Rosacea is a common facial rash, of unknown aetiology. It is typically chronic and persistent.

It causes sterile inflammatory papules, pustule and nodes and it may sometimes be mistaken for acne, however it does not cause comedones.

There is an association between rosacea and a mite called demodex folliculorum. This mite usually lives on the skin of healthy individuals in hair follicles, and is not considered pathogenic. However it is found sin higher concentrations on the face of those with rosacea. It is not know if higher concentrations cause rosacea, or if the conditions created by rosacea lead to higher concentrations of the mite.

Epidemiology and Aetiology

• Typically affects patients aged 30-50
• Mainly females
• “Celtic” ethnic origin (Irish / Scottish)
  • Fair skin
  • Blue eyes

Presentation

• Red rash, often with inflammatory papules
  • May often begin as a increasing tendency for fascial flushing, before progressing to papules, pustules and nodules
• Patients often reports that their face feels hot or burns
• Typically rash on the cheeks, forehead, nose and chin
• Worse when flushed or blushing
• Usually peri-orbital and peri-oral areas are spared
• May also be associated with increased skin sensitivity, and stinging sensations
• May be accompanied by:
  • Telangectasia
  • Facial oedema
  • Seborrheic dermatitis
  • Sensitive skin – burning sensation to creams and other agents applied to face

Complications

• Blepharitis
• Conjunctivitis
  • About 50% of patients with suffer from belpharoconjunctivitis which typically causes dry and itchy eyes
  • Rarely – corneal ulceration
• Rhinohpyma
  • Development of a large, bulbous nose

Differential diagnosis

• Acne
• Seborrheic dermatitis
• SLE
• Periorifical dermatitis

Management

• Stringent sun protection
• Use gentle soap-free cleanser (e.g. emollient)
• Avoid oil based creams – use water-based make-up and sunscreen
• Avoidance of factors that cause facial flushing:
  • Heat, wind, sudden changes in environmental temperature
  • Alcohol
  • Excessive exercise
  • Hot baths
  • Spicy food
  • Hot drinks
• Cool packs
• Medication
  • Topical metronidazole cream 0.75% OD or BD
    • Use for 6-12 weeks
    • Long term maintenance therapy is often required
  • Oral Antibiotics – used when topical agents have not been successful – e.g. Doxycycline 100mg OD or erythromycin 250-500mg BD for 4-8 weeks
  • In women of menopausal age – consider menopausal related flushing as the cause which may respond to HRT
• Laser treatment for telangectasia
• Surgical correction of rhinophyma
• Avoid topical steroids

Flashcard

References

• Rosacea – Dermnet NZ
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy

Read more about our sources

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Lichen planus (LP) is a chronic, inflammatory, puritic skin disorder, typically found on the limbs (especially flexor surfaces), mucous membranes (often in the mouth) and genitals – including inside the vagina.

Some divide lichen planus into various types – most commonly discerned by their location.

The cause is not well understood, but it likely a T-cell mediated autoimmune disorder.

Epidemiology

• It typically affects adults over the age of 40
• 1-4% worldwide prevalence
• 50% of patients have oral lichen planus
• 10% have lichen planus affecting the nails
• More common in women M:F 1:1.5

Aetiology

• Genetic predisposition
• Physical and psychological stress
• Skin trauma – often occurs after surgery, or at sites of herpes zoster infection
• Systemic viral infection – e.g. hepatitis B or C – can also trigger LP
• Contact dermatitis may precipitate LP

Pathology

• T-cell mediated autoimmune disorder
• T-cells attack an as-yet unidentified protein in the skin and nails

Presentation

• Typically an acute presentation
  • Often affects flexor surfaces on first presentation – the front of the elbows, inside of wrists and back of the knees
  • Itchy
  • Not typically painful, but can be
  • May also affect genitals
  • Mucuous membranes also common affected – inside of mouth, and to a lesser extent, vagina. Rarely – in the larynx or oesophagus
• Distinct, often round, purpuric, raised lesions
• Occasionally lesions blister
• As the initial lesions heal, they often leave small flat brown discoloured circles
• On mucous surfaces:
  • White, slightly raised lesions
  • Can appear like small ulcers, or like white streaks
  • Typically on tongue or inside of cheeks
  • Can be asymptomatic, but in some patients are very painful
  • Difficult to treat
• Nails
  • Affected in about 10% of patients
  • Longitudinal lines
  • Severe cases may involve destruction of the nail bed

