How will you proceed with management of pancreatitis?

Case History:

A 45 year old lady comes to your clinic with complaints of severe pain in epigastric region for 6 hours duration. The pain is sharp stabbing type with radiation to the back. There is slight relief of her pain on leaning forward. She also has vomited twice since her pain began. She gives you a history of incidental diagnosis of cholelithiasis two years back. On examination, she looks very distressed. Her pulse is 100bpm, BP is 100/60mmHg, RR is 24/min. There is significant tenderness in epigastric region with rigidity and guarding. What is your provisional diagnosis? How will you proceed with management of this case?  

Pancreatitis

Pancreatic inflammatory disease may be

    classified as (1) acute pancreatitis and (2) chronic pancreatitis.

Acute Pancreatitis

The pathologic spectrum of acute pancreatitis varies from edematous pancreatitis, which is usually a mild and self-limited disorder, to life threatening necrotizing pancreatitis.

The incidence of pancreatitis varies in different countries and depends on cause, e.g., alcohol, gallstones, metabolic factors, and drugs.

Causes of Ac. Pancreatitis

Common Causes

• Gallstones (including microlithiasis): 30-60%
• Alcohol (acute and chronic alcoholism): 15-30%
• Hypertriglyceridemia
• Endoscopic retrograde cholangiopancreatography (ERCP), especially after biliary manometry
• Trauma (especially blunt abdominal trauma)
• Postoperative (abdominal and nonabdominal operations)
• Drugs (azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline, valproic acid, anti-HIV medications)
• Sphincter of Oddi dysfunction

Uncommon causes

• Vascular causes and vasculitis (ischemic-hypoperfusion states after cardiac surgery)
• Connective tissue disorders and thrombotic thrombocytopenic purpura (TTP)
• Cancer of the pancreas
• Hypercalcemia
• Periampullary diverticulum
• Pancreas divisum
• Cystic fibrosis
• Renal failure

Rare causes

• Infections (mumps, coxsackievirus, cytomegalovirus, echovirus)
• Autoimmune (e.g., Sjo¨gren’s syndrome)

Causes to consider in patients with recurrent bouts of acute pancreatitis without an obvious etiology

• Occult disease of the biliary tree or pancreatic ducts, especially microlithiasis, sludge
• Drugs
• Hypertriglyceridemia
• Pancreas divisum
• Pancreatic cancer
• Sphincter of Oddi dysfunction
• Cystic fibrosis
• Idiopathic

Pathogenesis

• Acute pancreatitis occurs as a consequence of premature activation of zymogen granules,  releasing proteases which digest the pancreas and surrounding tissue 
• The severity of acute pancreatitis is dependent upon the balance between activity of released proteolytic enzymes and antiproteolytic factors. The latter comprise an intracellular pancreatic trypsin inhibitor protein and circulating β2-macroglobulin, α1-antitrypsin and Cl-esterase inhibitors.
• Usually mild and self-limiting with minimal organ involvement however in some cases, it is severe with local complications such as necrosis, pseudocyst or abscess, and systemic complications leading to multi-organ failure. 
• The mortality in this severe group is approximately 30%. 

Clinical Features

Symptoms

• upper abdominal pain and the pain usually begins in the epigastrium accompanied by nausea and vomiting.
•  As inflammation spreads throughout the peritoneal cavity the pain becomes more intense.
• There is radiation of the pain to the back with relief on bending forward because of involvement of the retro-peritoneum. 

Signs

• Only upper abdominal tenderness in mild cases
• In more severe disease, the patient may have a tachycardia, hypotension and be oliguric.
• Abdominal examination may show widespread tenderness with guarding as well as reduced or absent bowel sounds.
• Specific clinical signs that support a diagnosis of severe necrotizing pancreatitis include periumbilical (Cullen's sign) and flank bruising (Grey Turner's sign).

Investigations

• Serum amylase – within 24 hours, the rise is   > 3 times normal, the level falls down over next 3-5 days; persistent elevation is suggestive of pseudocyst formation
• Serum lipase – also raises in early period but its level remains elevated for 7 – 15 days, so important in cases of late presentation
• Other baseline investigations
• a full blood count , CRP, urea and electrolytes, blood glucose, liver biochemistry, plasma calcium and arterial blood gases
• These are documented at presentation and then repeated at 24 and 48 hours and provide a basis for assessing the severity of an attack and prognosis.

Radiological investigations

• Erect chest X-ray- to exclude gastro-duodenal perforation which may also raise amylase
• Abdominal USG- to exclude cholelithiasis and choledocholithiasis
• Contrast-enhanced spiral CT scanning - essential in all except for mild attacks of pancreatitis. Carried out within 2-3 days of presentation, it allows the extent of pancreatic necrosis to be assessed.
• MRI or MRCP – particularly useful in differentiating solid and fluid inflammatory masses

Assessment of severity

Factors during the first 48 hours that indicate severe pancreatitis and a poor prognosis (three or more factors present predict a severe episode)

• Age  >55 yrs
• WBC  > 15,000/cmm
• Blood glucose >10mmol/l
• Serum urea  >16mmol/l
• Serum albumin <30g/dl
• Serum aminotransferase >200U/l 
• Serum calcium <2mmol/l
• Serum LDH >600U/l
• PaO2 <60mmHg

In addition, serial assessment of C-reactive protein (CRP) is a useful indicator of progress. A peak CRP > 210 mg/l in the first 4 days predicts severe acute pancreatitis with 80% accuracy.

Complications of Acute Pancreatitis

LOCAL

• Necrosis
• Sterile
• Infected
• Pancreatic fluid collections
• Pancreatic abscess
• Pancreatic pseudocyst
• Pain
• Rupture
• Hemorrhage
• Infection
• Obstruction of gastrointestinal tract (stomach, duodenum, colon)
• Pancreatic ascites
• Disruption of main pancreatic duct
• Leaking pseudocyst
• Involvement of contiguous organs by necrotizing pancreatitis
• Massive intraperitoneal hemorrhage
• Thrombosis of blood vessels (splenic vein, portal vein)
• Bowel infarction
• Obstructive jaundice

SYSTEMIC

Pulmonary

• Pleural effusion
• Atelectasis
• Mediastinal abscess
• Pneumonitis
• Adult respiratory distress syndrome

Cardiovascular

• Hypotension
• Hypovolemia
• Sudden death
• Nonspecific ST-T changes in electrocardiogram simulating myocardial infarction
• Pericardial effusion

Hematologic

• Disseminated intravascular coagulation
• Gastrointestinal hemorrhage
• Peptic ulcer disease
• Erosive gastritis
• Hemorrhagic pancreatic necrosis with erosion into major blood vessels
• Portal vein thrombosis, variceal hemorrhage

Renal

• Oliguria
• Azotemia
• Renal artery and/or renal vein thrombosis
• Acute tubular necrosis

Metabolic

• Hyperglycemia
• Hypertriglyceridemia
• Hypocalcemia
• Encephalopathy

Central nervous system

• Psychosis
• Fat emboli
• Fat necrosis

Treatment

• Early fluid losses in acute pancreatitis may be large, requiring well-maintained intravenous access as well as a central line and urinary catheter to monitor circulating volume and renal function.
• Nasogastric suction: to prevent aspiration pneumonia
• Baseline arterial blood gases determine the need for continuous oxygen administration.
• Prophylactic antibiotics: cefuroxime or aztreonam
• Analgesia requirements. Pethidine and tramadol are the drugs of choice. The morphine derivatives should be avoided because they can cause sphincter of Oddi contraction.
• Feeding. In patients with a severe episode there is little likelihood of oral nutrition for a number of weeks. Total parenteral nutrition has been associated with a high risk of infection and has been replaced by enteral nutrition. This is administered via a nasojejunal tube, which is well tolerated and can maintain adequate nutritional input.
• In a small proportion of patients, multiorgan failure will develop in the first few days after presentation reflecting the extent of pancreatic necrosis. Such patients will require positive-pressure ventilation and often renal support. 
• These patients may also need surgical debridement of necrotic pancreatic tissue.
• The mortality in this group is extremely high (in excess of 80%).

Treatment of gallstone related pancreatitis

• In patients with gallstone-related pancreatitis and associated cholangitis, endoscopic intervention with sphincterotomy and stone extraction is of proven benefit and is the treatment of choice. 
• In the absence of cholangitis, sphincterotomy and stone extraction is only of proven benefit when the episode of pancreatitis is predicted as severe.
• In less severe cases of gallstone-related pancreatitis intervention for gallstone can be deferred until full recovery is obtained (an approximate 6-week period).

Prognosis

Mortality: 10-15%
One-third occur within the first week, usually from multi-organ failure. After this time the majority of deaths result from sepsis, especially that complicating infected necrosis.

Pathophysiology of Chronic Pancreatitis

• Chronic pancreatitis is a chronic inflammatory disease characterised by fibrosis and destruction of exocrine pancreatic tissue.
• Diabetes mellitus occurs in advanced cases because the islets of Langerhans are involved. 

Pathophysiology

• Around 80% of cases in Western countries result from alcohol misuse 
• In developing countries malnutrition and associated dietary factors have been implicated.

Other causes

• Cystic Fibrosis
• Benign and malignant processes obstructing pancreatic duct
• Congenital anomaly like pancreatic divisum
• Rarely, inherited as autosomal dominant with variable penetrance

Clinical features 

• Chronic pancreatitis predominantly affects middle-aged alcoholic men
• Pain is the most common presentation of chronic pancreatitis and is usually epigastric and often radiating through into the back.
• In 50%,episodes of 'acute pancreatitis‘ with each attack resulting in a degree of permanent pancreatic damage.
• In 35%, relentless, slowly progressive chronic pain without acute exacerbations
• remainder have no pain but diarrhoea
• Exocrine and endocrine insufficiency may develop at any time, and occasionally malabsorption or diabetes are the presenting features in the absence of abdominal pain.
• Steatorrhoea
• Protein malabsorption
• Diabetes Mellitus
• Weight loss is common and results from a combination of anorexia, avoidance of food because of post-prandial pain, malabsorption and/or diabetes

Complications

Pseudocyst - < 6cm, usually resolves spontaneously; > 6cm, requires intervention

  Ascites

Pleural effusion

Strictures – CBD, duodenum

Portal hypertention

Investigations

The extent dependens upon the clinical setting.

