Melanoma

Background/Epidemiology

• Malignant tumour arising from the melanocytes in the skin
  • Spread via lymph and/or blood
• Incidence ~5-20/100,000/year and rising
  • Not that most patients will have a mole (melacytic naevus) which is benign
• 4 subtypes: superficial spreading, nodular, lentigo maligna and acral lentiginous
• More common in women than men but more men die of it

Risk factors/Aetiology

• Approximately 50% of melanomas arise from a pre-existing naevus.
• There are several lesions which can be considered precursors to melanoma e.g. common acquired naevus (freckle); melanocytic naevus (mole); actinic lentigines
  • Many of theses (or a tendency to freckly), along with type I skin, increases the risk of transformation into melanoma
  • >100 common naevi and >2 atypical naevi (>5mm diameter or on unusual sites e.g. buttocks, scalp, ears, hands/feet) increases the risk dramatically
• UV/Sun overexposure
• Age
• There is a genetic/hereditary component to some degree (familial cases can be associated with genetic traits e.g. tumour suppressor dysfunction of the CDKN2A gene)
• Previous skin cancer

Presentation

• Typically affects the legs in women and the back in men
• Slowly enlarging, macular, pigmented lesion with increasing irregularity in shape and pigment
  • Radial growth phase can last 2 years.  Subsequently, the lesion can become palpable and the vertical growth phase (invasive)
  • NB in nodular melanoma, there is classically a rapidly growing nodule that can bleed/ulcerate which may or may not be deeply pigmented (can be confused with vascular lesions but pigment can usually be visualised using a dermatoscope)
• Features of the lesion
  • 7 point checklist (>=3 suspicious)
    • Major (2 points)
      • Change in size
      • Irregular shape/border
      • Irregular colour
    • Minor (1 point)
      • >6mm in largest diameter
      • Inflammation
      • Oozing or crusting
      • Change in sensation (e.g. itch)
  • ABCDEFG
  1. Asymmetry
  2. Border Irregularity
  3. Colour variation/changes
  4. Diameter >6mm
  5. Elevated or Evolution (i.e. change in characteristics)
  6. Firm
  7. Growth

Diagnosis/Investigations

• Excision biopsy with 2mm margin
  • Breslow thickness/T staging
    • Distance from skin surface
      • T1 <1mm
        • NB in these cases the Clark level should also be documented i.e. what level of skin has been invaded
          • Level 1 is generally in situ melanoma (confined to the epidermis)
          • Level 2- papillary dermis
          • Level 3- reticular dermis
          • Level 4- reticular/deep dermis
          • Level 5- subcutaneous (fat)
      • T2 1-2mm
      • T3 2-4mm
      • T4 >4mm
  • Pathology should also try to identify any lymphovascular invasion and whether there is any ulceration (these are important for prognosis/choice of treatment)
• Sentinal lymph node biopsy
  • Particularly if tumour is ≥1mm deep
• Imaging (chest CT/liver USS/Abdominal CT/PET imaging) can also be done if tumour is ≥1mm, a

Management/Prognosis

• Surgical excision is the primary treatment for locoregional disease (stage I-III i.e. not metastatic disease)
  • Margin depends on breslow staging
    • T1 – 1cm
    • T2 – 1-2cm
    • T3/4 – 2cm
• For metastatic disease,
  • Dacarbazine can be used but response rates are poor and really only improves survival by several months
  • Radiotherapy/surgery can be of limited use for palliation of symptoms caused by metastases
• Prognosis can be estimated using Cochran’s Equation

Anaemia of Chronic Disease

Background

• Second most common form of anaemia.  Particularly common in hospital patients
  • Chronic infection, inflammation or neoplasia
  • Not related to bleeding, haemolysis or marrow infiltration
• Usually mild (85-115g/l) and is usually normochromic normocytic

Pathophysiology

• Not fully understood but different processes involving iron homeostasis, erythropoiesis and response to erythropoietin have been shown to be involved.
• A key factor involved is IL-6 (commonly expressed in a range of diseases e.g. inflammatory conditions and chronic renal disease)
  • Induces expression of hepcidin in the liver which binds to ferroportin on the membranes of iron-exporting cells e.g. enterocytes and macrophages, internalising the ferroportin and inhibiting the export of iron.
    • Iron is trapped as ferritin within the cells
      • Serum iron is low but ferritin is normal/high

Conditions commonly associated with ACD

• Infections (viral, bacterial, parasitic or fungal)
• Autoimmune conditions (rheumatoid arthritis; SLE; Vasculitides; Sarcoidosis; IBD)
• Chronic kidney disease
• Chronic heart failure

Presentation

• Usually there will be an underlying cause with its own symptoms
• Patients may be more tired, breathless, pale etc than normal

Investigations

• It can be difficult to differentiate ACD from Iron-deficiency anaemia (both can have a reduced haemoglobin and MCV)
  • Iron studies will usually show low iron but normal/high ferritin in ACD (cf IDA in which both will be low)

Management

• Often conservative management is all that is required (usually mild symptoms)
• If there is an iron deficiency, treat this with iron.  If uncertain, a trial of oral iron can be given to assess the response.
• If severe anaemia and/or symptoms are problematic, consider transfusion.  However, this is often only used as a palliative measure (symptom control)

Iron deficiency anaemia

Background and Epidemiology

• Occurs when the body’s iron demand is not met by iron absorption such to cause anaemia
• It is common- 2-5% of the adult male and post-menopausal female population
  • Most common cause of referral to gastroenterology
• IMPORTANT: Iron deficiency anaemia is NOT a diagnosis but a sign (blood test- see below) often with symptoms (see below).
  • Whilst the cause may not always be found, it is important that a cause is investigated