• Scalp
  • Usually spared
  • If it is affected, can cause severe scarring and alopecia
    

Some subtypes of LP include:

• Hypertrophic LP – thick, raised lesions, typically leave hyper pigmentation as they resolve. Often very itchy

• Erosive / ulcerative – often on mucosal surfaces. Often painful

Diagnosis

Diagnosis is usually clinical, but biopsy may be taken if there is uncertainty.

Histology of a skin biopsy has several characteristic features:

• Saw-tooth pattern of epidermal hyperplasia
• T-cell infiltration of dermis
• Reduced melanocytes
• Direct immunofluorescence shows globular deposits of Ig (usually IgM, sometimes IgG and IgA)

Differential diagnosis

• Drug reaction – Lichenoid drug eruption. Commonly implicated drugs include:
  • Gold
  • Hydroxychloroquine
  • Captopril
  • Quinine
  • Thiazide diuretics
• Eczema – especially when distributed on flexor surfaces
• Psoriasis
• Candidiasis – when affecting the mouth or vagina
• Lichen sclerosis – when affecting the external genitals
• Pemphigus
• Sarcoidosis
• Basal cell carcinoma – when single lesions

Management

• Many cases resolve spontaneously within a year
  • Itch tends to slowly decline with time, even if LP does not resolve
  • Mucous membrane disease tends to be more resistant to treatment
• Topical steroids
  • Mainstay of treatment for particularly itchy or persistent lesions
  • Moderately potent steroids are typically used first
  • Stronger potency may be required – especially for lesions on the shins
  • Are also considered first line for mucous membrane lichen planus
• Other treatments
  • Typically reserved for specialist use in particularly troublesome cases
  • Azathioprine, mycophenolate, retinoids and hydroxychloroquine may be used

Any scarring that occurs is permanent – including on the scalp – where it causes permanent baldness. This is usually rare.

Complications

• Hyperpgimentation from previous lesions – especially hypertrophic lesions
• 1% lifetime risk of oral squamous cell carcinoma. Higher risk if:
  • Smoker
  • Alcohol dependency
  • Hepatitis C infection
• Rarely, carcinoma of the vulva is associated with LP

Flashcard

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy
• Lichen planus – dermnetnz
• Lichen Planus – patient.info

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Lichen sclerosus (LS) is a relatively common chronic, autoimmune skin disorder involving the anogenital region, particularly in women.

• In men, it was previously referred to balanitis xerotica obliterans (BXO), but this term should no longer be used
• It can also exist outside of the genital area

It can occur at any age, but typically affects women over the age of 50, and to a lesser extent, children of both genders pre-puberty.

It is thought to be caused by a combination of genetic and environmental factors but the exact causes are not well understood.

Treatment typically involves a avoiding skin irritants, regular use of emollients, and topical steroids. In women, topical oestrogen may also be of benefit. Rarely, immunomodulating drugs, such as methotrexate, cyclosporine or retinoids (e.g. isotretinoin) may be used.

LS is associated with an increased risk of squamous cell carcinoma (SCC) and as such, special attention needs to be paid to skin lesions to assess their likelihood of SCC, and excision if required. The scarring caused by the lesions of LS may also result in the need for surgery – typically circumcision in men, and more complex procedures in women. In some cases, the scarring and adhesions may lead to the closing of the vagina.