In a patient with known alcohol abuse and typical pain few confirmatory tests are required.

Tests performed include:

• Faecal elastase level will be abnormal in the majority
• Serum amylase and lipase levels are rarely significantly elevated in established chronic pancreatitis
• Pancreolauryl test
• Transabdominal ultrasound scan is used for initial assessment.
• Contrast-enhanced spiral CT scan – test of choice
• MRCP
• Endoscopic ultrasound – specifically for assessing complications
• Diagnostic ERCP – replaced by MRCP in developed countries

CT scan showing a grossly dilated and irregular duct with a calcified stone (arrow A). Note the calcification in the head of the gland (arrow B). 

MRCP of the same patient showing marked ductal dilatation with abnormal dilated side branches (arrows A). A small cyst is also present (arrow B).

Endoscopic retrograde cholangiogram shows grossly dilated pancreatic ducts (arrows) in a patient with long-standing pancreatitis

Treatment

• Alcohol avoidance is crucial in halting the progression of the disease and reducing pain.

Pain relief 

• Analgesics particularly NSAIDs are useful
• Opiates reserved for chronic unremitting pain and often leads to addiction
• Oral pancreatic enzyme supplementation reduces pancreatic secretion of enzymes and thus provides pain relief in some patients.
• Coeliac plexus neurolysis or minimally invasive thoracoscopic splanchnicectomy – provides long term pain relief but pain eventually recurs

Patients who are abstinent from alcohol and who have severe chronic pain which is resistant to conservative measures are considered for intervention with following procedures:

•  Endoscopic therapy

Dilatation or stenting of pancreatic duct strictures 

Removal of calculi (mechanical or shock-wave lithotripsy) 

Surgical methods

Partial pancreatic resection, preserving the duodenum 

Pancreatico-jejunostomy 

Total pancreatectomy – high morbidity and mortality with the procedure

• Steatorrhoea - dietary fat restriction , oral pancreatic enzyme supplements; a proton pump inhibitor is added to optimise duodenal pH for pancreatic enzyme activity
• Management of complications

ANTIBIOTIC REGIMENS FOR H. PYLORI ERADICATION

Case History:

A 30 year old lady comes to your clinic with complaints of pain in upper abdomen on and off for past 2 months. She tells you that there is some relief of pain after eating. She also tells you that immediately after taking meal she has the feeling of fullnes of abdomen and also that she doesn’t eat as much as she used to before. On examination, there are no abnormalities except for mild epigastric tenderness. How will you manage the case?

Peptic Ulcer Disease (PUD)

• Definition 
• Epidemiology 
• Etiology 
• Clinical Manisfestations
• Diagnosis 
• Treatment

Definition 

• The term 'peptic ulcer' refers to an ulcer in the lower oesophagus, stomach or duodenum, in the jejunum after surgical anastomosis to the stomach or, rarely, in the ileum adjacent to a Meckel's diverticulum.
• Acute or chronic and penetrating muscularis mucosae

Epidemiology 

The prevalence of peptic ulcer is decreasing in many Western communities as a result of widespread use of H. pylori eradication therapy but it remains high in developing countries. 

The male to female ratio for duodenal ulcer varies from 5:1 to 2:1, whilst that for gastric ulcer is 2:1 or less.

Etiology

• H. pylori
• NSAIDs
• Infection Cytomegalovirus ,Herpes simplex virus, Helicobacter heilmanni
• Drug/Toxin Bisphosphonates, Chemotherapy, Clopidogrel, Crack cocaine, Glucocorticoids (when combined with NSAIDs) ,Mycophenolate mofetil, Potassium chloride
• Miscellaneous Duodenal obstruction (e.g., annular pancreas), Infiltrating disease, Ischemia, Radiation therapy, Sarcoidosis, Crohn's disease, Idiopathic hypersecretory state

Helicobacter pylori 

The vast majority of colonised people remain healthy and asymptomatic and only a minority develop clinical disease.

Around 90% of duodenal ulcer patients and 70% of gastric ulcer patients are infected with H. pylori; the remaining 30% of gastric ulcers are due to NSAIDs.

Pathogenesis and pathophysiology of infection

The bacteria spread by person-to-person contact via gastric refluxate or vomit.

exclusively colonises gastric-type epithelium and is only found in the duodenum in association with patches of gastric metaplasia.

• The bacterium stimulates chronic gastritis by provoking a local inflammatory response in the underlying epithelium
• Host genetic polymorphisms :
• expression of the proinflammatory cytokine interleukin-1β (IL-1β)
• host inflammatory response to infection (e.g. IL-10 and TNF-α)
• approximately 1% of infected people, H. pylori causes a pangastritis leading to gastric atrophy and hypochlorhydria. May predispose to gastric cancer

Dx of H. pylori

Non-invasive tests

• Urea breath testing: very sensitive and widely performed
• serology
• Stool antigen assay

Invasive tests i.e. with endoscopic procedures

• Biopsy urease testing
• Brush cytology 
• Bacterial culture and sensitivity testing

INDICATIONS FOR H. PYLORI ERADICATION

1. Peptic ulcer 
2. MALToma 
3. H. pylori-positive dyspepsia 

ANTIBIOTIC REGIMENS FOR H. PYLORI ERADICATION

• 'First-line therapy is a proton pump inhibitor (12-hourly), clarithromycin 500 mg 12-hourly, and amoxicillin 1 g 12-hourly or metronidazole 400 mg 12-hourly, for 7 days. 
• Second-line therapy is a proton pump inhibitor (12-hourly), bismuth 120 mg 6-hourly, metronidazole 400 mg 12-hourly, and tetracycline 500 mg 6-hourly, for 7 days.'

Clinical Manisfestations of PUD 

• Postprandial fullness
• Early satiety
• Epigastric pain
• Aggravated by food in gastric ulcer
• Relieved by food in duodenal ulcer
• Complication may be the first presentation
• Bleeding
• Perforation
• Gastric  outlet obstruction

Diagnosis

Barium meal- gastric ulcer

Gastrodudenoendoscopy – duodenal ulcer

Treatment

General measures

• Cigarette smoking, aspirin and NSAIDs should be avoided
• Alcohol in moderation is not harmful 

Short-term management 

• Various drugs are available
• Antacids and alginates
• Aluminium hydroxide, magnesium trisilicate

H2-antagonists

• Ranitidine, cimetidine, famotidine, nizatidine

Proton pump inhibitors (PPIs

• Omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole

Complex salts

• Sucralfate

Prostaglandin analogues
Misoprostol

• H. pylori eradication
• Maintenance treatment 

Usually not necessary after H. pylori eradication
A minority of pts. with relapsing disease may need it and the lowest effective dose of PPI or H2 blocker should be used

Surgery

• A rare event now because of cure of most peptic ulcers by H. pylori eradication therapy and the availability of safe and potent acid-suppressing drugs
• Highly selective vagotomy
• Selective vagotomy
• Bilroth I and Bilroth II

Indications for surgery in peptic ulcer disease

• Emergency 
• Perforation 
• Haemorrhage 
• Elective
• Complications, e.g. gastric outflow obstruction 
• Recurrent ulcer following gastric surgery 
• Management of complications

PEPTIC ULCER DISEASE IN OLD AGE

Gastroduodenal ulcers: have a greater incidence, admission rate and mortality.
Causes: high prevalence of H. pylori and NSAID use, and impaired defence mechanisms.
Atypical presentations: pain and dyspepsia are frequently absent or atypical so older people develop complications such as bleeding or perforation more frequently.
Bleeding: older patients require more intensive management than younger patients because they tolerate hypovolaemic shock poorly.

Valvular Heart Diseases : Aortic Regurgitation/Insufficiency

Aetiology (Causes)

Congenital-
     Bicuspid valve or disproportionate cusps
Acquired
     Rheumatic disease
     Infective endocarditis
     Failure of prosthetic heart valve
     Aortic dilatation (Marfan's syndrome, aneurysm, dissection, syphilis, ankylosing spondylitis)


Pathophysiology

Symptoms
   
Mild to moderate AR
     
Often asymptomatic
     Awareness of heart beat, 'palpitations'
     Severe AR
     Breathlessness
     Angina
Signs
     Pulses-
       Large volume or ‘collapsing pulse’
       Low diastolic and increased pulse preassure
       Bounding peripheral pulses- A rapidly rising "water-hammer" pulse, which collapses suddenly as arterial pressure falls rapidly during late systole and diastole (Corrigan's pulse)
       Capillary pulsations, an alternate flushing and paling of the skin at the root of the nail while pressure is applied to the tip of the nail (Quincke's pulse/sign)
       Femoral bruit (‘pistol shot’)- Duroziez’s sign/ Traube’s sign
       Head nodding with pulse- de Musset’s sign
     


Murmurs-
          Early diastolic murmur
          Systolic murmur (increased stroke volume)
          Austin Flint murmur (soft mid-diastolic)
Other signs
          Displaced, heaving apex beat (volume overload)
          Pre-systolic impulse
          Fourth heart sound
          Pulmonary venous congestion (crepitations)


Investigatons


ECG –
           Initially normal, later LV hypertrophy and T-wave inversion
Chest X-ray –
           Cardiac dilatation, maybe aortic dilatation
           Features of left heart failure
Echo Dilated left ventricle
           Hyperdynamic left ventricle
           Fluttering anterior mitral leaflet
           Doppler detects reflux
Cardiac catheterisation (may not be required)
          Dilated LV
          Aortic regurgitation
          Dilated aortic root


Treatment

Treat the cause- underlying conditions like endocarditis or syphilis.
Nefidipine or ACE inhibitors to lower the systolic blood preassure.
If end systolic dimension of left ventrical is =>55mm then- Aortic valve replacement is undertaken.
Aortic root replacement – in aortic root dilatation (eg. Marfan syndrome)

Essentials of Diagnosis
Usually asymptomatic until middle age; presents with left-sided failure or chest pain.
Wide pulse pressure.
Hyperactive, enlarged LV.
Diastolic murmur along left sternal border.
ECG shows LVH; radiograph shows LV dilation.
Echocardiography/Doppler is diagnostic.
Afterload reduction is beneficial if the LV is dilated (LV end-diastolic dimension > 5.0 cm).
Surgery indicated for symptoms, EF < 55%, or LV end-systolic dimension > 5.0 cm.

