33. A 48-year-old woman presents with headache, blurred vision and palpitations. She has been having more frequent headaches that are associated with blurring of her vision. Her past medical history is unremarkable. Her family history includes a mother who died suddenly at 35 years from a cerebral haemorrhage and her maternal grandfather died from renal failure. Routine observations record a blood pressure reading of 168/100 mmHg with a pulse of 115 beats/min. The results of laboratory investigations are shown below. Which is the most likely diagnosis?
| Value | Reference range | |
|---|---|---|
| Arterial pH | 7.35 | 7.35–7.45 |
| Sodium (mmol/L) | 144 | 137–145 |
| Potassium (mmol/L) | 3.1 | 3.2–4.5 |
| Bicarbonate (mmol/L) | 18 | 26–35 |
| Creatinine (μmol/L) | 278 | 50–100 |
| C-reactive protein (mg/L) | 8 | <10 |
| Plasma renin (μIU/mL) | 37 | 7.0–50.0 |
34. A 57-year-old woman presents with sudden severe breathlessness. She was diagnosed with hypertension about a year before this presentation. Her blood pressure remains poorly controlled despite compliance with a combination of hydrochlorothiazide, amlodipine, perindopril and metoprolol. Her other medical problems include hyperlipidaemia and type 2 diabetes. She denies having headaches, palpitations or chest pain. Her blood pressure is 200/100 mmHg. The results of laboratory investigations and chest X-ray are shown below. What is the most likely diagnosis?
| Value | Reference range | |
|---|---|---|
| Arterial pH | 7.25 | 7.35–7.45 |
| PaO2 (on 6 L/min of oxygen) (mmHg) | 63 | >80 |
| Sodium (mmol/L) | 132 | 137–145 |
| Potassium (mmol/L) | 5.4 | 3.2–4.5 |
| Bicarbonate (mmol/L) | 18 | 26–35 |
| Creatinine (μmol/L) | 137 | 50–100 |
| C-reactive protein (mg/L) | 22 | <10 |
| Plasma renin (μIU/mL) | 57.0 | 7.0–50.0 |
Chest X-Ray
Answers
Basic Science
1. Answer C
Vasovagal syncope can follow prolonged standing, standing quickly or other upsetting and unpleasant stimuli (Sutton et al., 2012). Vasovagal syncope involves a massive parasympathetic response, associated with pooling of blood in the peripheries and leading to reduced cerebral perfusion. The patient generally has cold, clammy, pale skin but blood is pooled in deeper vasodilated muscle vessels. Mechanoreceptors in the left ventricle are not only innervated by stretch but also by vigorous and forceful systolic contraction. In patients with vasovagal syncope, overzealous left ventricular contraction occurs in response to reduced venous return. Hence, the afferent signals from the left ventricle override the baroreceptor responses, leading to an inappropriate decrease in sympathetic tone and an increase in parasympathetic (vagal) tone. The peripheral pulses are weak and a reflex vagal bradycardia is accompanied by a reduced cardiac output and fall in blood pressure. In distinction to most forms of shock, the heart rate in vasovagal syncope decreases rather than increases. This can be a helpful sign to distinguish vasovagal syncope from other more serious causes.
Vasovagal syncope can follow prolonged standing, standing quickly or other upsetting and unpleasant stimuli (Sutton et al., 2012). Vasovagal syncope involves a massive parasympathetic response, associated with pooling of blood in the peripheries and leading to reduced cerebral perfusion. The patient generally has cold, clammy, pale skin but blood is pooled in deeper vasodilated muscle vessels. Mechanoreceptors in the left ventricle are not only innervated by stretch but also by vigorous and forceful systolic contraction. In patients with vasovagal syncope, overzealous left ventricular contraction occurs in response to reduced venous return. Hence, the afferent signals from the left ventricle override the baroreceptor responses, leading to an inappropriate decrease in sympathetic tone and an increase in parasympathetic (vagal) tone. The peripheral pulses are weak and a reflex vagal bradycardia is accompanied by a reduced cardiac output and fall in blood pressure. In distinction to most forms of shock, the heart rate in vasovagal syncope decreases rather than increases. This can be a helpful sign to distinguish vasovagal syncope from other more serious causes.