Presentation

• History
  • PC- may be fatigue, SOB on exertion, palpitations
    • Other symptoms which may present include: sore tongue/taste disturbance; changes in hair/hair loss; pruritus; headache; tinnitus; angina (particularly if there is pre-existing CAD)
      • Rarely, other complaints may include dysphage due to an oesophageal web (Paterson Brown-Kelly/Plummer-Vinson syndrome)
      • In severe cases, patients can be SOB at rest; angina and ankle swelling
    • Ask about other symptoms e.g. of hypothyroidism or hyperthyroidism; weight loss; night sweats; etc which may be indicative of another cause AND ask about symptoms of diseases which may cause an iron deficient anaemia e.g. change in bowel habit, PR bleeding etc
    • Ask about any episodes of overt bleeding (particularly heavy periods in women- may be appropriate to take a full menstrual history, nosebleeds, PR bleeding etc)
  • Ask about PMHx and RHx
    • Drugs e.g. NSAIDs (peptic ulcer)
    • Previous GI disease/surgery
    • Recent illness
    • ?Recent blood donation
  • Ask about any FHx, Social Hx (in particular diet, but also smoking and alcohol (risk of cancer and other illness)), Travel history
• Examination
  • On General examination
    • Pallor (can be particularly obvious in the mucous membranes e.g. conjunctiva, mouth etc)
    • Koilonychia (spoon shaped nails with longitudinal ridging)
    • Angular cheilitis
    • Beefy tongue (atrophic glossitis)
    • NB Be aware for signs of associated conditions which may be causing the anaemia e.g. stigmata of chronic liver disease; hereditary haemorrhagic telangiectasia, Peutz-Jeghers sydrome (pigmentation)
  • CVS examination may reveal a mild tachycardia (usually worse cases- rarely there may also be signs of heart failure (e.g. ankle oedema))
  • Abdominal Examination should look for any masses/organomegaly
    • +/- PR examination if appropriate (e.g. change in bowel habit, PR bleeding etc)
  • In patients with menorrhagia- see here for examination

Causes

• Most commonly GI (in adult men and postmenopausal women)
  • Occult GI malignancy (e.g. gastric or colorectal cancers)
  • Peptic ulcer disease (check NSAID use)
• Gynaecological (most common cause in premenopausal women)
• • Menstruation
  • Pregnancy (due to increased demand (x3) rather than loss)
• Malabsorption
• • e.g. Coeliac, gastrectomy; PPI use
• Other causes include
  • Blood donation
  • Poor intake (rare in non-pregnant individuals/growing children)
  • Rarely other sources of bleeding e.g. nosebleeds, haematuria etc could potentially cause anaemia

Investigations

• Blood tests:
  • For the diagnosis: FBC – Low Haemoglobin (anaemia) with microcytosis/Low MCV (microcytic).  Next check ferritin/iron levels (low <15μg/l)
    • NB Can be affected inflammation (e.g. rheumatoid, liver disease, malignancy, hyperthyroidism, kidney disease and alcoholism), can also be high even with anaemia
• For identifying the cause
  • Screen for Coeliac disease (EMA/tissue transglutaminase antibody)
  • OGD (oesophagastroduodenoscopy) should be performed first if the screen is negative, then colonoscopy (if gastric cancer/peptic ulcer or other cause were identified on OGD)

Management

• Refer anyone with severe anaemia (Men <110g/l and Women <100g/l); patients with anaemia and signs of heart-failure; anaemia with dyspepsia; patients who do not respond to treatment or who have responded but subsequently developed anaemia again
  • (Women with menorrhagia and iron-deficiency anaemia, who don’t respond to first-line management of both, should be referred to gynaecology)
• Iron supplementation should be given before the results of investigations
  • Ferrous fumarate is the first choice in Tayside (210mg TDS)
    • Ferrous sulphate is an alternative (and is often used first line in other areas)
• Manage the underlying cause

Side effects and Follow-up

• Most common side effect is gastric irritation e.g. heartburn, nausea, abdominal pain (for absorption- iron should be taken on an empty stomach but if side-effects are problematic, they may be taken after food)
  • Other side effects include constipation (stools also tend to go black); diarrhoea (less common)
• Patients should have a FBC 2-4 weeks after starting treatment (to check if Hb is improving or worsening); in 2-4 months (to check improvement of Hb) and treatment should be continued for 3 months following this (Hb should be checked every 3 months for a year and then one year later)
  • If Hb does not improve,
    • Check compliance and manage side effects
    • If, after 2-4 weeks, Hb has not improved by more than 20g/l, refer to a specialist (Hb should rise by 10g/l every 7-10 days)
      • Transfusion is only really used in patients with CVS risk as a result of anaemia.
• Patients with malabsorption or chronic gut disease may require parenteral iron replacement with iron sucrose (dose based on weight and iron deficiency)

Mesangiocapillary Glomerulonephritis

Background and Epidemiology, and Aetiology

• Also known as membranoproliferative glomerulonephritis
• Mainly occurs in children >5/young people
• Characterised by a diffuse thickening and lobular appearance of the glomerular basement associated with increased cellularity
• Can be primary (idiopathic) or secondary (more common)
  • Idiopathic can be classed as
    • Type I- subendothelial deposits of IgG/IgM and C3 (most common)
    • Type II- dense deposits of C3 in a linear fashion along the basement membrane
    • Type III- subendothelial and subepithelial deposits (usually as a result of scarring after HUS or TTP)
• Secondary disease is usually due to
  • Autoimmune diseases e.g. SLE, Rheumatoid arthritis, Coeliac disease
  • Infections, particularly Hep B and Hep C