Rx of Coronary hear disease (CHD)

Coronary hear disease (CHD)/Ischemic heart disease (IHD) is a condition in which there is an inadequate supply of blood and oxygen to a portion of the myocardium.
It typically occurs when there is an imbalance between myocardial oxygen supply and demand.
The most common cause of myocardial ischemia is atherosclerotic disease - which results in inadequate perfusion of the myocardium.
the single most important cause of premature death in Europe, the Baltic states, Russia, North and South America, Australia and New Zealand.
By 2020 it is estimated that it will be the major cause of death in all regions of the world.
Abnormal constriction or failure of normal dilation of the coronary resistance vessels can also cause ischemia. When it causes angina, this condition is referred to as microvascular angina.


Factors influenting myocardial oxygen supply and demand/Pathophysiology

Oxygen demand

Cardiac work
Heart rate
Blood pressure
Myocardial contractility
Left ventricular hypertrophy
Valve disease, e.g. aortic stenosis


Oxygen supply

Coronary blood flow
Duration of diastole
Coronary perfusion pressure (aortic diastolic minus coronary sinus or right atrial diastolic pressure)
Coronary vasomotor tone
Oxygenation
Haemoglobin
Oxygen saturation


Coronary Atherosclerosis-

Epicardial coronary arteries are the major site of atherosclerotic disease.
The major risk factors for atherosclerosis disturb the normal functions of the vascular endothelium:
high plasma low-density lipoprotein (LDL),
low plasma high-density lipoprotein (HDL),
cigarette smoking,
hypertension, and
diabetes mellitus

These functions include local control of vascular tone, maintenance of an antithrombotic surface, and impairment of inflammatory cell adhesion and diapedesis.
The loss of these defenses leads to inappropriate constriction, luminal thrombus formation, and abnormal interactions with blood leukocytes, especially monocytes, and platelets.
This leads to atherosclerosis.





CORONARY HEART DISEASE: CLINICAL MANIFESTATIONS AND PATHOLOGY

Angina

Angina pectoris is the symptom complex caused by transient myocardial ischaemia and constitutes a clinical syndrome rather than a disease.
It may occur whenever there is an imbalance between myocardial oxygen supply and demand.
Coronary atheroma is by far the most common cause of angina.
The symptom may also be a manifestation of other forms of heart disease, particularly aortic valve disease and hypertrophic cardiomyopathy.


Stable Angina

Occurs when coronary perfusion is impaired by fixed or stable atheroma of the coronary arteries.

Activities precipitating angina
Common
Physical exertion
Cold exposure
Heavy meals
Intense emotion
Uncommon
Lying flat (decubitus angina)
Vivid dreams (nocturnal angina)



Clinical Features

Chest discomfort/pain-
                       
usually described as heaviness, pressure, squeezing, smothering, or choking, and only rarely as frank pain.
typically lasts 2–5 min, and can radiate to either shoulder and to both arms (especially the ulnar surfaces of the forearm and hand).
typically caused by exertion (e.g., exercise, hurrying, or sexual activity) or emotion (e.g., stress, anger, fright, or frustration) and are relieved by rest, they may also occur at rest.
Physical findings-

Usually negative
Evidence of valve disease (particularly aortic)
Important risk factors (eg. Hypertension, diabetes.)
Evidence of left ventricular dysfunction (cardiomegaly and gallop rhythm)
Other conditions- carotid bruits, peripheral vascular disease, anemia and thyrotoxicosis (unrelated conditions)


Cardiovascular Disease Classification Chart



Investigations

Resting ECG- Ischemia causes characteristic changes in the electrocardiogram.
Repolarization abnormalities, as evidenced by inversion of T waves and, when more severe, by displacement of ST segments.
Transient T-wave inversion likely reflects nontransmural, intramyocardial ischemia.
Transient ST-segment depression often reflects subendocardial ischemia.
 ST-segment elevation is thought to be caused by more severe transmural ischemia.


Exercise ECG- is performed using a standard treadmill or bicycle ergometer protocol while monitoring the patients ECG, BP and general condition.
Planar or down-sloping of ST segment depression of 1 mm or more is indicative of ishemia.
Up-sloping ST depression is less specific.



A positive exercise test. The resting 12-lead ECG shows some minor T-wave changes in the inferolateral leads but is otherwise normal. After 3 minutes' exercise on a treadmill there is marked planar ST depression in leads II, V4 and V5 (right offset). Subsequent coronary angiography revealed critical three-vessel coronary artery disease.


Other forms of stress testing

Myocardial perfusion scanning-

Stress echocardiography-

Coronary arteriography-

A technetium scan showing reversible anterior myocardial ischaemia. The images are cross-sectional tomograms of the left ventricle. The resting scans (right) show even uptake of technetium and look like doughnuts; during stress (in this case a dobutamine infusion) there is reduced uptake of technetium, particularly along the anterior wall (arrows), and the scans look like crescents (left).




Coronary angiogram from a patient with stable angina. There is severe stenosis of the left main stem (arrow).




Management

Assessment of the likely extent and severity of arterial disease
Identification and control of signifiacant risk factors
The use of measures to control symptoms
The identification of high-risk patients and application of treatments to improve life expectancy


Advice to patients with stable angina

Do not smoke
Aim at ideal body weight
Take regular exercise (exercise up to, but not beyond, the point of chest discomfort is beneficial and may promote collateral vessels)
Avoid severe unaccustomed exertion, and vigorous exercise after a heavy meal or in very cold weather
Take sublingual nitrate before undertaking exertion that may induce angina



Medical Therapy

Antiplatelet therapy-   Low-dose (75-150 mg) aspirin, Clopidogrel (75 mg daily) is an equally effective antiplatelet agent that can be prescribed if aspirin causes troublesome dyspepsia or other side-effects.
Anti-anginal drug treatment-

Nitrates GTN  (in the form of metered dose aerosol and sublingual tablets), transdermal and oral (isosorbide dinitrate and mononitrate).
Beta blockers
Calcium channel blockers
Potassium channel activators-  eg Nicorandil

Invasive Treatment

Percutaneous Coronary Intervention

Coronary Artery Bipass Grafting

Severe stenosis of the circumflex artery (arrow). A balloon has been advanced into the stenosis, over a guidewire, and has been inflated. (Note the waisting caused by the lesion.) Residual stenosis and dissection (tramline shadow-arrow) after balloon dilatation. A stent is deployed on a balloon. The stent is visible on plain fluoroscopy (arrow). Angiogram after stenting. A short balloon is used to dilate the stent at high pressure. Final result.

Coronary artery bypass graft surgery. Narrowed or stenosed arteries are bypassed using saphenous vein grafts connected to the aorta, or by utilising the internal mammary artery.

A scheme for the investigation and treatment of stable angina on effort. (PCI = percutaneous coronary intervention; CABG = coronary artery bypass grafting)

A silent killer : Hypertension

In children and adolescents, hypertension is generally defined as systolic and/or diastolic blood pressure consistently >95th percentile for age, gender, and height.
Blood pressures between the 90th and 95th percentiles are considered prehypertensive and are an indication for lifestyle interventions.
A recent classification recommends blood pressure criteria for defining normal blood pressure, prehypertension, hypertension (stages I and II), and isolated systolic hypertension, which is a common occurrence among the elderly.

Blood Pressure Classification

Causes of secondary hypertension

Alcohol
Obesity
Pregnancy (pre-eclampsia)
Renal disease (Ch. 17) Renal vascular disease,Parenchymal renal disease, particularly glomerulonephritis , Polycystic kidney disease
Endocrine disease Phaeochromocytoma, Cushing's syndrome, Primary hyperaldosteronism (Conn's syndrome), Hyperparathyroidism, Acromegaly, Primary hypothyroidism, Thyrotoxicosis, Congenital adrenal hyperplasia due to 11-β-hydroxylase or 17-hydroxylase deficiency, Liddle's syndrome,11-β-hydroxysteroid dehydrogenase deficiency.
Drugs e.g. Oral contraceptives containing oestrogens, anabolic steroids, corticosteroids, non-steroidal anti-inflammatory drugs, carbenoxolone, sympathomimetic agents


Measurement of Blood Pressure

Use a machine that has been validated, well maintained and properly calibrated
Measure sitting BP routinely, with additional standing BP in elderly and diabetic patients and those with possible postural hypotension
Remove tight clothing from the arm
Support the arm at the level of the heart
Use a cuff of appropriate size (the bladder must encompass > two-thirds of the arm)
Lower the mercury slowly (2 mm per second)
Read the BP to the nearest 2 mmHg
Use phase V (disappearance of sounds) to measure diastolic BP
Take two measurements at each visit


Patient's Relevant History

Duration of hypertension
Previous therapies: responses and side effects
Family history of hypertension and cardiovascular disease
Dietary and psychosocial history
Other risk factors: weight change, dyslipidemia, smoking, diabetes, physical inactivity
Evidence of secondary hypertension: history of renal disease; change in appearance; muscle weakness; spells of sweating, palpitations, tremor; erratic sleep, snoring, daytime somnolence; symptoms of hypo- or hyperthyroidism; use of agents that may increase blood pressure
Evidence of target organ damage: history of TIA, stroke, transient blindness; angina, myocardial infarction, congestive heart failure; sexual function.