Sutton, R., Brignole, M., and Benditt, D.G. (2012). Key challenges in the current management of syncope. Nat Rev Cardiol 9, 590–598.
2. Answer B
Magnesium is integral to the function of adenosine triphosphate (ATP) and plays a role in many enzymatic reactions and transport processes, as well as the synthesis of protein, DNA and RNA. About 99% of total body magnesium is intracellular and located in bone, muscles and non-muscular soft tissue. Extracellular magnesium is primarily found in serum and red blood cells (Jahnen-Dechent and Ketteler, 2012).
In muscle contraction, magnesium stimulates calcium reuptake by the calcium-activated ATPase of the sarcoplasmic reticulum. Magnesium homeostasis is maintained by the intestine, bone and kidneys. Magnesium is mainly absorbed in the small intestine by a passive paracellular mechanism, which is driven by an electrochemical gradient and solvent. Intestinal absorption of magnesium is dependent on magnesium status rather than the intake.
The kidneys are an important regulator of magnesium because its concentration is mainly controlled by excretion in urine. Of the filtered load, about 95% is immediately reabsorbed and only 3–5% is excreted in the urine. The major reabsorption site is the thick ascending limb of the loop of Henle where 60–70% of magnesium is reabsorbed.
Magnesium is integral to the function of adenosine triphosphate (ATP) and plays a role in many enzymatic reactions and transport processes, as well as the synthesis of protein, DNA and RNA. About 99% of total body magnesium is intracellular and located in bone, muscles and non-muscular soft tissue. Extracellular magnesium is primarily found in serum and red blood cells (Jahnen-Dechent and Ketteler, 2012).
In muscle contraction, magnesium stimulates calcium reuptake by the calcium-activated ATPase of the sarcoplasmic reticulum. Magnesium homeostasis is maintained by the intestine, bone and kidneys. Magnesium is mainly absorbed in the small intestine by a passive paracellular mechanism, which is driven by an electrochemical gradient and solvent. Intestinal absorption of magnesium is dependent on magnesium status rather than the intake.
The kidneys are an important regulator of magnesium because its concentration is mainly controlled by excretion in urine. Of the filtered load, about 95% is immediately reabsorbed and only 3–5% is excreted in the urine. The major reabsorption site is the thick ascending limb of the loop of Henle where 60–70% of magnesium is reabsorbed.
Jahnen-Dechent, W. and Ketteler, M. (2012). Magnesium basics. Clin Kidney J 5 (Suppl 1), i3–i14.
3. Answer B
Cocaine acts by blocking the reuptake of three neurotransmitters – dopamine, norepinephrine (noradrenaline) and serotonin. By binding to the transporters that normally remove the excess of these neurotransmitters from the synaptic gap, cocaine prevents them from being reabsorbed by the neurones that released them and thus increases their concentration in the synapses. The group of neurones thus modified produces the euphoria (from dopamine), feelings of confidence (from serotonin) and energy (from norepinephrine) typically experienced by people who take cocaine.
4. Answer C
Ezetimibe reduces absorption of dietary and biliary cholesterol by inhibiting its transport across the intestinal wall. This leads to an upregulation of low-density lipoprotein (LDL) receptors on the surface of cells and an increased LDL–cholesterol uptake into cells, thus decreasing levels of LDL in the blood plasma, which contributes to atherosclerosis and cardiovascular events.
Statins competitively inhibit 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase (a rate-limiting enzyme in cholesterol synthesis). Statins increase hepatic cholesterol uptake from blood, reduce concentrations of total cholesterol, LDL and triglyceride (modest), and produce a small increase in high-density lipoprotein (HDL) concentrations.
Fibrates activate peroxisome proliferator-activated nuclear receptors and modulate lipoprotein synthesis and catabolism. They reduce plasma triglyceride, moderately increase HDL and have a variable effect on LDL concentrations.
Bile acid-binding resins bind bile acids in intestinal lumen, preventing reabsorption and increasing bile acid excretion in the faeces. Increased demand for cholesterol for bile acid synthesis results in an increase in LDL uptake and removal from plasma.