Pathophysiology

• Primarily due to complement activation (resulting in decreased circulating complement)
  • Type I/Secondary MCGN is via the classical pathway and type II is via the alternative pathway
  • Type II- also many patients have autoantibodies against Nephritic factor which regulates complement and may lead to its excessive activation

Presentation

• May be asymptomatic with proteinuria/haematuria on urinalysis
• Proteinuria may be sufficient to cause a nephrotic syndrome
• In some cases, patients may present with an acute nephritic syndrome (more common in children)
  • Haematuria (microscopic or gross)
  • Proteinuria
  • Hypertension
  • +/- Uraemia and oliguria
• Other symptoms can include fat atrophy (strong association with partial lipodystrophy) which most commonly affects the upper limbs, trunk and face
  • Occasionally visual problems can occur and drusen/neovascularisation may be seen on fundoscopy
  • Both of these are associated with Type II disease (dense deposit disease- complement deficiency)

Investigations

• See also nephrotic syndrome
• Other tests which may be appropriate include autoantibodies (to rule out secondary causes), complement levels
• Kidney biopsy is usually the definite test

Management

• Treat any underlying causes
• If primary disease, immunosuppressive agents e.g. cyclophosphamide/MMF are usually the treatment +/- steroids
• Reduce any cardiovascular risk i.e. BP control with ACE inhibitors/ARBs

Prognosis varies between type (type II/dense deposit disease has a worse prognosis in general).  Around 50% will develop end-stage kidney disease in 10 years.

Membranous Nephropathy/Glomerulonephritis

Background/Epidemiology

• Most common cause of nephrotic syndrome in adults (20-30%)
• It can be primary (idiopathic) or secondary (usually due to other disease processes e.g. in SLE
• It is often quoted that
  • 1/3 will go into remission
  • 1/3 will remain nephrotic
  • 1/3 will go onto develop chronic kidney disease

Aetiology

• Associated diseases/conditions include: SLE; Rheumatoid arthritis; drugs (gold- rarely used now; penicillamine; captopril); malignancy (commonly bronchus, colon, stomach, prostate, breast); Hep B; thyroid disease/diabetes mellitus (other autoimmune causes)
• Cause unknown in idiopathic disease

Pathophysiology

• Thought to be caused by an autoimmune reaction (type III- immunoglobulin deposition)
  • Antibodies involved are thought to be ‘M-type phospholipse A2 receptor’ (that is, in idiopathic disease)
  • Disease is characterised by diffuse thickening of the glomerular basement membrane with subepithelial ‘spikes’ on histology.  On fluoroscopy, this can be shown to be due to IgG and complement deposition

Presentation

• Nephrotic syndrome (75%)
  • Some patients will have proteinuria only; haematuria is rare; around 1/3 of patients will be hypertensive at Dx.

Investigations

• See nephrotic syndrome- definitive diagnosis is with a renal biopsy

Management

• Depends on symptoms/risk of progression to CKD
• At presentation
  • If there is normal renal function (eGFR, creatinine etc) and <4g/day of proteinuria
    • Treat with ACE inhibitor +/- ARB to maintain BP <125/75mmHg and monitor the patient regularly
  • If proteinuria is (or increases to) 4-8g/day for more than 12 months
    • Cyclosporin +/- low dose steroid for at least 6 months (consider longer depending on response
• Other treatments include cyclophosphamide and corticosteroids, rituximab and MMF.

Chronic Obstructive Pulmonary Disease

Background and Epidemiology

• COPD is a preventable, treatable but not curable disease characterised by persisten airflow limitation that is usually progressive.  It is a combination of airway disease (obstructive bronchiolitis) and parenchymal disease (emphysema) and is mainly due to an inflammatory response of the lungs, usually to noxious chemicals/particles.
• It is estimated that about 3-5% of the population have COPD.  Around 1 in 8 emergency hospital admissions are due to COPD.  It also contributes towards 5% of all deaths globally.
• More common in men and with age

Aetiology/Risk factors

• Tobacco smoking (up to 95% of cases can be due to smoking in the UK)
• Other risk factors include indoor air pollution, occupational exposure to harmful chemicals e.g. coal dust; poor lung development (can, again, be due to smoking but can also be due to repeated chest infections
• Lower socioeconomic status

Pathophysiology

•  Chronic inflammation of the lungs is usually a result of inhalation of toxic chemicals (usually as a result of smoking)
  • In patients who get COPD, there is a heightened immune response to these toxins
  • Neutrophils, macrophages and T lymphocytes (CD8>CD4) are recruited to the lungs.  The result is a release of a number of inflammatory mediators e.g. leukotriene B4, IL8, TNF and IL1β and IL6, which cause inflammation and tissue fibrosis and destruction
• There is also often an imbalance of protease activity and production of free oxygen radicals (and oxidative damage)
• This results in
  • Mucous hypersecretion and ciliary dysfunction (squamous metaplasia, increased goblet cell number and activity)
  • Airflow obstruction and hyperinflation/air trapping
    • Airflow obstruction mainly occurs in the small airways (<2mm) and is due to inflammation and airway remodelling/narrowing (other contributing factors include loss of lung’s elastic recoil due to destruction of the alveolar walls and alveolar support/attachments)
    • Because expiration is a passive process, the small airways can close and trap in inspired air, causing hyperinflation at rest and dynamic hyperinflation during exertion, limiting lung function on exertion and causing breathlessness.
  • These structural changes can also cause gas exchange abnormalities – due to abnormal ventilation-perfusion ratio – usually resulting in arterial hypoxaemia +/- hypercapnia
• In severe disease, pulmonary hypertension and right ventricular failure (cor pulmonale) can develop and severely impair gas exchange