Aetiology and Epidemiology

• The cause is essentially unknown. Likely due to a combination of genetic and environmental factors
• Genetic factors:
  • 15% of cases have a family history
• Associated with:
  • Increased BMI
  • Coronary artery disease
  • Smoking
  • Preceding infections
  • Preceding trauma
• About 10x more common in women
  • Affects about 3% of women and about 0.05% of men
  • Particularly rare in men circumcised in infancy
• Usually aged >50
  • Probably related to post-menopausal reduction in oestrogen
• Sometimes seen in pre-pubescent children
• Associated with other autoimmune skin conditions, e.g. psoriasis, lichen planus, vitiligo
• Assocaited with other autoimmune diseases
  • 20% of patients have another autoimmune disease
  • Most commonly – thyroid disease or pernicious anaemia

Pathology

• Up to 80% of patients have extra cellular matrix protein-1 (ECM-1) antibodies
• Not clear if these are a cause or result of the condition

Presentation

• Lesions present as white papules and plaques
• Affects the non-hair bearing areas of the vulva and perneum
  • Labia minora and clitoral hood can also be affected
  • ”Figure-of-8” area around the genitals and anus
• NEVER affects the vaginal mucosa
• Symptoms
  • Itch
    • The main symptom
    • Often worse at night and disturbs sleep
  • Dysuria
  • Dyspareunia
  • Pain when passing stool due to anal fissures
• Can lead to adhesions and scarring
  • Scarring is permanent and destructive
  • Reduced size of opening of vagina – occasionally completely occluded
  • Reduced size of labia minora
  • Phimosis of clitoris (becomes buried by surrounding tissue)
• In men
  • Affects the glans of the penis
  • Glans can become white, firm and scarred
  • Painful erections and/or pain on sexual intercourse
  • Urethra strictures – which may alter urinary flow
• Extragenital manifestations
  • 10% of cases
  • >95% of extragenital cases also have genital disease
  • Small, white dry plaques – like “cigarette paper”
  • Typically on inner thigh and buttocks, but can also affect the torso and axillae

Complications

The complications of lichen sclerosis are particularly important.

Squamous cell carcinoma

• Occurs in 5% of LS patients
• More likely to occur if LS is poorly controlled
• Presents as an enlarging lump that does not resolve
• Treated either by surgical excision or cryotherapy

Diagnosis

Diagnosis is often clinical, but can be confirmed by skin biopsy if there is uncertainty.

Consider thoroughly documenting the lesions for follow-up – including with photography if the patient consents to this.

If lesions fail to respond to treatment then biopsy is essential.

Despite the association with other autoimmune diseases, there is no role for blood tests to screen for auto-antibodies or thyroid function, unless this is clinically indicated by specific symptoms of another autoimmune disorder.

Differential diagnosis

• Vitiligo
• Lichen planus
• SCC / Bowen’s disease
• Candida (thrush)

Management

Supportive measures

• Wash gently once or twice a day
• Use a non-soap cleanser (e.g. an emollient such as QV cream, cetaphil) or water only
• Avoid tight clothing
• Avoid synthetic fabrics
  • Loose fitting cotton clothing is best
• Avoidance of certain activities
  • Cycling
  • Horse riding

Topical therapies

• Emollients (for more about emollients in skin conditions – see eczema)
• Topical steroids
  • Typically an ultrapotent steroid is used – such as clobetasol propionate 0.05%
  • Potent agents – e.g. mometasone fumorate 0.1% may be used in milder cases or when symptoms are under control
  • Typically once daily at night
  • A thin smear applied to the affected areas
  • Typically required for 1-3 months daily and then dose can be reduced to once or twice weekly when symptoms are under control
  • Works well to control the itch
  • Skin appearance may improve or even return to normal, but not always
  • A 30g tube should typically last 3-6 months
  • Be aware of over-use of cream
    • Red irritated skin
    • increased risk of thrush
    • Burning pain
• Follow-up after one month to assess the effectiveness of treatment
• Extra-genital lesions typically respond well to topical steroids
• Topical oestrogen
  • May be tried
  • May be of some benefit in some patients
  • Of most benefit when there is also co-existing atrophic vulvovaginitis

Oral therapies

• Reserved for resistant cases
• Typically used under the supervision of a specialist
• Options include:
  • Oral steroids
  • Oral retinoids – e.g. isotretinoin
  • Methotrexate
  • Ciclosporin

