of hyperthyroidism…

When TSH is persistently below the lower limit of normal but greater than or equal to 0.1 mU/L, asymptomatic patients under age 65 without cardiac disease or osteoporosis can be observed without further investigation of the etiology of the subnormal TSH or treatment.

Insulin pump versus multiple injections for DM 1

From a large population based cohort study:

Conclusions and Relevance Among young patients with type 1 diabetes, insulin pump therapy, compared with insulin injection therapy, was associated with lower risks of severe hypoglycemia and diabetic ketoacidosis and with better glycemic control during the most recent year of therapy. These findings provide evidence for improved clinical outcomes associated with insulin pump therapy compared with injection therapy in children, adolescents, and young adults with type 1 diabetes.

SGLT-2 inhibitors: no increased risk of ketoacidosis in clinical trials in meta-analysis

This is in contrast to what is seen in the real world.

The link between the metabolic syndrome and sudden cardiac death

From a large database:

Clinical Perspective

What Is New?

In a longitudinal, population‐based sample of 13 168 residents from 4 US communities followed for a median of 23.6 years, participants with the metabolic syndrome had a 4.1% incidence of sudden cardiac death compared with 2.3% among participants without it.

The metabolic syndrome was independently associated with sudden cardiac death irrespective of sex or race.

Sudden cardiac death risk was proportional to the number of metabolic syndrome components.

What Are the Clinical Implications?

Sudden cardiac death risk associated with the metabolic syndrome may be reduced by treatment of high blood pressure, impaired glucose tolerance, and lipid levels.

Parathyroid disease and heart disease

Here is a free full text review on the associations.

From the review:

Parathyroid hormone (PTH) acts on G-protein coupled receptors in the heart to exert changes in cardiac myocyte contractility, proliferation, and hypertrophy.

In the vasculature, PTH alters the endothelium.

Excess PTH (as seen in primary and secondary hyperparathyroidism) is associated with a higher incidence of hypertension, left ventricular hypertrophy, heart failure, cardiac arrhythmias, and valvular calcific disease, which may contribute to higher cardiac morbidity and mortality.

Low PTH states (as seen in congenital and acquired disorders of the parathyroid glands) are associated with cardiac arrhythmias and dilated cardiomyopathy.

Early medical and/or surgical treatment of parathyroid disorders can reverse detrimental structural and functional changes in the cardiovascular system such as left ventricular mass, conduction abnormalities, atherosclerotic disease, and valvular calcifications. This may result in reduced cardiac morbidity and mortality.

Pioglitazone use improves NASH and associated fibrosis

JAMA Internal Medicine:

Question What is the association of thiazolidinedione therapy with advanced liver fibrosis in nonalcoholic steatohepatitis?

Findings In this meta-analysis of 8 randomized clinical trials enrolling 516 patients with biopsy-proven nonalcoholic steatohepatitis, thiazolidinedione therapy was associated with reversed advanced fibrosis, improved overall fibrosis stages, and resolution of nonalcoholic steatohepatitis. Pioglitazone hydrochloride use accounted for all of the effects of thiazolidinedione therapy in nonalcoholic steatohepatitis, and these benefits were observed in patients without diabetes as well.

Meaning Pioglitazone use improves advanced fibrosis in nonalcoholic steatohepatitis, even in patients without diabetes, and may thus halt disease progression to end-stage liver disease in this patient population.