Presentation

• Suspect in patients >35 who presents who has risk factors (namely smoking) and who present with
  • Exertional breathlessness
    • Important to try and grade the severity e.g. how much can you do?
  • Chronic cough
  • Regular sputum production
  • Frequent episodes of bronchitis/chronic bronchitis
  • Wheezing
• Signs on examination may include
  • Weight loss (cachexia may be present late on in the disease)
  • Cyanosis (‘blue bloaters’ – or ‘pink puffer’)
  • Raised JVP
  • Hyperinflated chest (+/- reduced cricosternal distance), pursed lip breathing, use of accessory muscles
  • Wheeze/quiet breath sounds.  There may also be some crackles (either infection or bronchiectasis)
  • Also ask about waking at night, ankle swelling and fatigue; chest pain and haemoptysis

Investigations

• CXR (exclude alternative/concomitant diagnosis) +/- high-resolution chest CT (used increasingly more to identify any emphysema)
• FBC (exclude any anaemia/polycythaemia) +/- ABGs (hypoxia)
• Measure BMI
• Spirometry (Diagnostic)- Perform post-bronchodilator tests (reversibility is not a feature of COPD)
  • FEV1/FVC <0.7 must be present for diagnosis
  • Severity can be graded by FEV1 predictions (vs patient)
    • ≥80% + presence of symptoms is mild
    • 50-79%- Moderate
    • 30-49% – Severe
    • <30% (or FEV1 <50% but with respiratory failure)- Very severe
  • Other lung function tests, e.g. lung volumes, gas exchange (gas transfer factor for CO) can also be performed to assess hyperinflation and emphysema (respectively)
• Other tests may be appropriate e.g.
  • In particularly young patients with minimal smoking history + family history, genetic testing for Alpha-1-antitrypsin deficiency
  • ECG/Echo to assess cardiac function
  • Pulse oximetry to assess degree of desaturation
    • If <92%, consider oxygen therapy
  • Sputum culture

Management

• Smoking cessation – Recommend smoking cessation to all patients who smoke.  Do this and offer help/support at every opportunity.
• Inhaled therapy
  • Short-acting β-2 agonists (e.g. salbutamol) (or a short-acting muscarinic antagonist e.g. ipratropium, although SABA is often preferred as this can be continued at other stages of treatment) should be offered for initial treatment for PRN relief of breathlessness.
  • If there are continuing exacerbations or persistent breathlessness (using SAMA/SABA >4x/day)-
    • If the FEV1 ≥ 50%
      • Add a long acting β2-agonist e.g. salmeterol, or a long-acting muscarinic antagonist e.g. tiotropium
    • If the FEV1 <50%
      • Add a LABA + inhaled corticosteroid (combination inhaler) or a LABA + LAMA or (if BAs are not appropriate) LAMA only
  • If symptoms are still problematic
    • Consider LABA + ICS + LAMA
• Oral therapy
  • Not routinely recommended
  • Theophyllines can be trialled (after short- and long-acting inhaled therapy or in those in whom inhaled therapy is not possible)
  • Mucolytics e.g. carbocysteine can be used for patients with chronic productive cough but should not be used to prevent exacerbations
  • Corticosteroids are not routinely recommended, but can be used low-dose and ideally short-term following an acute exacerbation
• Oxygen therapy (Long-term)
  • Consider in people with
    • Very severe COPD (FEV1 <30% predicted)
    • Cyanosis
    • Polycythaemia
    • Peripheral Oedema
    • Raised JVP (Pulmonary hypertension)
    • Saturating at <92% on air
  • Assess the need by measuring ABGs for hypoxia on two occasions at least 3 weeks apart in patients receiving optimum treatment
    • If pO2<7.3 kPa when stable, offer oxygen therapy
    • If 7.3kPa < pO2 < 8 kPa when stable and one of
      • secondary polycythaemia, nocturnal hypoxaemia, peripheral oedema or pulmonary hypertension
      • .. offer therapy
  • Patients should be breathing using the oxygen for ideally a minimum of 15 hours/day.
  • AVOID if possible in patients who smoke.

Management of an Acute Exacerbation of COPD

• Treat acutely unwell patients with ABCDE approach
  • NB If there is a clinical diagnosis of COPD- aim for oxygen saturations of 88-92%
    • NOTE: This, however, IS NOT and indication to withhold high-flow oxygen if the patient needs this.  If a diagnosis is not known- aim for 98-100%.
  • ABGs should be taken early (if type II resp failure- continue to maintain sats at 88-92%)
• Manage breathlessness with
  • Nebulised salbutamol (2.5mg)
  • Prednisolone 50mg oral for up to 7 days (or IV Hydrocortisone 100mg TDS)
  • If severely ill (and/or PaCO2 >8kPa and/or pH <7.35)- consider also starting IV aminophyllin infusion 5mg/kg in 100ml normal saline over 20 mins then 500 micrograms/kg/hr
  • Consider BiPAP and escalation of care if not improving
• Manage exacerbation with antibiotics if there are signs of infection (increased purulent sputum, fever, dyspnoea)
  • Amoxicillin 500mg TDS (5 days) or doxycycline 200mg loading dose then 100mg OD (5 days) if penicillin allergic
    • NB If CXR shows new infiltrates/consolidation- treat as per pneumonia

Diabetic Ketoacidosis (DKA)

Background/Epidemiology

• Medical emergency- has a 2% mortality in the UK
• Complication associated with Type 1 Diabetes– occurs in 1-5% of patients with T1DM (20% in undiagnosed patients)
• Triad of hyperglycaemia, acidosis and ketosis.

