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A 45-year-old woman presented to the Emergency Room with acute shortness of breath such that she was barely able to give a history. She was a life-long non-smoker and had a past history of moderately severe asthma requiring on average two courses of oral glucocorticoid steroids per year. In addition, over the previous year she had noted deterioration in her exercise tolerance that was unrelated to her asthma. Non-invasive cardiac investigations (an echocardiogram) 6 months previously had demonstrated impaired left ventricular function. Over the day prior to admission, use of her β2-adrenergic agonist inhalers had not proved beneficial. When seen, she had a blood pressure of 130/75 mmHg, a tachycardia of 130/min, a respiratory rate of 30/min and widespread wheeze in her chest. No cardiac murmurs were heard. The peak expiratory flow rate was 120 l/min (normal for her age and height 450 l/min). Chest X-ray showed borderline cardiomegaly (Box 8.2).
The dilemma for the medical team in this case was to distinguish the cause of her dyspnea when she clearly had two possible causes; asthma or pulmonary edema due to poor left ventricular (LV) function. In this case, knowledge of the endocrinology of heart failure facilitated the differential diagnosis.
Impaired LV function causes a primary decrease in cardiac output and, as a result, arterial blood pressure falls. Venous pressure rises because of the inability of the heart to match input to output. This can cause edema due to increased pre-load on the venous side of the circulation and this is usually manifest as pulmonary edema. The arterial underfilling, due to failure of the LV, activates the baroreceptor reflex via stretch receptors in the aortic arch and carotid sinuses as well as several neurohumoral reflexes. Increased sympathetic tone in the CVS results in increased myocardial contractility, tachycardia and arterial vasoconstriction thus increasing cardiac afterload.
Increased sympathetic stimulation of the juxtaglomerulosa apparatus of the kidney, as well as decreased perfusion pressure, induces release of renin that activates the angiotensin-aldosterone system (see Box 4.34). This, together with increased sympathetic vasoconstrictor tone, leads to increased renal sodium (and, hence, water) retention. Thus, in heart failure the renin-angiotensin-aldosterone system is activated and the peripheral blood concentration of renin can be used as an indicator of its severity. Furthermore, the effectiveness of aldosterone on salt and water retention in the kidney in such patients is maintained (i.e. there is no mineralocorticoid ‘escape’).
Apart from stimulating aldosterone secretion, angiotensin II has direct vasoconstrictor effects on both afferent and efferent renal arterioles and a constrictor effect on mesangial cells reducing glomerular filtration surface. It also has direct mitogenic effects on cardiac myocytes and may also play a role in increasing thirst in heart failure via a central CNS effect. There is considerable evidence for local tissue renin-angiotensin systems and increasing experimental work indicates that angiotensin II plays an intracrine role in the heart to affect cell proliferation and apoptosis.
Non-osmotic release of AVP also occurs in heart failure as a result of activation of carotid baroreceptors. This (combined with an increase in thirst) leads to a decrease in free water excretion and potentially hyponatremia (see Box 7.42). Hyponatremia in heart failure is an ominous prognostic sign.
LV dysfunction results in increased left atrial pressure and atrial natriuretic peptide (ANP) is secreted from the atria in response to increased distension (Box 8.3). This 28 amino acid peptide increases glomerular filtration, decreases collecting duct sodium reabsorption and inhibits the renal renin-angiotensin-aldosterone system. Brain natriuretic peptide (BNP), belonging to the same family of peptides, is a 32 amino acid hormone (Box 8.3). It is not only synthesized in the brain but also in the ventricles and is released into the circulation in response to ventricular failure. It has the same effects as ANP and can act on the same receptors. Circulating concentrations of BNP are sensitive measures of heart failure and were used in Clinical Case 8.1 to clarify the cause of dyspnea. The serum BNP was markedly elevated (21 pmol/l, NR 0.5–6.1 pmol/l) strongly supporting a diagnosis of pulmonary edema. In clinical studies, measures of BNP have the ability to detect heart failure with a sensitivity of nearly 100% and a specificity of about 85%.