History and Examination

History- family history, life style (exercise, salt intake, smoking habit), and other risk factors. Drug or alcohol consumption, other features of secondary hypertension causes eg. Pheochromocytoma (paroxysmal headache, palpitation and sweating.)
Examination- measure blood pressure, look for radio-femoral delay, enlarged kidneys (PKD), abdominal bruits (renal artery stenosis), and characteristic facies and habitus of Cushing’s syndrome, central obesity and xanthomas.


Target organ damage

Retinal changes in hypertension.   Grade 4 hypertensive retinopathy showing swollen optic disc, retinal haemorrhages and multiple cotton wool spots (infarcts).   Central retinal vein thrombosis showing swollen optic disc and widespread fundal haemorrhage, commonly associated with systemic hypertension.


Hypertensive encephalopathy-

A rare condition characterised by high blood pressure and neurological symptoms.
Includs transient disturbances of speech or vision, paraesthesiae, disorientation, fits and loss of consciousness. Papilloedema is common.
A CT scan of the brain often shows haemorrhage in and around the basal ganglia; however, the neurological deficit is usually reversible if the hypertension is properly controlled.


‘Malignant’ or ‘accelerated’ phase hypertension

A rare condition which may complicate hypertension of any etiology.
Characterized by accelerated microvascular damage with necrosis in the walls of small arteries and arterioles (fibrinoid necrosis) and by intravascular thrombosis.
Diagnosis based on- high blood pressure and
Rapidly progressive end organ damage- such as retinopathy of grade 3 or 4, renal dysfunction (proteinuria), and/or hypertensive encephalopathy.
Left ventricular failure may occur and if not treated death may occur within months.


Investigation of all patients

Urinalysis for blood, protein and glucose
Blood urea, electrolytes and creatinine
Blood glucose
Serum total and high-density lipoprotein (HDL) cholesterol
12-lead ECG (left ventricular hypertrophy, coronary artery disease)


Investigations in selected patients

Chest X-ray: to detect cardiomegaly, heart failure, coarctation of the aorta
Ambulatory BP recording: to assess borderline or 'white coat' hypertension
Echocardiogram: to detect or quantify left ventricular hypertrophy
Renal ultrasound: to detect possible renal disease
Renal angiography: to detect or confirm presence of renal artery stenosis
Urinary catecholamines: to detect possible phaeochromocytoma.


Treatment

Lifestyle Modifications to Manage Hypertension



Antihypertensive drugs

Thiazide and other diuretics- mechanism of action is incompletely understood. A daily dose of 2.5 mg bendroflumethiazide or 0.5 mg cyclopenthiazide is appropriate. Furosemide(loop diuretics) have few advantages over thiazides in hypertension.
Beta-adrenoceptor antagonists (β-blockers)- Metoprolol (100-200 mg daily), atenolol (50-100 mg daily) and bisoprolol (5-10 mg daily) are cardioselective.


Labetalol and carvidilol- are combined β- and α-adrenoceptor antagonists. Labetalol (200 mg-2.4 g daily in divided doses) and carvedilol (6.25-25 mg 12-hourly).
Angiotensin-converting enzyme (ACE) inhibitors: e.g. enalapril 20 mg daily, ramipril 5-10 mg daily or lisinopril 10-40 mg daily. They should be used with particular care in patients with impaired renal function or renal artery stenosis because they can reduce the filtration pressure in the glomeruli and precipitate renal failure. Electrolytes and creatinine should be checked before and 1-2 weeks after commencing therapy.
Side-effects include first-dose hypotension, cough, rash, hyperkalaemia and renal dysfunction.


Angiotensin receptor blockers- These drugs (e.g. losartan 50-100 mg daily, valsartan 40-160 mg daily) block the angiotensin II type I receptor and have similar effects to ACE inhibitors but do not cause cough and are better tolerated.
Calcium antagonists- The dihydropyridines (e.g. amlodipine 5-10 mg daily, nifedipine 30-90 mg daily) are effective and usually well-tolerated antihypertensive drugs that are particularly useful in the elderly.
Side-effects include flushing, palpitations and fluid retention.
Diltiazem 200-300 mg daily, verapamil 240 mg daily can be useful when hypertension coexists with angina but they may cause bradycardia. The main side-effect of verapamil is constipation.


Other drugs- These include the α1-adrenoceptor antagonists (α-blockers), such as prazosin (0.5-20 mg daily in divided doses), indoramin (25-100 mg 12-hourly) and doxazosin (1-16 mg daily), and drugs that act directly on vascular smooth muscle, such as hydralazine (25-100 mg 12-hourly) and minoxidil (10-50 mg daily).
Side-effects include first-dose and postural hypotension, headache, tachycardia and fluid retention.
Centrally acting drugs, such as methyldopa (initial dose 250 mg 8-hourly) and clonidine (0.05-0.1 mg 8-hourly), are effective antihypertensive drugs but cause fatigue and are usually poorly tolerated.
Adjuvant drug therapy – Aspirin and Statins.


It is unwise to lower blood pressure too quickly because this may compromise tissue perfusion (due to altered autoregulation) which may lead to cerebral damage, including occipital blindness, and precipitate coronary or renal insufficiency.
Even in the presence of cardiac failure or hypertensive encephalopathy, a controlled reduction, to a level of about 150/90 mmHg, over a period of 24-48 hours is ideal.
Intravenous or intramuscular labetalol (2 mg/min to a maximum of 200 mg), intravenous glyceryl trinitrate (0.6-1.2 mg/hour), intramuscular hydralazine (5 or 10 mg aliquots repeated at half-hourly intervals) and intravenous sodium nitroprusside (0.3-1.0 μg/kg body weight per minute) are all effective remedies but require careful supervision, preferably in a high-dependency unit.

Treatment of Acute Rheumatic Fever

Acute Rheumatic Fever

Acute rheumatic fever (ARF) is a multisystem disease resulting from an autoimmune reaction to infection with group A streptococci.
Although many parts of the body may be affected, almost all of the manifestations resolve completely.
The exception is cardiac valvular damage [rheumatic heart disease (RHD)], which may persist after the other features have disappeared.
Acute rheumatic fever (ARF) usually affects children (most commonly between 5 and 15 years) or young adults.
 It remains endemic in parts of Asia, Africa and South America. It is still the most common cause of acquired heart disease in childhood and adolescence.

Pathogenesis

Organism factors- exclusively caused by infection of the upper respiratory tract with group A streptococci. Any strain of group A streptococcus has the potential to cause ARF.
Host factors- Approximately 3–6% of any population may be susceptible to ARF. Presence of familial susceptibility.
The immune response- When a susceptible host encounters a group A streptococcus, an autoimmune reaction results, which leads to damage to human tissues as a result of cross-reactivity between epitopes on the organism and the host.
Epitopes present in the cell wall, cell membrane, and the A, B, and C repeat regions of the streptococcal M protein are immunologically similar to molecules in human myosin, tropomyosin, keratin, actin, laminin, vimentin, and N-acetylglucosamine.

Antibodies developed against group A streptococcal M proteins cross react with similar proteins in human tissue (endocardium, myocardium and pericardium as well as joint and skin).
Also results in T-cell sensitization. These T cells are then recalled following subsequent exposure to group A streptococci bearing immunologically similar epitopes.
Histologically, fibrinoid degeneration is seen in the collagen of connective tissues. Aschoff nodules are pathognomonic and occur only in the heart. They are composed of multinucleated giant cells surrounded by macrophages and T lymphocytes, and are not seen until the subacute or chronic phases of rheumatic carditis.



Typically follows an episode of streptococcal pharyngitis and usually presents with fever, anorexia, lethargy and joint pains.
Symptoms characteristically occur 2-3 weeks after the initial attack of pharyngitis but the patient may not give history of sore throat.
Arthritis- The most common major manifestation and is characterised by acute, painful, asymmetric and migratory inflammation of the large joints (typically the knees, ankles, elbows and wrists). Occurs in approximately 75% of patients, usually an early feature that tends to occur when streptococcal antibody titres are high.

Carditis- a 'pancarditis' that involves the endocardium, myocardium and pericardium to varying degrees.
May manifest as breathlessness (due to heart failure or pericardial effusion),
Palpitations or chest pain (usually due to pericarditis or pancarditis).
Tachycardia, cardiac enlargement and new or changed cardiac murmurs.
Murmurs- A soft systolic murmur due to mitral regurgitation is very common. A soft mid-diastolic murmur (the Carey Coombs murmur) is typically due to valvulitis, with nodules forming on the mitral valve leaflets.
Pericarditis may cause chest pain, a pericardial friction rub and precordial tenderness.

Skin lesions- Erythema marginatum occurs in less than 5% of patients. Occur mainly on the trunk and proximal extremities but not the face.
Subcutaneous nodules occur in 5-7% of patients. They are small (0.5-2.0 cm), firm and painless, and are best felt over extensor surfaces of bone or tendons.
Appear more than 3 weeks after the onset of other manifestations and are therefore a feature that helps to confirm rather than make the diagnosis.

Sydenham's chorea (St Vitus dance)- a late neurological manifestation that typically appears at least 3 months after the episode of ARF when all the other signs may have disappeared.
Emotional lability may be the first feature and is typically followed by purposeless involuntary choreiform movements of the hands, feet or face. Spontaneous recovery usually occurs within a few months.
Other systemic manifestations are rare, but include pleurisy, pleural effusion and pneumonia.