Precipitating Factors (Aetiology)

• Poor compliance with insulin treatment
• Bacterial infection and concurrent illness (not uncommonly, Klebsiella pneumonia)
• Medical, surgical or emotional stress
  • e.g. hypothyroidism, cardiovascular disease, stroke, MI
  • e.g. pregnancy, trauma
  • drugs e.g. steroids, sympathomimetics, α- and β-blockers

Pathophysiology

• The main biochemical features are
  • Hyperketonaemia (≥3mmol/l) and ketonuria (more than 2+ on dipstick)
  • Hyperglycaemia (blood glucose ≥11mmol/l)
  • Metabolic Acidosis (venous bicarbonate <15mmol/l and/or venous pH <7.3)
• Hyperglycaemia causes osmotic diuresis, leading to dehydration and electrolyte loss (particularly sodium and potassium)
  • Potassium loss is exacerbated by secondary hyperaldosteronism due to decreased kidney perfusion, as well as the acidosis caused by ketones, which drives H+ into the cells and K+ out
    • NB (Almost) ALL patients with DKA will be low in potassium but blood levels can be false normal due to K+ displacement by H+ and due to concomitant water loss**
• Ketosis results from insulin deficiency, exacerbated by increased catecholamines and other stress hormones, leading to massive lipolysis and supply of FFAs for ketogenesis.
  • If and when this exceeds the capacity of the liver to metabolise the ketones, they begin to accumulate in the blood, resulting in acidosis
• Water and electrolyte loss can be severe in DKA (intracellular loss initially asymptomatic -> extracellular loss becomes symptomatic later)

Presentation

• It is often useful to ask about common precipitants (e.g. fever, dyspnoea, chest pain, palpitations, abdominal pain, change in medication, alcohol consumption, change in diet etc)
• Symptoms are almost that of a severe presentation of T1DM i.e.
  • Polyuria, polydipsia (thirst), weight loss
  • Other features include weakness, nausea and vomiting (vague abdominal pain is also very common in young children), myalgia, visual disturbance (blurry vision)
• Signs
  • Common signs can be tachycardia, breathlessness, confusion
  • Signs of dehydration can be difficult to see (often more apparent in severe cases)
    • e.g. dry mucous membranes, loss of skin turgor, furred tongue, cracked lips, sunken eyes, hypotension
  • A unique sign for DKA is the sweet-smelling/fetid smelling breath
  • Reduced consciousness and coma is relatively uncommon but can occur

Investigations

• NB If DKA is clinically suspected, do not delay treatment for investigations/results.
• Blood tests
  • FBC- WBC may be raised but does not (always) indicate infection; CRP
  • U&Es- Hypernatraemia (dehydration) or hyponatraemia (glucose/ketone interference); Hyperkalaemia is common (due to acidosis but patients will be deplete of K intracellularly); urea/creatinine may be high if renal function is impaired
  • ABGs– metabolic acidosis (low pH, low HCO3; usually normal pCO2 but can be low due to respiratory compensation; pO2 also usually normal unless underlying respiratory problem)
  • If available, ketone measurements
  • Glucose
• BM blood glucose
• Urinalysis (glycosuria and ketonuria) and microscopy and culture
• CXR and ECG are also routinely performed in the acute setting

Diagnosis

• Capillary (BM) Blood Glucose >11mmol/l
• Capillary ketones >3mmol/l or Urinary ketones ++ or more
• Venous pH <7.3 and/or Bicarbonate <15mmol/l

Management

• EMERGENCY- treat in hospital/HDU.  NB If diagnosis unknown/acute setting, manage with ABCDE