Apart from activation of the renal renin-angiotensin-aldosterone system and the counter-regulatory ANP/BNP peptides, the reduced cardiac output seen in heart failure also activates local hormones involved in the control of vasoconstriction. These include the endothelins (see below) that are very potent hormones working, primarily via paracrine actions, to increase vasoconstrictor tone. High circulating concentrations may be seen in heart failure and again are indicative of a poor prognosis.
The treatment for heart failure is to reduce peripheral resistance (antagonize vasoconstriction) and to reduce total plasma volume so as to decrease preload on the heart. Whilst diuretics remain a therapeutic mainstay, the involvement of the endocrine system means that the vast majority of treatments for heart failure are in fact related to its endocrine control (Box 8.4). Clinical Case 8.1 was treated with inhaled β2-adrenergic agonist and parenteral glucocorticoid steroid for her asthma; an intravenous diuretic (furosemide) and an oral angiotensin converting enzyme inhibitor was given for her heart failure.
A previously fit 54-year-old man has suffered a ‘cold’ for a week before developing a cough, productive of green sputum. He presented to the Emergency Room with increasing shortness of breath such that he was unable to complete sentences. He was an ex-smoker on no medication and with no significant past medical history. He was pyrexial (39.4°C) and cyanosed with capillary blood oxygen saturations of 90% on 6 l/min inspired oxygen via a face-mask. His blood pressure was 120/70 mmHg with a tachycardia of 140/min. His chest contained bilateral crackles on auscultation. His peripheral blood white cell count was raised at 16 × 109 /l and the chest X-ray markedly abnormal with evidence of a cavitating pneumonia (Box 8.5). He deteriorated markedly and required transfer to the Intensive Care Unit where he underwent artificial ventilation.
A pulmonary artery catheter was inserted and investigations showed the cardiac output to be high at 14 l/min with a normal pulmonary artery capillary wedge pressure (15 mmHg). The peripheral resistance was low (SVR 380 dynes s/cm5 - normal 770–1500 dynes s/cm5) and pulmonary vascular resistance PVR 80 dynes s/cm5 - normal <200 dynes s/cm5). At this time, peripheral blood, taken as part of a research study, contained markedly elevated concentrations of calcitonin gene-related peptide (CGRP).
In sepsis, the presence of endotoxin and early inflammatory cytokines (e.g. TNF, IL-1) results in endothelial cell activation and disruption, disturbing the tonic release of the vasoconstrictor endothelin-1 (ET-1) and the vasodilators nitric oxide (NO) and prostacyclin (PGI2). The activated cells (and also the smooth muscle cells) produce much larger quantities of ET-1, NO and prostaglandins.
The 21 amino acid endothelins, of which there are three isoforms (ET-1, ET-2 and ET-3, Box 8.6) are the most potent vasoconstrictors known. They are cleaved from the precursor pro-ET (sometimes referred to as big-endothelin) by a membrane-bound metallopeptidase enzyme. ET-1 is the dominant form in the human vasculature where it occurs mainly in endothelial cells, though it is also found in smooth muscle cells and cardiac myocytes. It is not stored but synthesized de novo. ET receptors occur in two forms ET-A and ET-B. ET-A has a high affinity for ET-1 and is expressed on smooth muscle cells. It is considered to mediate the direct vasoconstrictor effects via calcium influx through a non selective ion channel. ET-B receptors are expressed on both endothelial cells and smooth muscle cells in some vascular beds. ET-B stimulation leads to the release of NO (vasodilator) and the prostaglandins thromboxane (vasoconstrictor) and PGI2 (vasodilator). The exact roles of the ET peptides in sepsis are not certain and, experimentally, the use of ET receptor antagonists produces variable results.
Locally produced NO is synthesized from arginine by the action of the constitutively expressed form of endothelial nitric oxide synthase (eNOS). It induces relaxation of smooth muscle cells via paracrine activation of soluble guanylate cyclase that converts GTP to cGMP (Box 8.7). In sepsis, the increased NO production is the result of expression of the inducible isoform of NO synthase (iNOS) stimulated by exposure to endotoxin and cytokines. The lung is a major site of iNOS expression in sepsis and increases circulating concentrations of NO. At the same time the physiological action of eNOS is downregulated.