Investigations

Evidence of a systemic illness (non-specific)
Leucocytosis, raised ESR, raised CRP

Evidence of preceding streptococcal infection (specific)
Throat swab culture: group A β-haemolytic streptococci (also from family members and contacts)
Antistreptolysin 0 antibodies (ASO titres): rising titres, or levels of > 200 U (adults) or > 300 U (children)

Evidence of carditis
Chest X-ray: cardiomegaly; pulmonary congestion
ECG: first- and rarely second-degree heart block; features of pericarditis; T-wave inversion; reduction in QRS voltages
Echocardiography: cardiac dilatation and valve abnormalities

Jones Criteria for the Diagnosis of Rheumatic Fever

Major manifestations
Carditis
Polyarthritis
Chorea
Erythema marginatum
Subcutaneous nodules

Minor manifestations Fever
Arthralgia
Previous rheumatic fever
Raised ESR or CRP
Leucocytosis
First-degree AV block (ECG changes)

PLUS  Supporting evidence of preceding streptococcal infection: recent scarlet fever, raised antistreptolysin 0 or other streptococcal antibody titre, positive throat culture.

Treatment

Bed rest and supportive therapy -
Antibiotics-
Penicillin is the drug of choice and can be given orally (as penicillin, 500 mg PO twice daily for 10 days) or as a single dose of 1.2 million units IM benzathine penicillin G.
Erythromycin, 250 mg bid, may be used for patients with penicillin allergy.
Salicylates and NSAIDs- for the treatment of arthritis, arthralgia, and fever, once the diagnosis is confirmed.
Aspirin is the drug of choice. An initial dose of 80–100 mg/kg per day in children (4–8 g/d in adults) in 4–5 divided doses is often needed for the first few days up to 2 weeks.
Corticosteroids- prednisolone 1-2mg/kg per day in divided doses.


Secondary prevention-

Early medical management of MI

Myocardial Infraction
Myocardial infarction occurs when cardiac myocytes die due to prolonged myocardial ischaemia.
The diagnosis can be made in patients with an appropriate clinical history together with findings from repeated 12-lead ECGs and elevated biochemical markers - troponin I and T, CK-MB.
STEMI occurs when a coronary artery thrombus develops rapidly at a site of vascular injury.
This injury is produced or facilitated by factors such as cigarette smoking, hypertension, and lipid accumulation.
A mural thrombus forms at the site of plaque disruption, and the involved coronary artery becomes occluded.
Histologic studies indicate that the coronary plaques prone to disruption are those with a rich lipid core and a thin fibrous cap.

Clinical Features

Symptoms
Prolonged cardiac pain: Chest, throat, arms, epigastrium or back (pain is not uniformly present in patients with STEMI).
Anxiety and fear of impending death
Nausea and vomiting
Breathlessness
Collapse/syncope

Physical signs
Signs of sympathetic activation
Pallor, sweating (The combination of substernal chest pain persisting for >30 min and diaphoresis strongly suggests STEMI), tachycardia
Signs of vagal activation (up to one-half with inferior infarction)
Vomiting, bradycardia
Signs of impaired myocardial function (physical signs of ventricular dysfunction )
Hypotension, oliguria, cold peripheries
Narrow pulse pressure
Raised jugular venous pressure
Third heart sound
Quiet first heart sound
Diffuse apical impulse
Lung crepitations
Signs of tissue damage
Fever
Signs of complications, e.g. mitral regurgitation, pericarditis.

Investigations
Electrocardiogram
Serum cardiac biomarkers-
 Cardiac-specific troponin T (cTnT) and cardiac-specific troponin I (cTnI)
 CKMB
Cardiac Imaging-
 Echocardiography: estimation of left ventricular (LV) function is useful prognostically; detection of reduced function serves as an indication for therapy with an inhibitor of the renin-angiotensin-aldosterone system.
 Identify the presence of right ventricular (RV) infarction, ventricular aneurysm, pericardial effusion, and LV thrombus.



Typical ECG changes in myocardial infarction (STEMI)

Cardiac biomarkers

Typical cardiac biomarkers that are used to evaluate patients with STEMI include the MB isoenzyme of CK (CKMB) and cardiac-specific troponins. The black horizontal line depicts the upper reference limit (URL) for the cardiac biomarker in the clinical chemistry laboratory.



Early medical management

brief history/risk factors. Examination
intravenous access + blood for markers (plus FBC, biochemistry, lipids, glucose)
12 lead ECG
intravenous opiate, e.g. morphine sulphate 5-10 mg or diamorphine 2.5-5 mg + anti-emetic, e.g. metoclopramide 10 mg
aspirin 150-300 mg chewed
sublingual glyceryl trinitrate 0.3-1 mg. Repeat
oxygen - nasal cannula 2-4 L/min
beta-blocker (if no contra-indication) for ongoing chest pain, hypertension, tachycardia
if primary PCI available give GP IIb/IIIa inhibitor. Alternatively give thrombolysis.

Fibrinolysis/Thrombolysis
Fibrinolytic agents enhance the breakdown of occlusive thromboses by the activation of plasminogen to form plasmin.
The initial thrombolytic agent used in clinical trials was streptokinase. Others are tissue plasminogen activator (alteplase), Newer-generation analogues of tPA (tenecteplase (TNK))
This agent is derived from bacteria, which can lead to the development of neutralizing antibodies that limit its repeated use.
Given as early as possible: <30 mins of onset of symptoms.

Streptokinase, 1.5 million U in 100 ml of saline given as an intravenous infusion over 1 hour, is a widely used regimen.
Alteplase (human tissue plasminogen activator or tPA) is a genetically engineered drug that is not antigenic and seldom causes hypotension.
The standard regimen is given over 90 minutes (bolus dose of 15 mg, followed by 0.75 mg/kg body weight, but not exceeding 50 mg, over 30 minutes and then 0.5 mg/kg body weight, but not exceeding 35 mg, over 60 minutes).

Contraindications to thrombolysis

Primary percutaneous coronary intervention (PCI)
In institutions that are able to offer rapid access (within 3 hours) to a 24-hour catheter laboratory service, percutaneous coronary intervention is the treatment of choice.
In comparison to thrombolytic therapy, it is associated with a 50% greater reduction in the risk of death, recurrent myocardial infarction or stroke.
Intravenous thrombolytic therapy remains the first-line reperfusion treatment in many hospitals with advanced cardiac unit.

Valvular Heart Diseases : Tricuspid Stenosis

Tricuspid Stenosis

Etiology-

Generally rheumatic in origin
Females more than in males
Usually associated with Mitral Stenosis
Clinicallly evident Tricuspid Stenosis occurs in 5-10% of cases
Rheumatic Tricuspid Stenosis is commonly associated with some degree of Tricuspid Regurgitation
Nonrheumatic causes of TS are rare.

Pathophysiology
A diastolic pressure gradient between the Right Atrium and Right Ventricle defines Tricuspid Stenosis.
A mean diastolic pressure gradient of 4 mmHg is usually sufficient to elevate the mean RA pressure to levels that result in systemic venous congestion.
This results in a reduced cardiac output, which is restored towards normal when the right atrial pressure increases.
The elevated Right Atrial preassure and Systemic venous congestion gives the clinical features of Tricuspid Stenosis

Clinical Features

Symptoms-
Since the development of MS generally precedes that of TS, many patients initially have symptoms of pulmonary congestion.
Spontaneous improvement of these symptoms should raise the possibility that TS may be developing.
Fatigue secondary to low cardiac output.
Discomfort due to edema, ascitis and hepatomegaly.

Signs-
The jugular veins are ditended. In cases of sinus rhythm (i.e. in absence of atrial fibrillation and other arrhythmias) there is prominent a wave and a slow y descent.
Mid-diastolic murmur- usually best heard at the lower left sternal border. Augmented during inspiration and reduced during expiration.
Features of right heart failure- hepatic congestion (hepatomegaly), ascitis and bilateral pitting edema.

Investigations
The ECG features of RA enlargement include tall, peaked P waves in lead II, as well as prominent, upright P waves in lead V1.
The chest x-ray in patients with combined TS and MS shows particular prominence of the RA and superior vena cava without much enlargement of the PA and with less evidence of pulmonary vascular congestion than occurs in patients with isolated MS.
On echocardiographic examination, the tricuspid valve is usually thickened and domes in diastole.
The transvalvular gradient can be estimated by Doppler echocardiography.

Management

Medical management consists of diuretic therapy and salt restriction. Specially during preoperative period.
Tricuspid valvotomy is occasionally possible, but tricuspid valve replacement is often necessary.
Other valves usually also need replacement because tricuspid valve stenosis is rarely an isolated lesion.

Tricuspid Regurgitation

Etiology-

Primary- Rheumatic heart disease
                 Endocarditis, particularly in IV drug abusers
                 Ebstein’s congenital anomaly

Secondary- Right ventricular dilatation due to chronic heart failure.
                     Right ventricular infraction
                     Pulmonary Hypertension (eg. Cor pulmonale)

Clinical Features
Symptoms-
Nonspecific related to reduced forward flow like tiredness.
Signs-
Features of systemic venous congestion. Ascitis, bilateral pitting edema, hepatic enlargement and raised JVP.
JVP- systolic wave a cv wave replacing normal x descent.
A pansystolic murmur at the left sternal edge.
Investigations
ECG- right axis deviation
Chest X-ray- right ventricular enlargement
Echo- reveals dilated right ventricles, thickened tricuspid valve of Rheumatic origin, Endocarditis vegetation and Ebstein anomaly.
Management
Often improves when the cause of right ventricular overload is corrected. Eg. Diuretics and vasodilator treatment of CCF.
Patient with normal pulmonary artery pressure tolerate isolated tricuspid reflux well so the valve replavement is not always necessary.
Annuloplasty ring- with marked dilatation of tricuspid annulus
Tricuspid valve replacement in rheumatic damage.

ACUTE CORONARY SYNDROMES and its types ?