1. Immediate Management (0-60 mins)
   1. Commence IV 0.9% saline
      1. If SBP<90mmHg
         1. Give 500ml over 10-15 mins.  If SBP remains <90mmHg, repeat and seek senior advice.
         2. Consider involving ITU/Critical care (depending on patient symptoms e.g. change in consciousness)
         3. If SBP increases to >90mmHg, give 1000ml 0.9% saline over next 60 mins.
            1. NB Patient can become rapidly hypokalaemic with fluid replacement and may require supplementation
               • If >5.5mmol/l – none; if 3.5-5.5mmol/l – give 40mmol/l; if <3.5mmol/l – get senior review, more potassium required
   2. Commence IV insulin infusion (0.1 unit/kg/hour; 50 units in 50ml of 0.9% saline)
      1. NB If the patient is also on a long-acting insulin, continue this as normal
   3. Assess patient
      1. Resp rate, temperature, BP, Pulse, saturation
      2. GCS
      3. Full head-toe examination
      4. Investigations e.g. capillary and laboratory glucose, Venous/Arterial BGs; U&Es, FBC; Blood cultures; ECG; CXR; MSSU
   4. Monitor
      1. Hourly BM and capillary blood ketones; measure venous bicarbonate and potassium at 60 and 120 minutes then every 2 hours
      2. Measure electrolytes every 4 hours
      3. Consider any other causes and manage appropriately
   5. NB A central line may be appropriate in young/old people, pregnant women, Heart/kidney problems, serious comorbidity, severe DKA 
      1. e.g. Ketones >6 mmol/l; Venous bicarb <5mmol/l; venous pH <7.1; hypokalaemia on admission, GCS<12, O2 sats <90%; BP<90mmHg, pulse >100 or <60
      2. Anion gap
2. Management at 1-6 hours (Resolution/Maintenance)
   1. Monitor the patients (hourly blood glucose and ketones, venous BGs and potassium if it’s abnormal
   2. Continue fluid replacement
      1. 1l 0.9% saline with KCl over 2 hours (×2)
      2. 1l 0.9% saline with KCl over 4 hours
         1. Add 10% glucose 125ml/hour if blood glucose falls <14mmol/l
   3. Aim
      1. Capillary ketones not dropping by >0.5mmol/l/hour
      2. Venous bicarbonate not rising by >3mmol/l/hour
      3. Plasma glucose not fallinf by >3mmol/l
      4. Continuous IVII until ketones <0.3mmol/l, venous pH >7.3 and/or venous bicarb >18mmol/l
3. Management at 6-12 hours (if the patient is not improved)
   1. Continue IV fluids at a reduced rate
      1. 1l 0.9% saline with KCl over 4 hours then repeat over 6 hours
         1. Add 10% glucose 125/ml/hour if glucose is <14mmol/l
   2. Re-assess biochemistry at 6 hours e.g. Venous pH, bicarb, potassium, ketones, glucose. Assess CVS risk at 12 hours and check for fluid overload.
      1. Resolution: Ketones <0.3mmol/l ; venous pH >7.3 (bicarb not used)
      2. If not resolved, review IVII and fluids
4. Recovery
   1. Make sure the patient is eating and drinking
   2. Treat any precipitating factors e.g. infection
   3. Re-assess for complications e.g. fluid overload
   4. Switch to subcut insulin if the patient is recovering ok.
      1. (If not, specialist input is required).
      2. NB Do not stop IVII until 30 mins after first subcut short acting insulin injection

Type 2 Diabetes Mellitus

Background and Epidemiology

• Similarly, characterised by persistently high circulating blood glucose but instead due to resistance to the activity of insulin.
• Most common form of diabetes (90%)
• Prevalence increases with age (1/20 people >65 and 1/5 people >85)
• Estimated incidence of around 1.7 in 1000 people / year
• Diagnosis of exclusion (should rule out T1DM, and other types of DM prior to diagnosis)

Aetiology/Pathogenesis

• Age
• Weight/Obesity (central obesity > peripheral) and lack of physical activity
• Family History
• Hypertension and hypercholesterolaemia
• PCOS
• Insulin resistance is the underlying pathogenic process, although the exact mechanisms of this are not fully understood.
  • In early/pre-diabetic disease, the pancreas may compensate by producing more insulin
  • If the problem persists, the pancreas eventually can no longer keep up with blood sugar and may begin to become damaged (glycotoxicity)
  • This process is generally slower than that seen in T1DM

Presentation

• Because relatively small amounts of insulin are required to suppress lipolysis, this does not tend to occur in T2DM (cf T1DM) (neither does proteolysis). => NO weight loss/ketoacidosis
• Many patients are asymptomatic because the degree of hyperglycaemia is usually mild.  Non-specific symptoms e.g. fatigue and malaise are most common
  • Diagnosis is commonly incidental after blood tests (e.g. abnormal LFTs suggestive of NAFLD/check for diabetes)
• Patients with T2DM are typically obese/overweight (often central), will often have other cardiovascular risk factors e.g. Hypertension

Investigations

• See investigations for T1DM
• Check cholesterol levels

Management

1. Dietary and lifestyle advice
2. Metformin
   1. Or sulfonylurea if the patient is not overweight or if particularly high glucose levels
3. If HbA1c remains >48mmol/mol (6.5%); try metformin + sulfonylurea
   1. If hypoglycaemia is a problem on sulfonylurea, consider thiozolidinedione
   2. A rapid acting secretagogue (meglitinides e.g. repaglinide) may be considered for people with non-routine daily lifestyle (rare)
4. If HbA1c persists and rises to ≥59mmol/mol (7.5%), add thiozolidinedione or insulin
   1. Exenatide may be considered when body weight is a problem or if insulin is not an option
5. If HbA1c remains above 59mmol/mol (7.5%), insulin + metformin +sulfonylurea