Nicotinic acid probably suppresses fatty acid release from peripheral tissue, especially adipose tissue. In doses of greater than 1 g daily, nicotinic acid reduces LDL and triglycerides, increases HDL and lowers potentially atherogenic lipoprotein.
Cocaine acts by blocking the reuptake of three neurotransmitters – dopamine, norepinephrine (noradrenaline) and serotonin. By binding to the transporters that normally remove the excess of these neurotransmitters from the synaptic gap, cocaine prevents them from being reabsorbed by the neurones that released them and thus increases their concentration in the synapses. The group of neurones thus modified produces the euphoria (from dopamine), feelings of confidence (from serotonin) and energy (from norepinephrine) typically experienced by people who take cocaine.
4. Answer C
Ezetimibe reduces absorption of dietary and biliary cholesterol by inhibiting its transport across the intestinal wall. This leads to an upregulation of low-density lipoprotein (LDL) receptors on the surface of cells and an increased LDL–cholesterol uptake into cells, thus decreasing levels of LDL in the blood plasma, which contributes to atherosclerosis and cardiovascular events.
Statins competitively inhibit 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase (a rate-limiting enzyme in cholesterol synthesis). Statins increase hepatic cholesterol uptake from blood, reduce concentrations of total cholesterol, LDL and triglyceride (modest), and produce a small increase in high-density lipoprotein (HDL) concentrations.
Fibrates activate peroxisome proliferator-activated nuclear receptors and modulate lipoprotein synthesis and catabolism. They reduce plasma triglyceride, moderately increase HDL and have a variable effect on LDL concentrations.
Bile acid-binding resins bind bile acids in intestinal lumen, preventing reabsorption and increasing bile acid excretion in the faeces. Increased demand for cholesterol for bile acid synthesis results in an increase in LDL uptake and removal from plasma.
Nicotinic acid probably suppresses fatty acid release from peripheral tissue, especially adipose tissue. In doses of greater than 1 g daily, nicotinic acid reduces LDL and triglycerides, increases HDL and lowers potentially atherogenic lipoprotein.
5. Answer D
Liddle syndrome is characterised by hypokalaemia, metabolic acidosis, low renin activity and low aldosterone levels. It is caused by an autosomal dominant gain-of-function mutation in the epithelial sodium channel (ENaC) expressed at the apical surface of cells of the collecting duct. Serum levels of potassium and bicarbonate may remain normal in this group of patients if salt intake is limited. Hypokalaemia and metabolic alkalosis only manifest after oral sodium intake increases.
Liddle syndrome is characterised by hypokalaemia, metabolic acidosis, low renin activity and low aldosterone levels. It is caused by an autosomal dominant gain-of-function mutation in the epithelial sodium channel (ENaC) expressed at the apical surface of cells of the collecting duct. Serum levels of potassium and bicarbonate may remain normal in this group of patients if salt intake is limited. Hypokalaemia and metabolic alkalosis only manifest after oral sodium intake increases.
6. Answer B
Gordon syndrome or pseudohypoaldosteronism type IIA is an autosomal dominant disorder characterised by hyperkalaemia, metabolic acidosis, low plasma renin activity and normal aldosterone levels. The normal plasma aldosterone level is a remarkable feature as hyperkalaemia should stimulate aldosterone secretion. All the abnormalities of Gordon syndrome are corrected after administration of a thiazide diuretic. Genetic studies indicate that a mutation in WNK4, a kinase that regulates the activity of the thiazide-sensitive sodium–chloride co-transporter (NCCT), leads to increased expression of the NCCT and thus increased sodium absorption. These monogenic inherited forms of hypertension demonstrate a number of renal mechanisms involved in arterial hypertension.
Renal mechanisms involved in arterial hypertension include:
Gordon syndrome or pseudohypoaldosteronism type IIA is an autosomal dominant disorder characterised by hyperkalaemia, metabolic acidosis, low plasma renin activity and normal aldosterone levels. The normal plasma aldosterone level is a remarkable feature as hyperkalaemia should stimulate aldosterone secretion. All the abnormalities of Gordon syndrome are corrected after administration of a thiazide diuretic. Genetic studies indicate that a mutation in WNK4, a kinase that regulates the activity of the thiazide-sensitive sodium–chloride co-transporter (NCCT), leads to increased expression of the NCCT and thus increased sodium absorption. These monogenic inherited forms of hypertension demonstrate a number of renal mechanisms involved in arterial hypertension.