ACUTE CORONARY SYNDROMES

Acute coronary syndromes (ACS) include:
Non-ST-elevation myocardial infarction (NSTEMI), and
Unstable angina,
ST-elevation myocardial infarction (STEMI)

Myocardial infarction occurs when cardiac myocytes die due to myocardial ischaemia, and can be diagnosed on the basis of:
appropriate clinical history,
12-lead ECG and
elevated biochemical markers - troponin I and T, creatinine-kinase-MB (CK-MB).


The spectrum of acute coronary syndromes. The relation between ECG changes, biochemical markers of damage and the extent of myocardial necrosis. (CK = creatine kinase)



The above figure explains ECG changes in ischemis with regard to extent of myocardial damage:
Ischemia with no myocardial damage- Unstable angina- ST and T wave changes (like ST depression and T wave inversion)
Ischemia with minimal myocardial damage,
Partial thickness (non ST elevation or non-Q wave) myocardial infraction, and
Full thickness (Q wave myocardial infraction)

Pathophysiology
The common mechanism to all ACS (Acute coronary syndrome- unstable angina, non ST elevation MI and ST elevation MI) is rupture or erosion of the fibrous cap of a coronary artery plaque.
This leads to platelet aggregation and adhesion, localized thrombosis, vasoconstriction, and distal thrombus embolization.
The presence of a rich lipid pool within the plaque and a thin fibrous cap, are associated with an increased risk of rupture.
Thrombus formation and the vasoconstriction produced by platelet release of serotonin and thromboxane A2, results in myocardial ischaemia due to reduction of coronary blood flow.

Unstable Angina

Unstable angina (UA) is defined as- angina pectoris or equivalent ischemic discomfort with at least one of three features:
(1) it occurs at rest (or with minimal exertion), usually lasting >10 min;
(2) it is severe and of new onset (i.e., within the prior 4–6 weeks); and/or
(3) it occurs with a crescendo pattern (i.e., distinctly more severe, prolonged, or frequent than previously).

The diagnosis of NSTEMI is established if a patient with the clinical features of UA develops evidence of myocardial necrosis, as reflected in elevated cardiac biomarkers.

Clinical Findings


The clinical hallmark of UA/NSTEMI is (symptoms)
chest pain, typically located in the substernal region or sometimes in the epigastrium, that radiates to the neck, left shoulder, and left arm.
Anginal "equivalents" such as dyspnea and epigastric discomfort may also occur.

The examination resembles that in patients with stable angina and may be unremarkable.
If the patient has a large area of myocardial ischemia or a large NSTEMI, the physical findings can include
diaphoresis,
pale cool skin,
sinus tachycardia,
a third and/or fourth heart sound,
basilar rales, and
sometimes hypotension, resembling the findings of large STEMI.

Investigations

ECG- In UA, ST-segment depression, transient ST-segment elevation, and/or T-wave inversion, depending on the severity of the clinical presentation.
T-wave changes are sensitive for ischemia but less specific, unless they are new, deep T-wave inversions.

Cardiac Biomarkers (bichemical test)- Creatinine Kinase (CKMB) and Troponin.
Elevated levels of these markers distinguish patients with NSTEMI from those with UA.
In patients with an unclear history, small troponin elevations may not be diagnostic of an ACS.


A guide to the investigation and treatment of unstable angina and non-ST segment elevation myocardial infarction (NSTEMI).

What are the Causes of Thyrotoxicosis?

Thyrotoxicosis is defined as the state of thyroid hormone excess and is not synonymous with hyperthyroidism, which is the result of excessive thyroid function.


Causes of Thyrotoxicosis

Regulation of thyroid hormone synthesis. Left. Thyroid hormones T4 and T3 feed back to inhibit hypothalamic production of thyrotropin-releasing hormone (TRH) and pituitary production of thyroid-stimulating hormone (TSH). TSH stimulates thyroid gland production of T4 and T3. Right. Thyroid follicles are formed by thyroid epithelial cells surrounding proteinaceous colloid, which contains thyroglobulin. Follicular cells, which are polarized, synthesize thyroglobulin and carry out thyroid hormone biosynthesis (see text for details). TSH-R, thyroid-stimulating hormone receptor; Tg, thyroglobulin; NIS, sodium-iodide symporter; TPO, thyroid peroxidase; DIT, diiodotyrosine; MIT, monoiodotyrosine.

Signs and Symptoms of Thyrotoxicosis (Descending Order of Frequency)

Symptoms
Hyperactivity, irritability, dysphoria
Heat intolerance and sweating
Palpitations
Fatigue and weakness
Weight loss with increased appetite
Diarrhea
Polyuria
Oligomenorrhea or amenorrhea, loss of libido
Typical features indicative of Grave’s disease may also be present.

Signs
Tachycardia; atrial fibrillation in the elderly
Tremor
Goiter
Warm, moist skin
Muscle weakness, proximal myopathy without fasciculation
hyperreflexia, muscle wasting
Lid retraction or lag
Gynecomastia
Osteopenia in long-standing thyrotoxicosis
Lid retraction, causing a staring appearance, can occur in any form of thyrotoxicosis and is the result of sympathetic overactivity.

Investigations

Thyroid function test:
Serum TSH is suppressed in hyperthyroidism (< 0.05 mU/L), except for the very rare instances of TSH hypersecretion.
Diagnosis is confirmed with a raised free T4 or T3; T4 is almost always raised but T3 is more sensitive as there are occasional cases of isolated 'T3 toxicosis'.
TSH receptor antibodies are present in the Grave’s disease.
Radio-iodine uptake test: but have been superseded by 99m technetium scintigraphy scans.

Non-specific laboratory abnormalities
Serum enzymes: raised ALT, gamma-glutamyl transferase and alkaline phosphatase from liver and bone.
Raised bilirubin
Mild hypercalcaemia
Glycosuria; associated diabetes mellitus, ‘Lag storage’ glycosuria (rapid gastric emptying and hence increased absorption of glucose)

Mangaement
Definitive treatment of thyrotoxicosis depends on the underlying cause.
Treatment option includes: antithyroid drugs, radioactive iodine or surgery.
In all: a beta blocker (propanolol 160mg daily or nadolol 48-80mg daily) will alleviate the symptoms within 24-48 hours. Only useful as short term.
Atrail fibrillation: common in thyrotoxicosis; little influenced by Digoxin,  but responds with beta blocker.
Thrombo-embolic vascular complication also common in thyrotoxic atrial fibrillation; warfarin given usless contraindicated.

Thyrotoxic crisis (‘thyroid storm’)
It is a medical emergency.
The mortality rate is 10%
A rare and life-threatening increase in the severity of the clinical features of thyrotoxicosis.
Fever, agitation, confusion, tachycardia or atrail fibrillation and cardiac failure in older patients are prominent features.
Most commonly precipitated by infection in patients with unrecognized or inadequately treated thyrotoxicosis.
Also precipitated by stress, surgery in an unprepared patient, or radioiodine therapy (acute irradiation may lead to a transient rise in serum thyroid hormone levels).
Treatment
Rehydration
A broad spectrum antibiotics (aminopenicillins)
Propanolol (80mg 6 hourly orally or IV 1-5mg 6 hourly)
Sodium ipodate; a radiographic contrast medium which inhibits the release of thyroid hormones, but also reduces the conversion of T4 to T3, 500mg per day orally will restore serum T3 levels to normal in 48-72 hours.
It is more effective then potassium iodide or Lugol’s solution.
Dexamethasone (2mg 6 hourly) and amiodarone have similar effects.
Carbimazole 40-60mg daily orally inhibits the synthesis of new hormome. Can be administered rectally as well but no IV preparation is available.

Essentials of diagnosis
Sweating, weight loss or gain, anxiety, loose stools, heat intolerance, irritability, fatigue, weakness, menstrual irregularity.
Tachycardia; warm, moist skin; stare; tremor.
In Graves disease: goiter (often with bruit); ophthalmopathy.
Suppressed TSH in primary hyperthyroidism; increased T4, FT4, T3, FT3.

Hyperthyroidism : Graves' disease ?

Introduction
Graves' disease accounts for 60–80% of thyrotoxicosis.
More common in females.
Rarely begins before adolescence.
Typically occurs between 20 and 50 years of age.
Indirect evidence suggests that stress is an important environmental factor.
Smoking is a minor risk factor for Graves' disease.
Sudden increases in iodine intake may precipitate Graves' disease.
There is a threefold increase in the occurrence of Graves' disease in the postpartum period.

Pathophysiology
Production of IgG antibodies (thyroid-stimulating immunoglobulins or TSH receptor antibodies TRAb) directed against the TSH receptor.
This stimulate hormone production and goitre formation.
Utimate thyroid failure is seen in some patients is thought to result from the presence of blocking antibodies against the TSH receptor, and
From tissue distruction by cytotoxic antibodies and cell-mediated immunity.
Cytokines appear to play a major role in thyroid-associated ophthalmopathy.
Infiltration of the extraocular muscles by activated T cells; the release of cytokines results in fibroblast activation and increased synthesis of glycosaminoglycans that trap water, thereby leading to characteristic muscle swelling.
Late in the disease, there is irreversible fibrosis of the muscles.
Increased fat is an additional cause of retrobulbar tissue expansion.
The increase in intraorbital pressure can lead to proptosis, diplopia, and optic neuropathy.
Smoking is strongly linked with the development of ophthalmopathy.
Trigger for the development of thyrotoxicosis in genetically susceptible individuals may be infection with viruses or bacteria.
Escherichia coli and Yersinia enterocolitica possess cell membrane TSH receptors; antibodies to these microbial agents may cross react with the TSH receptors.
Clinical features
Signs and symptoms include features that are common to any cause of thyrotoxicosis as well as those specific for Graves' disease.
The clinical presentation depends on the severity of thyrotoxicosis, the duration of disease, individual susceptibility to excess thyroid hormone, and the patient's age.
In the elderly, features of thyrotoxicosis may be subtle or masked, and patients may present mainly with fatigue and weight loss, a condition known as apathetic thyrotoxicosis.
Symptoms
Hyperactivity, irritability, dysphoria
Heat intolerance and sweating
Palpitations
Fatigue and weakness
Weight loss with increased appetite
Diarrhea
Polyuria
Oligomenorrhea, loss of libido
Signs
Tachycardia; atrial fibrillation in the elderly
Fine Tremor
Goiter
Warm, moist skin
Muscle weakness, proximal myopathy
Lid retraction or lag
Gynecomastia
aExcludes the signs of ophthalmopathy and dermopathy (The typical lesion is a noninflamed, indurated plaque with a deep pink or purple color and an "orange-skin" appearance.) specific for Graves' disease.
The high cardiac output produces a bounding pulse, widened pulse pressure, and an aortic systolic murmur and can lead to worsening of angina or heart failure.