Surgery

• Excision of SCCs or suspected SCCs
• Circumcision may relieve symptoms in men
• Surgery may be required to release adhesions and excise scar tissue in women, especially if the vaginal orifice opening is affected

Prognosis

• Chronic and incurable
• Most cases are well controlled with topical agents
  • Symptomatic remission is achieved in 98% of women
  • 75% men are cured by circumcision
  • 60% of men responde to ultra-potent steroids
• Resistant cases are often associated with lichen planus
• Extragenital lesions are less likely to be chronic and often completely resolve

Flashcard

References

• Lichen sclerosus – patient.info
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy
• Lichen sclerosus – dermentnz

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Rheumatic fever was a common infectious disease until around the middle of the 20th century, and was a major cause of childhood mortality and rheumatic (structural) heart disease.

In developed countries, the incidence rapidly declined during the second half of the 20th century, however it remains a common and important disease in developing countries and amongst indigenous populations, particularly in Australia, New Zealand, the Pacific Island nations, and to a lesser extent in South America.

• The decline in incidence is believed to be multifactorial, due to the advent of penicillin, a decline in virulence in the strains of streptococci that cause the infection, and improved living conditions

It is the result of infection with Group-A beta-haemolytic streptococcus (GpA BHS). These infections are typically pharyngitis or tonsillitis, and less commonly scarlet fever or skin infections.

Rheumatic fever typically begins several weeks after the initial infection – which has often resolved by this point. It is thought that antibodies produced to streptococcal proteins begin to react against cardiac and other tissues.

As well as acute rheumatic fever, there is also a recurrent from of the illness – with episodes of fever months or years after the initial infection (thought to be due to re-infection). About 50% of patients will go on to develop rheumatic heart disease in the long term – the risk is higher in those who have recurrent episodes of fever.

It it not only the heart that is affected, but also skin, joints and nervous system.

You should suspect a diagnosis of rheumatic fever in any patient who presents with chorea (neurological signs) or carditis, without another identifiable cause.

Diagnosis is based on the Jones Criteria.

Management aims to control the symptoms of the arthritis, skin manifestations and chorea, but it is the carditis that is the most serious manifestation of rheumatic fever. It can lead to heart failure, and in some cases, can be fatal in the acute phase.

• Acute rheumatic fever has a mortality of about 1.5% in the developed world.
• It is usually recommended that patient start on prophylactic antibiotics to prevent a recurrent infection
• No treatment has been proven to reduce the risk of progression from rheumatic fever to rheumatic heart disease

In the long-term, any patient who has had previous rheumatic fever, is at almost 50% risk of rheumatic heart disease. This typically manifests as mitral value disease, although other valves can be affected.

Epidemiology

• High incidence in areas of overcrowding and poor access to healthcare
• Higher incidence in winter
• Typically affects school age children
  • Median age 10.4
  • Rare before age 3 and after age 21
• In developed countries, incidence is <1 in 100 000
• In indigenous populations in Australia, the incidence is about 375 per 100 000
  • 60% of patients will go on to develop heart disease

Aetiology

• Poverty
• Overcrowding
• Family history / genetic factors

Pathology

The exact pathology is not well understood. It is caused by Group A beta-haemolytic streptococci, of which there are many types. Those with the M antigen are most likely to cause Rheumatic Fever.

• It is thought that the organ damage caused in the disease is actually a result of a type hypersensitivity reaction – the damage is caused by cross-reacting antibodies – and not by the bacteria itself
  • The antibodies for streptoccoal M protein also act against cardiac myosin
• Heart valves are infiltrated by T cells – which are reacting against cardiac myosin, having been activated against the M antigen
• It is believed there is also a genetic susceptibility, as there is great variation in disease in those infected with similar strains
• In acute rheumatic heart disease, the mitral valve is most commonly affected, although often all 4 valves can be affected.