Renal mechanisms involved in arterial hypertension include:
- Reduced glomerular filtration rate
- Impaired renal tubular sodium handling
- Reduced nephron mass
- Activation of the sympathetic nervous system
- Activation of the renin–angiotensin–aldosterone system
- Endothelin and prostaglandin release.
Clinical
7. Answer A
Chronic alcohol ingestion enhances the effect of gamma-aminobutyric acid (GABA) on brain neuroreceptors, resulting in decreased brain excitability (Kosten and O’Connor, 2003; Welch, 2011). With abrupt cessation of alcohol, brain hyperexcitability results in symptoms of withdrawal. Early symptoms of withdrawal include tremor, insomnia, anxiety, palpitations, sweating, anxiety, agitation, nausea and vomiting. Approximately 24 h after alcohol withdrawal, generalised seizures may develop but these can occur as early as 2 h after cessation of alcohol. Alcohol withdrawal seizures are more common in those with multiple prior alcohol withdrawal episodes. At 48–72 h following withdrawal, hallucinations, tachycardia, low-grade fever, delirium tremens and agitation typically occur and these symptoms peak at 5 days. Delirium tremens is characterised by fluctuating disturbance of consciousness, changes in cognition, exacerbation of autonomic symptoms (sweating, nausea, palpitations and tremor), fear or terror, and may include hallucinations, delusions, seizures, cardiac arrhythmias and even circulatory collapse. Korsakoff is an amnesic syndrome with impaired recent memory and relatively intact intellectual function and is seen in patients with chronic alcohol abuse. Patients may confabulate to fill gaps in their memory. In many patients there is overlap with Wernicke encephalopathy.
Chronic alcohol ingestion enhances the effect of gamma-aminobutyric acid (GABA) on brain neuroreceptors, resulting in decreased brain excitability (Kosten and O’Connor, 2003; Welch, 2011). With abrupt cessation of alcohol, brain hyperexcitability results in symptoms of withdrawal. Early symptoms of withdrawal include tremor, insomnia, anxiety, palpitations, sweating, anxiety, agitation, nausea and vomiting. Approximately 24 h after alcohol withdrawal, generalised seizures may develop but these can occur as early as 2 h after cessation of alcohol. Alcohol withdrawal seizures are more common in those with multiple prior alcohol withdrawal episodes. At 48–72 h following withdrawal, hallucinations, tachycardia, low-grade fever, delirium tremens and agitation typically occur and these symptoms peak at 5 days. Delirium tremens is characterised by fluctuating disturbance of consciousness, changes in cognition, exacerbation of autonomic symptoms (sweating, nausea, palpitations and tremor), fear or terror, and may include hallucinations, delusions, seizures, cardiac arrhythmias and even circulatory collapse. Korsakoff is an amnesic syndrome with impaired recent memory and relatively intact intellectual function and is seen in patients with chronic alcohol abuse. Patients may confabulate to fill gaps in their memory. In many patients there is overlap with Wernicke encephalopathy.
Kosten, T.R. and O’Connor, P.G. (2003). Management of drug and alcohol withdrawal. N Engl J Med 348, 1786–1795.
Welch, K.A. (2011). Neurological complications of alcohol and misuse of drugs. Pract Neurol 11, 206–219.
8. Answer E
Bone scan provides a sensitive, non-invasive modality for diagnosing a number of skeletal conditions (Lee et al., 2012). It uses technetium-99m-labelled bisphosphonates [e.g. technetium (99mTc) medronic acid]. Like their therapeutic counterparts, these radiolabelled bisphosphonates bind to hydroxyapatite at sites of active bone formation (osteogenesis). Osteogenesis is a non-specific response of bone to a range of stimuli, such as physiological growth/turnover, mechanical stress or injury, fractures, infection and involvement by tumour.
Bone scan is indicated in the following situations:
Bone scan has low sensitivity for tumours that are confined to the marrow, such as myeloma, and those that are predominantly osteolytic with little osteogenic reaction, such as metastasis from renal cell carcinoma. Bone scan is also not helpful for the diagnosis of osteoporosis.