Investigations

Thyroid function test:
Serum T3 and T4- elevated, T4 at upper normal range.
T3 is raised in only in 5% of the patients.
Serum TSH is undetected and less then 0.05mU/L.
Further investigation:
TSH receptor antibody (TRAb elevated)
Factitious thyrotoxicosis: by consuming excess amount of thyroid hormone preparation, esp. thyroxine which supress TSH and the release of endogenous thyroid hormone.
T4:T3 ratio in conventional thyrotoxicosis 30:1 is increased to 70:1 due to exogenous T4.





Management
The hyperthyroidism of Graves' disease is treated by reducing thyroid hormone synthesis, using antithyroid drugs, or reducing the amount of thyroid tissue with radioiodine (131I) treatment or by thyroidectomy.
The main antithyroid drugs are the thionamides, such as propylthiouracil, carbimazole, and the active metabolite of the latter, methimazole.
All inhibit the function of TPO, reducing oxidation and organification of iodide.
Propylthiouracil inhibits deiodination of T4 T3.
The initial dose of carbimazole or methimazole is usually 10–20 mg every 8 or 12 h, but once-daily dosing is possible after euthyroidism is restored.
Propylthiouracil is given at a dose of 100–200 mg every 6–8 h, and divided doses are usually given throughout the course.
Thyroid function tests and clinical manifestations are reviewed 3–4 weeks after starting treatment, and the dose is titrated based on unbound T4 levels.
Most patients do not achieve euthyroidism until 6–8 weeks after treatment is initiated. TSH levels often remain suppressed for several months and therefore do not provide a sensitive index of treatment response.
All patients should be followed closely for relapse during the first year after treatment and at least annually thereafter.
The common side effects of antithyroid drugs are rash, urticaria, fever, and arthralgia (1–5% of patients).
Rare but major side effects include hepatitis, an SLE-like syndrome, and, most importantly, agranulocytosis (<1%).

Propranolol (20–40 mg every 6 h) or longer-acting beta blockers such as atenolol, may be helpful to control adrenergic symptoms, especially in the early stages before antithyroid drugs take effect.
Radioiodine causes progressive destruction of thyroid cells and can be used as initial treatment or for relapses after a trial of antithyroid drugs.
Pregnancy and breast feeding are absolute contraindications to radioiodine treatment, but patients can conceive safely 6 months after treatment.
Subtotal or near-total thyroidectomy is an option for patients who relapse after antithyroid drugs and prefer this treatment to radioiodine.
The titration regimen of antithyroid drugs should be used to manage Graves' disease in pregnancy, as blocking doses of these drugs produce fetal hypothyroidism. Propylthiouracil is usually used because of relatively low transplacental transfer and its ability to block T4 T3 conversion.

Hypercortisolism : Cushing's syndrome and Cushing's disease

Introduction

Cushing's syndrome is the term used to describe the clinical state of increased free circulating glucocorticoid, by excessive activation of glucocorticoid receptor.
The most common cause is iatrogenic, due to prolong administration of synthetic glucocorticoids such as prednisolone.
About 40% of cases are due to Cushing "disease," by which is meant the manifestations of hypercortisolism due to ACTH hypersecretion by the pituitary.

About 15% of cases are due to ACTH from a source that cannot be initially located.
About 30% of cases are due to excessive autonomous secretion of cortisol by the adrenals—independently of ACTH, serum levels of which are usually low.
Regardless of etiology, all cases of endogenous Cushing's syndrome are due to increased production of cortisol by the adrenal.

Etiology

ACTH-dependent

Pituitary adenoma secreting ACTH (i.e. Cushing's disease)
Ectopic ACTH syndrome (e.g. bronchial carcinoid, small-cell lung carcinoma, pancreatic neuro-endocrine tumour)
latrogenic (ACTH therapy)

Non-ACTH-dependent

Iatrogenic (chronic glucocorticoid therapy, e.g. for asthma)
Adrenal adenoma
Adrenal carcinoma

Pseudo-Cushing's syndrome, i.e. cortisol excess as part of another illness
Alcohol excess (biochemical and clinical features)
Major depressive illness (biochemical features only, some clinical overlap)
Primary obesity

Clinical features

Hypercortisolism promotes the deposition of adipose tissue in characteristic sites, notably the upper face (producing the typical "moon" facies), the interscapular area (producing the "buffalo hump"), supraclavicular fat pads, and the mesenteric bed (producing "truncal" obesity)
Catabolic responses in peripheral supportive tissue causes muscle weakness and fatigability, osteoporosis,
Broad violaceous cutaneous striae and easy bruisability (secondary to weakening and rupture of collagen fibers in the dermis).
Osteoporosis may cause collapse of vertebral bodies and pathologic fractures of other bones.
Increased hepatic gluconeogenesis and insulin resistance can cause impaired glucose tolerance.

Hypertension is common, and emotional changes may be profound, ranging from irritability and emotional lability to severe depression, confusion, or even frank psychosis.
The face appears plethoric, even in the absence of any increase in red blood cell concentration.
Pigmentation occurs only with ACTH-dependent causes.
In women, increased levels of adrenal androgens can cause acne, hirsutism, and oligomenorrhea or amenorrhea.
Some signs and symptoms in patients with hypercortisolism—i.e., obesity, hypertension, osteoporosis, and diabetes—are nonspecific and therefore are less helpful in diagnosing the condition.

On the other hand, easy bruising, typical striae, myopathy, and virilizing signs (although less frequent) are, if present, more suggestive of Cushing's syndrome.
A cushingoid appearance can be caused by excess alcohol consumption (pseudo-Cushing's syndrome) - the pathophysiology is poorly understood.
Impaired glucose tolerance or frank diabetes are common, especially in the ectopic ACTH syndrome.
Hypokalaemia due to the mineralocorticoid activity of cortisol is common with ectopic ACTH secretion.

Clinical features in decending order of frequency
Typical habitus (centripetal obesity)a  97%
Increased body weight 94%
Fatigability and weakness 87%
Hypertension (blood pressure > 150/90) 82%
Hirsutisma  80%
Amenorrhea 77%
Broad violaceous cutaneous striaea  67%
Personality changes 66%
Ecchymosesa  65%
Proximal myopathya  62%
Edema  62%
Polyuria, polydipsia  23%
Hypertrophy of clitoris 19%



Investigations

Investigations to confirm the diagnosis include:

48-hour low-dose dexamethasone test. Normal individuals suppress plasma cortisol to < 50 nmol/L.
Patients with Cushing's syndrome fail to show complete suppression of plasma cortisol levels (although levels may fall substantially in a few cases).
This test is highly sensitive (> 97%). The overnight dexamethasone test is slightly simpler, but has a higher false-positive rate.
The hypothalamic-pituitary adrenal axis may escape from supression by Dexamethasone if more potent influence such as psychological stress supervenes.
24-hour urinary free cortisol measurements.
This is simple, but less reliable - repeatedly normal values (corrected for body mass) render the diagnosis most unlikely, but some patients with Cushing's have normal values on some collections (approximately 10%).


Circadian rhythm.
After 48 hours in hospital, cortisol samples are taken at 0900 h and 2400 h (without warning the patient).
Normal subjects show a pronounced circadian variation;
Those with Cushing's syndrome have high midnight cortisol levels (> 100 nmol/L), though the 0900 h value may be normal.
Other tests.
There are frequent exceptions to the classic responses to diagnostic tests in Cushing's syndrome.
If any clinical suspicion of Cushing's remains after preliminary tests then specialist investigations are still indicated, these may include insulin stress test, desmopressin stimulation test and CRH tests.

Differential diagnosis of the cause:
This can be extremely difficult since all causes can result in clinically identical Cushing's syndrome.


The classical ectopic ACTH syndrome is distinguished by a short history, pigmentation and weight loss, unprovoked hypokalaemia, clinical or chemical diabetes and plasma ACTH levels above 200 ng/L.
But many ectopic tumours are benign and mimic pituitary disease closely both clinically and biochemically.
Biochemical and radiological procedures for diagnosis include:
Adrenal CT or MRI scan.
Adrenal adenomas and carcinomas causing Cushing's syndrome are relatively large and always detectable by CT scan.
Carcinomas are distinguished by large size, irregular outline and signs of infiltration or metastases.
Bilateral adrenal hyperplasia may be seen in ACTH-dependent causes or in ACTH-independent nodular hyperplasia.


Pituitary MRI.
A pituitary adenoma may be seen but the adenoma is often small and not visible in a significant proportion of cases.
Plasma potassium levels.
Hypokalaemia is common with ectopic ACTH secretion. (All diuretics must be stopped.)
High-dose dexamethasone test
Failure of significant plasma cortisol suppression suggests an ectopic source of ACTH or an adrenal tumour.
Plasma ACTH levels. Low or undetectable ACTH levels (< 10 ng/L) on two or more occasions are a reliable indicator of non-ACTH-dependent disease.
CRH test. An exaggerated ACTH and cortisol response to exogenous CRH suggests pituitary-dependent Cushing's disease, as ectopic sources rarely respond.
Chest X-ray is mandatory to look for a carcinoma of the bronchus or a bronchial carcinoid. Carcinoid lesions may be very small; if ectopic ACTH is suspected, whole-lung and mediastinal CT scanning should be performed.