Diabetic Medications

• Metformin
  • Indication- first line oral antihyperglycaemic in patient with T2DM who are overweight
  • Mechanism: Decrease Hepatic glucose output and increase peripheral glucose uptake by enhancing insulin action via AMPK pathways
    • Usually decreases blood glucose (HbA1c by 11-15mmol/l or 1-1.5%) by 1.6-2mmol/l (BM)
  • Contraindications: severe renal failure (totally metabolised/excreted by kidney)
    • NB Cimetidine increases the action of metformin by up to 50%
  • Advantages
    • Effective; no hypoglycaemia risk; possible weight loss (no gain); possible CVS benefit; can be used well in conjunction with insulin; low cost
  • Disadvantage
    • Common side effects (GI- dose related; can also cause B12 anaemia); should not be used in patients with a risk of lactic acidosis (i.e. severe major organ dysfunction; alcoholism)
• Sulfonylureas (e.g. Gliclazide)
  • Indication: Second line oral antihyperglycaemic (first line if normal/underweight patients)
  • Mechanism: Increase insulin secretion (both basal and prandial)- effect on blood sugar is similar to metformin
    • NB due to effect on insulin- there is a risk of hypoglycaemia
    • Metabolised by the liver (CYP450 system– be weary of enzyme inhibitors/inducers)
      • e.g. Clarithromycin (increase activity); Fluconazole (increase activity); Rifampicin (decrease activity)
  • Advantages
    • Effective; well tolerated; ok in renal insufficiency; once only dosing; low cost
  • Disadvantages
    • Hypoglycaemia risk; weight gain; efficacy can decline with time (insulin resistance increases)
• Thiazolidinediones
  • Indication: Mainly used as a substitute for sulfonylureas in patients at risk of hypoglycaemia or are intolerant of sulfonylureas (NB DPP-4 inhibitors and GLP analogues are becoming more widely used as 3rd line agents over TZDs)
  • Mechanism: Increase peripheral glucose uptake by enhancing insulin action and decreases hepatic glucose output via action of PPAR-γ receptors
    • Again, similar effect on blood glucose
    • Also metabolised by CYP450
  • AVOID IN HEART FAILURE
  • Advantages:
    • Effective; more durable glycaemic control than sulfonylureas; no hypoglycaemia risk; generally well tolerated and once daily dosing possible
  • Disadvantages:
    • Slow onset of maximal effect (8-12 weeks); Weight gain; Risk of fracture, MI and bladder cancer; Should not be used in:
      • Fluid retention/oedema
      • Risk of worsening heart failure (contraindication)
• DPP-4 Inhibitor (Gliptin)
  • Indication: May be preferable to a TZD if body weight is a problem or there are contraindications/intolerability of TZDs
  • Mechanism: Inhibits the action of DPP-4 receptors which are important in controlling gastric enzymes including GLP-1.  Actions include increasing insulin activity and secretion (prominently prandial secretion) and decrease glucagon secretion.
    • Occur only with raised blood sugar i.e. effect is minimal/none in a normal individual
    • Has a milder effect on blood glucose than other drugs above (half the reduction)
  • Advantages:
    • No hypoglycaemia; weight neutral; well tolerated; once daily (anytime) dosing
  • Disadvantages:
    • Not as efficient; Avoid in patients with features of damaged pancreas (pancreatitis, alcoholism, high triglycerides etc); expensive
• GLP-1 Agonists (exenatide)
  • Indication: generally used third line as an add-on therapy to MET+SUL when there is persistently high blood glucose
  • Mechanism: GLP1 is a gastric hormone responsible, in part, for regulating blood glucose and insulin action- same actions as DPP4 inhibitors
    • More effective, however, than DPP-4 inhibitors (similar to metformin)
    • Contraindicated in renal failure (uncertain of effect)
  • Advantages
    • Efficacy; No hypoglycaemia; Dose-related weight loss
  • Disadvantages
    • Long term effects uncertain (?thyroid cancer); avoid in pancreatitis like pictures; must be injected; Expensive

Type 1 Diabetes Mellitus

Background/Epidemiology

• Systemic disorder characterised by a lack of insulin due to destruction of β-islet cells
• It accounts for around 15% of all cases of diabetes mellitus and around 90% of DM in children/young adults

Aetiology/Pathogenesis

• Genetic factors account for up to a third of type 1 DM (polygenic).
  • In particular HLA-DR3 and DR4, HLA-DQA1 and DQB1
  • Family history, however, is relatively rare
• T-cell mediated autoimmune destruction of the insulin-secreting β-islet cells of the pancreas.
• Causes a progressive loss of β-cell function over months-years
  • Inflammatory process (insulitis)- involving activated macrophages, helper cytotoxic and suppressor T lymphocytes, natural killer cells and B lymphocytes.
  • Initial (and even later) stage disease is patchy, with inflammation of specific areas surrounded by otherwise normal tissue.  Symptoms only manifest once 80-90% of the β-islet cells are destroyed, once inflammation has spread throughout the pancreas.
  • ONLY β-cells are affected (α/γ cells remain unaffected)
• Because the final stages of the pathogenesis (i.e. global destruction of the islet cells due to both autoimmune destruction and glucose toxicity) is quite rapid, features of the disease tend to appear subacutely-acutely with features of hypoinsulinaemia (see below)

Presentation

• Hyperglycaemia leads to
  • Glycosuria and dehydration
    • Fatigue, polyuria, nocturia, thirst, polydipsia, susceptibility to UTIs
  • Lipolysis and proteolysis
    • Weight loss
  • Persistently very high blood glucose levels may also present with diabetic ketoacidosis (may be an emergency presentation or not)
• Symptoms usually develop over several weeks

Investigations

• Urine testing
  • Often used to screen patients in whom there is a clinical suspicion
    • Dipstick urinalysis for glucose and ketones
      • Note that there are other causes of glycosuria (e.g. pregnancy, drugs (antibiotics))
      • Ketonuria, particularly in children and in association with glycosuria, warrants an urgent referral to the diabetic clinic for quick diagnosis and management/long-term treatment
    • Proteinuria may indicate development of diabetic nephropathy
• Blood
  • Glucose
    • Diabetes may be diagnosed with a blood glucose level of ≥11.1mmol/l (random or 2hrs after a 75g glucose load) or a fasting glucose of ≥7mmol/l if the patient is symptomatic
      • If the patient is asymptomatic, two tests on separate occasions are required
    • NB Pre-diabetes is defined as
      • Impaired fasting glucose i.e. fasting glucose ≥6mmol/l (<7mmol/l) (without raised glucose post-75mg load)
      • Impaired glucose tolerance i.e. fasting glucose <7mmol/l and 2hr glucose after 75mg load is 7.8-11.1mmol/l
  • Ketones (β-OHB)
    • <0.6mmol/l- normal- no action required
    • 0.6-1.5mmol/l- suggests metabolic control may be deteriorating- continue to monitor and seek medical advice if sustained/progressive
    • 1.5-3mmol/l- With high blood glucose (>10mmol/l), there is a significant risk of DKA- seek medical advice
    • >3mmol/l- Severe ketosis; with raised blood glucose, high risk of DKA- seek urgent medical help
  • Glycated haemoglobin (measures glycaemic control averaged over weeks/months- roughly a rise of 1% = 2mmol/l of blood glucose)
    • An HbA1c of >48mmol/mol (or 6.5%) is suggestive of diabetes
    • Target HbA1c is usually <53mmol/mol (<7%)
    • NB HbA1c may not be accurate in patients with haemoglobinopathies; haemolytic anaemia; iron deficient anaemia; children; HIV; chronic kidney disease
  • Autoantibodies are not routinely measured