Bone scan provides a sensitive, non-invasive modality for diagnosing a number of skeletal conditions (Lee et al., 2012). It uses technetium-99m-labelled bisphosphonates [e.g. technetium (99mTc) medronic acid]. Like their therapeutic counterparts, these radiolabelled bisphosphonates bind to hydroxyapatite at sites of active bone formation (osteogenesis). Osteogenesis is a non-specific response of bone to a range of stimuli, such as physiological growth/turnover, mechanical stress or injury, fractures, infection and involvement by tumour.
Bone scan is indicated in the following situations:
- Diagnosis and follow-up of metastatic cancer
- To differentiate between soft-tissue infection and osteomyelitis
- To evaluate fractures difficult to assess on X-ray, especially stress fracture and fractures of complex structures
- To evaluate prosthetic joints for infection, loosening or fracture
- To determine a bone biopsy site
- The evaluation of bone pain when X-ray is normal.
Bone scan has low sensitivity for tumours that are confined to the marrow, such as myeloma, and those that are predominantly osteolytic with little osteogenic reaction, such as metastasis from renal cell carcinoma. Bone scan is also not helpful for the diagnosis of osteoporosis.
Lee, J.C., Hennessy, A.D. and Khafagi, F.A. (2012). Bone scans. Aust Fam Physician 41, 689–692.
9. Answer B
Bone is among the most common sites of breast cancer metastasis, and metastasis can result in pain, hypercalcaemia, pathological fracture, loss of mobility and spinal cord compression (Irvin et al., 2011). Patients with symptomatic hypercalcaemia of malignancy or severe hypercalcaemia usually require immediate treatment with intravenous hydration with isotonic saline and intravenous bisphosphonates. Pain caused by bone metastasis should be treated as necessary with non-steroidal anti-inflammatory drugs, opioid and non-opioid analgesics, corticosteroids, adjuvant agents, interventional procedures, local radiation therapy and surgery. Spinal cord compression (manifesting as leg weakness) is an emergency that requires prompt neurosurgical and radiation oncology consultation, and the use of corticosteroids, usually in the form of intravenous dexamethasone.
Denosumab, a monoclonal antibody to receptor activator of nuclear factor κ-B ligand, is effective for prolonging the time to skeletal-related events and inhibiting the onset of pain via the suppression of osteoclast activation. Denosumab has been shown to have a greater effect compared with zoledronic acid in patients with breast or prostate cancer.
For those with advanced breast cancer, mood disorders, such as major depression, and anxiety disorders, are common. Anti-depressants and anxiolytics can be effective, but monitoring for drug interactions is essential. Women taking tamoxifen for breast cancer should avoid taking cytochrome P450 (CYP450) 2D6 strong inhibitors, such as fluoxetine, paroxetine and bupropion. Tamoxifen metabolism is complex, but it is known that CYP2D6 is necessary to form its two most important active metabolites.
For neuropathic pain related to metastases, adjuvant analgesics such as anti-depressants (e.g. amitriptyline, imipramine, duloxetine or venlafaxine) and anti-convulsants (i.e. gabapentin or pregabalin) are first-line therapies in conjunction with opioids, with the recommendation to start with a low dose and increase every 3–14 days as tolerated.
Bone is among the most common sites of breast cancer metastasis, and metastasis can result in pain, hypercalcaemia, pathological fracture, loss of mobility and spinal cord compression (Irvin et al., 2011). Patients with symptomatic hypercalcaemia of malignancy or severe hypercalcaemia usually require immediate treatment with intravenous hydration with isotonic saline and intravenous bisphosphonates. Pain caused by bone metastasis should be treated as necessary with non-steroidal anti-inflammatory drugs, opioid and non-opioid analgesics, corticosteroids, adjuvant agents, interventional procedures, local radiation therapy and surgery. Spinal cord compression (manifesting as leg weakness) is an emergency that requires prompt neurosurgical and radiation oncology consultation, and the use of corticosteroids, usually in the form of intravenous dexamethasone.