Prostaglandins (PGs) are important regulators of endothelial and kidney functions. A number of PGs is released by endothelial cells. PGI2, like NO, induces vasodilatation whilst thromboxane A2 is a potent vasoconstrictor. The kidney also produces PGs and PGA2 and PGE2 can antagonize the hypertension induced by the retention of salt and water.
PGs are synthesized by the cyclooxygenase enzyme(s) (COX) and, as with NOS, there is a constitutively expressed isoform, COX-1, and an inducible form, COX-2 (Box 8.8). The latter is rapidly induced at sites of inflammation to produce large quantities of prostaglandin and thromboxane. In sepsis, COX-2 is induced by endotoxin and cytokines whilst anti-inflammatory cytokines (e.g. IL-4 and IL-10) and glucocorticoids inhibit COX-2 expression.
CGRP is a 37-amino-acid peptide, occurring in two forms (α and β) and derived, as its name suggests, from the calcitonin gene by tissue-specific alternative processing (see Box 5.38). It belongs to a family of peptides including amylin and adrenomedullin. It is widely distributed with its receptors (of which there are also two types), particularly in the brain and the cardiovascular system, but also the thyroid gland and gut. Target cells for CGRP have a cell surface endopeptidase that can cleave the peptide. The t1/2 of the peptide in plasma is about 10 min and there is doubt as to whether it functions as a hormone or whether the blood concentration changes merely reflect ‘spillage’ of the peptide into the circulation. Its widespread distribution throughout the nervous and cardiovascular systems indicates a number of physiological roles. These include altering regional blood flow, direct chronotropic and inotropic effects on the heart, modulation of inflammation and pyrexia, reducing insulin and gastric acid secretion, modulation of sensory transmission. The use of CGRP analogs in a variety of vascular diseases is under active research.
A 46-year-old woman presented to the Emergency Room complaining of shortness of breath. There was no evidence for asthma or heart failure but her electrocardiogram was abnormal with evidence of pulmonary hypertension. She was a non-smoker and took no regular medication. There was no family history of serious illness. Echocardiography confirmed the pulmonary hypertension. Her hemoglobin was noted to be markedly elevated at 24 g/d (NR 11.5–14.5 g/d) with a hematocrit of 0.60 (NR 0.37–0.47). Analysis of arterial blood gas showed that she was not hypoxic. Chest X-ray showed a prominent pulmonary artery compatible with pulmonary hypertension (Box 8.9). CT scan of the lungs (see website) confirmed pulmonary emboli.
Erythropoiesis in bone marrow is regulated by the circulating concentration of Epo via the Epo receptor that belongs to the cytokine family of receptors. Signalling is via a number of kinases including JAK/STAT and Ras/MAP kinase pathways. Epo, a glycoprotein with a molecular weight of 34 000, has four effects on erythrocyte progenitor cells. It maintains their viability, promotes cell division, increases hemoglobin synthesis and stimulates morphological maturation. Mutations leading to truncation of the carboxyl terminus (thus removing a negative regulatory element) lead to inherited forms of erythrocytosis.
Epo has been used therapeutically prior to the removal of blood for autologous blood transfusion and illegally by athletes to improve oxygen carriage and, thus, performance. A mutation within the carboxyl terminus of the receptor that increases the sensitivity to Epo and results in a high hemoglobin concentration has been reported in a gold medallist in cross-country skiing in the Winter Olympics.
The cells making Epo are predominantly in peri-tubular interstitial sites in the kidney although other sites of synthesis (such as the liver and brain) are recognized. Epo synthesis is regulated by oxygen concentration via a poorly understood mechanism involving a heme-containing protein, probably resembling cytochrome b and the nuclear transcription factor HIF-1 leading to an increase in Epo gene expression.
It is clear that an increase in Epo secretion will occur in all forms of hypoxia whether these are physiological (e.g. altitude) or pathological (e.g. an abnormal hemoglobin or lung disease). It will also be apparent that renal failure will lead to Epo deficiency and anemia (Box 8.10).