Treatment
Untreated Cushing's syndrome has a 50% 5-year mortality.
Death result from hypertension, myocardial infarction, infection and heart failure.
Most patients are treated surgically with medical therapy given for a few weeks prior to operation.
The usual drug is metyrapone, an 11β-hydroxylase blocker, which is given in doses of 750 mg to 4 g daily in three to four divided doses.
Ketoconazole (200 mg three times daily) is also used and is synergistic with metyrapone.
Plasma cortisol should be monitored, aiming to reduce the mean level during the day to 150-300 nmol/L, equivalent to normal production rates.
Aminoglutethimide and trilostane (which reversibly inhibits 3β-hydroxysteroid dehydrogenase) are occasionally used.

Cushing's disease


Trans-sphenoidal surgery with selective removal of the adenoma is the treatment of choice.
Selective adenomectomy nearly always leaves the patient ACTH-deficient immediately postoperatively, and this is a good prognostic sign.
Overall, pituitary surgery results in remission in 75-80% of cases.
External pituitary irradiation alone is slow acting, only effective in 50-60% even after prolonged follow-up and mainly used after failed pituitary surgery.
 Medical therapy to reduce ACTH (e.g. bromocriptine, cyproheptadine) is rarely effective.
Bilateral adrenalectomy is an effective last resort if other measures fail to control the disease.
This can be performed laparoscopically.


Adrenal tumours

Adrenal adenomas are removed via laparoscopy or a loin incision.
Adrenal carcinomas are resected if possible, the tumour bed irradiated and the patient given the adrenolytic drug mitotane.
Cytotoxic chemotherapy may retard disease progression in patients with metastases.

Ectopic ACTH syndrome
Localised tumours causing this syndrome (e.g. bronchial carcinoid) should be removed.
During treatment or palliation of non-resectable malignancies, it is important to reduce the severity of the Cushing's syndrome using medical therapy.

Endocrinology : Adrenal Insufficiency

Introduction 

Results from inadequate secretion of cortisol and/or aldosterone.
It is potentially fatal and notoriously variable in its presentation.
Acute adrenal crisis is more commonly seen in primary adrenal insufficiency (Addison disease) than in disorders of the pituitary gland causing secondary adrenocortical hypofunction.
Adrenal crisis may occur in the following situations: 

(1) following stress, eg, trauma, surgery, infection, or prolonged fasting in a patient with latent insufficiency;
(2) following sudden withdrawal of adrenocortical hormone in a patient with chronic insufficiency or in a patient with temporary insufficiency due to suppression by exogenous corticosteroids or megestrol;
(3) following bilateral adrenalectomy or removal of a functioning adrenal tumor that had suppressed the other adrenal;
(4) following sudden destruction of the pituitary gland (pituitary necrosis), or when thyroid hormone is given to a patient with hypoadrenalism;
(5) following injury to both adrenals by trauma, hemorrhage, anticoagulant therapy, thrombosis, infection or, rarely, metastatic carcinoma; and
(6) following administration of etomidate, which is used intravenously for rapid anesthesia induction or intubation.


Etiology

The most common is ACTH deficiency (i.e. secondary adrenocortical failure), usually because of inappropriate withdrawal of chronic glucocorticoid therapy or a pituitary tumour.
In Addison's disease, either glucocorticoid or mineralocorticoid deficiency may come first, but eventually all patients fail to secrete both classes of corticosteroid.
Addison's disease results from progressive destruction of the adrenals, which must involve >90% of the glands before adrenal insufficiency appears.


Causes of adrenocortical insufficiency

Secondary (↓ACTH)
Withdrawal of suppressive glucocorticoid therapy
Hypothalamic or pituitary disease
Primary (↑ACTH)
Common causes
Tuberculosis
HIV/AIDS
Metastatic carcinoma
Autoimmune
Sporadic
Polyglandular syndromes

Rare causes:
Lymphoma
Intra-adrenal hemorrhage (Waterhouse-Friedrichsen syndrome following meningococcal septicemia)
Amyloidosis
Hemochromatosis
Corticosteroid biosynthetic enzyme defects:
Congenital adrenal hyperplasia
Drugs: Aminoglutethimide, metyrapone, ketokonazole, etomidate.


Clinical features

The patient complains of headache, lassitude, nausea and vomiting, abdominal pain, and often diarrhea.
Confusion or coma may be present.
Adrenocortical insufficiency caused by gradual adrenal destruction is characterized by an insidious onset of fatigability, weakness, anorexia, nausea and vomiting, weight loss, cutaneous and mucosal pigmentation, hypotension, and occasionally hypoglycemia.
Depending on the duration and degree of adrenal hypofunction, the manifestations vary from mild chronic fatigue to fulminating shock associated with acute destruction of the glands, as described by Waterhouse and Friderichsen.

The clinical features can be the manifestation of glucocorticoid deficiency and adrenal androgen deficiency with or without mineralocorticoid insufficiency and ACTH access.
Or all glucocorticoid and mineralocorticoid insufficiency with ACTH access without Adrenal androgen insufficiency.
The specific causes according to these features are:
Withdrawal of exogenous glucocorticoid: features of glucocorticoid insufficinecy is presnet, mineralocorticoid insufficiency is abscent, ACTH access abscent and adrenal androgen insufficiency is present. 
Hypopituitarism: glucocorticoid and adrenal androgen insufficiency present and rest is absent.

Addision’s disease: features of absence of all the hormones of adrenal cortex.
Congenital adrenal hyperplasia (21hydroxylase deficiency): features of absence of all hormones of adrenal cortex but there is features of excess of adrenal androgen.

Features due to glucocorticoid insufficiency
Weight loss 
Malaise 
Weakness
Anorexia
Gastrointestinal- diarrohea or constipation
Postural hypotension
Shock 
Hypglycemia 
Hyponatremia (Dilutional)
Hypercalcemia



Features due to mineralocorticoid insufficiency: 
Hypotension 
Shock 
Hyponatremia (depletional)
Hyperkalemia
Features due to ACTH access
Pigmentation in the: 
Sun exposed areas
Pressure areas eg elbows and knees
Palmer creases, knuckles
Mucus membreane 
Conjunctiva 
Recent scars
Features due to adrenal androgen insufficiency: 
Decreased body hair
Loss of libido especially in female. 



Investigations 

In patients with suspected acute adrenal crisis treatment should not be delayed pending results.
Assessment of glucocorticoid, mineralocorticoid and other non-specific test can be done to come to the diagnosis.
Assessment of glucocorticoid:
A random blood sample should be stored for measurement of cortisol.
A short ACTH stimulation test may be appropriate before administering hydrocortisone. Diagnoses primary or secondary adrenal insufficiency.
If an ACTH assay is unavailable, then a long ACTH stimulation test can be used (1mg depot ACTH i.m. daily for 3 days)

In secondary adrenal insufficiency there is a progressive increase in plasma cortisol with repeated ACTH administration.
In Addison’s disease cortisol remains less than 700 nmol/l (25.4ug/dl) at 8 hours after the last injection.
Assessment of mineralocorticoids
Plasma electrolyte measurements are insufficient to assess mineralocorticoid secretion in patients with suspected Addison's disease.
Hyponatraemia occurs in both aldosterone and cortisol deficiency.
In mineralocorticoid deficinecy plasma aldosterone is reduced or in low normal with high plasma renin activity.
Other tests
Blood glucose may be low, with symptomatic hypoglycaemia.
Adrenal antibodies are present in many cases of autoimmune adrenalitis.
Chest and abdominal X-rays may show evidence of tuberculosis and/or calcified adrenals.


Management 

Adrenal crisis is a medical emergency and requires urgent treatment:
Emergency Management of acute hypoadrenalism:
Clinical context:
hypotension, hyponatraemia, hyperkalaemia, hypoglycaemia, dehydration, pigmentation often with precipitating infection, infarction, trauma or operation.
The major deficiencies are of salt, steroid and glucose.
Assuming normal cardiovascular function, the following are required:
One litre of 0.9% saline should be given over 30-60 minutes with 100 mg of intravenous bolus hydrocortisone.

Subsequent requirements are several litres of saline within 24 hours (assessing with central venous pressure line if necessary) plus hydrocortisone, 100 mg i.m., 6-hourly, until the patient is clinically stable.
Glucose should be infused if there is hypoglycaemia.
Oral replacement medication is then started, unless unable to take oral medication, initially hydrocortisone 20 mg, 8-hourly, reducing to 20-30 mg in divided doses over a few days.
Fludrocortisone (9 alpha-fluoro-hydrocortisone: a mineralocorticoid) is unnecessary acutely as the high cortisol doses provide sufficient mineralocorticoid activity - it should be introduced later.


Adequacy of glucocorticoid dose is judged by:
clinical well-being and restoration of normal, but not excessive, weight gain
normal cortisol levels during the day while on replacement hydrocortisone (cortisol levels cannot be used for synthetic steroids).
Fludrocortisone replacement is assessed by:
restoration of serum electrolytes to normal
blood pressure response to posture (it should not fall > 10 mmHg systolic after 2 minutes' standing)
suppression of plasma renin activity to normal.

Patient advice All patients requiring replacement steroids should:
know how to increase steroid replacement dose for intercurrent illness
carry a 'Steroid Card‘
wear a Medic-Alert bracelet (or similar), which gives details of their condition so that emergency replacement therapy can be given if found unconscious
keep an (up-to-date) ampoule of hydrocortisone at home in case oral therapy is impossible, for administration by self, family or GP.
Replacement dose of Glucocorticoid in adults:
Hydrocortisone 20-30 mg daily e.g. 10 mg on waking, 5 mg at 1200 h, 5 mg at 1800 h or
Prednisolone 7.5 mg daily 5 mg on waking, 2.5 mg at 1800 h