Denosumab, a monoclonal antibody to receptor activator of nuclear factor κ-B ligand, is effective for prolonging the time to skeletal-related events and inhibiting the onset of pain via the suppression of osteoclast activation. Denosumab has been shown to have a greater effect compared with zoledronic acid in patients with breast or prostate cancer.
For those with advanced breast cancer, mood disorders, such as major depression, and anxiety disorders, are common. Anti-depressants and anxiolytics can be effective, but monitoring for drug interactions is essential. Women taking tamoxifen for breast cancer should avoid taking cytochrome P450 (CYP450) 2D6 strong inhibitors, such as fluoxetine, paroxetine and bupropion. Tamoxifen metabolism is complex, but it is known that CYP2D6 is necessary to form its two most important active metabolites.
For neuropathic pain related to metastases, adjuvant analgesics such as anti-depressants (e.g. amitriptyline, imipramine, duloxetine or venlafaxine) and anti-convulsants (i.e. gabapentin or pregabalin) are first-line therapies in conjunction with opioids, with the recommendation to start with a low dose and increase every 3–14 days as tolerated.
Irvin, W., Jr., Muss, H.B., and Mayer, D.K. (2011). Symptom management in metastatic breast cancer. Oncologist 16, 1203–1214.
10. Answer D
Non-specific low back pain is a major health problem (Balague et al., 2012). Non-specific low back pain is defined as low back pain not attributable to a recognisable, known specific pathology, such as infection, tumour, fracture, structural deformity, inflammatory disorder, radicular syndrome or cauda equina syndrome. A herniated lumbar disc should be considered in patients with back pain who have symptoms of radiculopathy, as suggested by pain radiating down the leg with symptoms reproduced by straight-leg raising. Magnetic resonance imaging (MRI) may be necessary to confirm a herniated disc, but should be interpreted with caution, because many asymptomatic persons have disc abnormalities. This patient has no signs of radiculopathy. Also, the MRI reports a bulging disc with no signs of compression: a finding that is frequently seen in healthy persons. Surgery would be considered if there were signs of radiculopathy and the MRI showed a herniated disc with evidence of spinal or nerve root compression; however, this is not the situation in this case. A repeat MRI is not indicated, because it is unlikely that a herniated disc is the cause of this patient’s symptoms.
The management of chronic back pain in this patient should include physiotherapy and an exercise programme. Regular paracetamol initially and judicious use of non-steroidal anti-inflammatory drugs (NSAIDs) may improve patient function and outcome. Anti-depressants are recommended as second-line treatment for patients with persistent low back pain in some guidelines as they have shown a small-to-moderate benefit. The place for surgery in chronic non-specific low back pain is very limited (if any) and its overuse has been criticised.
Non-specific low back pain is a major health problem (Balague et al., 2012). Non-specific low back pain is defined as low back pain not attributable to a recognisable, known specific pathology, such as infection, tumour, fracture, structural deformity, inflammatory disorder, radicular syndrome or cauda equina syndrome. A herniated lumbar disc should be considered in patients with back pain who have symptoms of radiculopathy, as suggested by pain radiating down the leg with symptoms reproduced by straight-leg raising. Magnetic resonance imaging (MRI) may be necessary to confirm a herniated disc, but should be interpreted with caution, because many asymptomatic persons have disc abnormalities. This patient has no signs of radiculopathy. Also, the MRI reports a bulging disc with no signs of compression: a finding that is frequently seen in healthy persons. Surgery would be considered if there were signs of radiculopathy and the MRI showed a herniated disc with evidence of spinal or nerve root compression; however, this is not the situation in this case. A repeat MRI is not indicated, because it is unlikely that a herniated disc is the cause of this patient’s symptoms.
The management of chronic back pain in this patient should include physiotherapy and an exercise programme. Regular paracetamol initially and judicious use of non-steroidal anti-inflammatory drugs (NSAIDs) may improve patient function and outcome. Anti-depressants are recommended as second-line treatment for patients with persistent low back pain in some guidelines as they have shown a small-to-moderate benefit. The place for surgery in chronic non-specific low back pain is very limited (if any) and its overuse has been criticised.
Balague, F., Mannion, A.F., Pellise, F., and Cedraschi, C. (2012). Non-specific low back pain. Lancet 379, 482–491.
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