Episodic, short-lasting changes in vasomotor tone in the cardiovascular system are seen in endocrine deficiencies and excesses. For example, estrogen deficiency may lead to episodic vasodilatation (‘hot flushes’) whilst release of catecholamines and other peptides from tumors of the adrenal medulla (pheochromocytomas) can stimulate episodic symptoms of hypertension and tachycardia or hypotension (Clinical Case 4.7). The final clinical case demonstrates the effects of the paroxysmal release of a different amine, in this case 5-hydroxy-tryptamine or serotonin, from what are known as carcinoid tumors.
A 47-year-old man was referred to the Endocrine out-patients clinic because he had been suffering intermittent episodes of flushing up to six times daily, each lasting approximately a minute associated with wheezing and loud bowel sounds (termed borborygmi). There was no history of skin problems or diarrhea. When seen, the only abnormality was a palpably enlarged liver. His blood pressure was normal. During a spontaneous attack in the clinic, he was noted to develop a ‘blush’ over the face, neck and upper chest; the trunk and legs were unaffected.
Carcinoid tumors are common and can be seen in 1:150 people at post-mortem and 1:300 appendectomies. The appendix is the commonest site for these tumors followed by the rectum, ileum, lungs, and stomach. Clinical presentations, however, are much less common (incidence ~5 per 100 000 per year) and they occur equally in both sexes with a mean age of about 50 years.
The cells of origin of carcinoids (and, thus, their biochemistry and clinical presentation) differ according to site of origin of the tumor (Box 8.11). Rarely, the production of peptides by the tumors leads to clinical presentation as acromegaly or Cushing's syndrome; these may cause great diagnostic difficulty. Classical carcinoid syndrome results from the effects of serotonin together with other contents of tumor secretory granules (including bradykinin, tachykinin, prostaglandins and histamine, depending on the cell of origin) that may be involved in the flushing. In approximately 60% of patients, fibrous plaques develop in the right side of the heart often affecting the tricuspid and pulmonary valves.
The benign clinical course of Clinical Case 8.4 illustrates why the term carcinoid was coined for this condition as the tumor generally behaves in a much more benign way than metastatic carcinoma. The relative rarity of the tumor, together with the variation in clinical behavior, indicates why comparative data on treatment outcomes (Box 8.14) are sparse. It also emphasizes the need for properly controlled therapeutic trials with adequate numbers of patients. Had Clinical Case 8.4 received any form of treatment when the tumor was first detected with distant metastases, it would have been regarded as a considerable success 22 years later.
A 56-year-old man with type 2 diabetes of 23 years duration was seen in the clinic. He was noted to have hypertension (blood pressure 160/100 mmHg) and microalbuminuria and his serum creatinine was 120 μmol/l (NR 50–110 mmol/l). He was prescribed a small daily dose of the angiotensin-converting enzyme inhibitor ramipril. Three days later, he was seen in the Emergency Room having become acutely short of breath. His blood pressure was 110/70 with a tachycardia of 110/min and he had bilateral basal crackles on auscultation of his chest. The chest X-ray indicated that he had developed pulmonary edema. The serum creatinine had risen markedly to 410 μmol/l.
Question 1: What pathophysiological process does the course of events suggest?
Question 2: Which investigation would you perform next?
A 73-year-old woman was seen in the Emergency Room. She had become increasingly short of breath over the previous 12 h. She was taking hydrochlorthiazide 5 mg with amiloride 5 mg daily. When seen she had a blood pressure of 130/70 with a sinus tachycardia of 120/min. The jugular venous pressure was raised 5 cm and the electrocardiogram and chest X-ray obtained are shown in Box Q8.2. Her serum sodium was reported to be 119 mmol/l (NR 135–145 mmol/l) with a potassium of 4.0 mmol/l (NR 3.5–4.7 mmol/l) and a urea of 8.0 mmol/l (NR 2.5–8.0 mmol/l). The electrocardiogram and chest X-ray are shown in Box Q8.2.
Question 1: What is the diagnosis?
Question 2: What is the cause of her hyponatremia?
Question 3: How would you treat her?