Management

• Insulin treatment is required for all patients with T1DM to prevent DKA and the associated mortality
• There are several types of insulins
  • Rapid-acting insulin analogues e.g. Insulin aspart, lispro and glulisine (onset of action ~15mins, peak at 1 hour and last 3-4 hours)- commonly used around meals to buffer the increase in glucose
  • Soluble (short-acting) insulin (onset 30 mins; peak at 2-3 hours and last ~8 hours)- ideally should be injected 30 mins before meals
  • Intermediate-acting (isophane) insulin (onset 2-4 hours, peak at 6-7 hours and lasts 20 hours)- used most commonly in twice daily regimens.  Can come ready mixed with shorter acting insulins.
  • Long-acting insulin analogues e.g. glargine/detemir (onset 1-3 hours, then plateau and last for 20-24 hours)- used once or twice daily to achieve steady state constant insulin (resembles physiological state)
• There are different regimes of insulin treatment.  The two most commonly used in T1DM are
  • Twice daily regime (two administrations of a mix of intermediate and short acting insulins at a ratio of 2:1- 2/3rds of the total dose given in the morning and the remainder before the evening meal)
  • Basal-bolus regime (single dose of long-acting insulin accompanied by boluses of rapid acting insulins at meal times)
    • Suitable for well-motivated individuals with a good understanding of the disease and need for insulin.
• Where appropriate, patients may be given BM kits for measuring blood sugar
  • Aim for pre-prandial BM of 4-7mmol/l and post-prandial BM of <9mmol/l

See also Complications of Diabetes

Coeliac Disease

Autoimmune disorder resulting from a heightened immune response to gluten-derived proteins.

Background and Epidemiology

• Immune-mediated, inflammatory disorder caused by gluten.  Gluten may be found in wheat, rye and barley products
• Prevalence of ~0.8-1.9%.  Thought that up to 85% of patients with coeliac disease are undiagnosed.
• Slightly more common in females (2:1)

Aetiology

• Polygenic factors
  • Most commonly associated with HLA-DQ2 and DQ8 (whilst these tend to be sensitive, they are not specific i.e. much of the general population also have these alleles)
  • Family hereditability (10-15% if a 1st degree relative; 70% in identical twins)

Pathophysiology

• Gliadin (a product of gluten) is thought to be de-aminated by tissue transglutaminases in the gut cell.  This is thought to increase its antigenicity.
  • Negatively charged gliadin is thought to activate the immune system directly (IL-15 -> NK cell and lymphocyte proliferation and recruitment)

Clinical Presentation

• Can present at any age (including old age).  Many patients can be largely asymptomatic
  • Can present shortly after weaning in babies
    • Diarrhoes (frequent, pale stools) or occasionally constipation; vomiting; weight loss/anorexia, irritability and failure to thrive
    • Children may present with a growth problem
  • In older children/adults
    • Anaemia (due to folate/iron deficiency)
    • Abdominal discomfort, arthralgia, fatigue and malaise
    • Diarrhoea, steatorrhoea
    • Mouth ulcers and angular stomatitis (mainly due to anaemia and vitamin deficiencies)
    • Occasionally, dermatitis herpetiformis
• Patients may have an associated autoimmune disease e.g.
  • T1DM
  • Thyroid disease
  • Primary Biliary Cirrhosis
  • Sjogrens Syndrome
  • IgA deficiency

Investigations

• Blood tests
  • FBC
    • Anaemia is common (microcytic- iron-deficient)
  • U&Es
    • Hypokalaemia, hypocalcaemia, hypomagnesaemia and metabolic acidosis may be present, as can signs of malnutrition e.g. hypoalbuminaemia
  • Before testing specifically for Coeliac, confirm the patient has been eating gluten-containing foods (at least twice a day for past 6 weeks)
    • Initial blood tests include
      • IgA tissue transglutaminase antibody (tTGA; first line according to NICE) or IgA endomysial antibody (EMA)
      • It can be useful to measure serum IgA also to rule out any false negatives (if IgA is low, test for specific IgGs)
• Most patients will also have endoscopic tissue biopsy to confirm coeliac by immunofluorescence
  • Villous atrophy and lymphocytic infiltrate can also be seen under microscopy
  • NB Prior to tissue biopsy, gluten should be reintroduced into the diet for a minimum of 6 weeks to increase the chance of true positive (decrease false negative)

Management

• Gluten free diet is the mainstay of management.  (Often referral to a dietician or self-help information/resources is extremely useful)
• Management of associated sequalae may be useful e.g. vitamin/iron replacement
• Follow up should involve measuring coeliac serology (as well as other bloods)

Prognosis/Complications

• Patients are at higher risk of T-cell lymphoma, small bowel carcinoma and other GI cancers
• Patients with poor disease control are also at higher risk of osteoporosis and should be managed where appropriate to prevent its development