Presentation

• Symptoms typically occur 1-5 weeks after an infection (e.g. after a sore throat)
  • In recurrent cases, this period is often shorter due to a quicker immune response
• Symptoms include:
  • Fever
    • Typically for about 1 week
  • Arthritis
    • The pain is often very severe, and if the lower limbs are affected, patients may be unable to walk
    • Usually asymmetrical, polyarthritis
  • Neurological signs of symptoms (30% of patients)
    • Syndenham’s chorea – rapid purposeless movements, especially of the face and upper limbs
    • Tourrette’s syndromes
    • Often cease during sleep
  • Skin signs and symptoms
    • Subcutaenous nodules (10% of patients)
    • Erythema marginatum / erythema annulare
      • Different names for the same rash
      • Rash with macule or paupules of 1-3cm on the trunk and arms
      • Face is spared

• • Cardiac signs and symptoms (40% of patients)
    • Aortic regurgitation –Austin Flint’s murmur
    • Carey Coombs’ sign refers to a characteristic soft diastolic murmur due to mitral valve invovlement
    • Pericardial rub
    • Tachycardia
    • Endocarditis and Myocarditis
    • Signs on echo include:
      • Mitral valve changes in 70% of patients
      • Aortic vale – 25%
      • Tricuspid – 10%
      • Pulmonary – rare

The Jones Criteria

Diagnosis is based on the Jones Criteria. For diagnoses, the following are required:

• Evidence of recent streptococcal infection
  • e.g. scarlet fever, or a positive throat or wound swab, or serologically confirmed streptococcal infection – e.g. with a raised anti-streptolysin O titre (ASOT) of >200U/ml
• PLUS two major criteria, OR one major and two minor criteria

Major Criteria

• Arthritis
• Sings of carditis (murmur, echo signs)
• Chorea
• Subcutaneous nodules
• Erythema marginatum / annulare

Minor Criteria

• Fever
• Raised CRP or ESR
• Arthralgia
  • Can’t be used in conjunction with arthritis as a major sign
• Prolonged PR interval
  • Cant be used in conjunction with carditis as a major sign

Even when the diagnostic criteria are not met consider rheumatic fever is any patient with chorea or carditis without an obvious cause. 

Differential Diagnosis

• Arthritis
  • Rheumatoid arthritis
  • Henoch-Schonlein purpura
  • Reactive arthritis
  • Erythema nodosum
• Cardiac causes
  • Infective endocarditis
  • Cardiomyopathy
  • Myocarditis (other causes)
• Neurological signs
  • Drug reactions – e.g. dystopias related to metoclopamide

Investigations

Throat swab

• Frequently performed – but often the acute infection is long gone by the time the diagnosis has become apparent

Blood tests

• Anti-streptolysin antibody titre (ASOT)
  • Levels >200 suggest a diagnosis of rheumatic fever
• anti-DNase B
• Antibody levels usually rise for the first month of the illness and remain stable for the following 3-6 months

ECG

• Prolonged PR interval

CXR

• Signs of heart failure

Echocardiography

• To detect signs of carditis
• Can result in earlier diagnosis – signs of carditis may be apparent on echo before the other symptoms develop

Management

Aims

• Treat any streptococcal infection that is still present
• Reduced inflammation related to the immune response
• Treat complications – especially carditis
  • Neurological, arthritic, and skin symptoms are often self-limiting. The cardiac complications can be life-threatening

Treating infection

• Penicillin is the treatment of choice against streptococcus
  • Guidelines vary. Both oral and intramuscular preparations are recommended. Intramuscular injections are slow-releasing and long-acting and prevent issues related to compliance with an oral regimen
  • Cephalosporins or erythromycin are suitable alternatives in penicillin allergy

Treating complications

• Aspirin or other NSAIDs are effective for arthritis
  • High doses are often required
  • Not proven to reduce carditis (but theoretically could)
• Cardiac complications
  • Treat heart failure as you would for any other patient – e.g. with ACE inhibitors, digoxin, and diuretics if required
  • Mitral valve replace may be required
• Neruological complications
  • Chorea is typically self-limiting. Diazepam can reduce symptoms in the short term

Prognosis

• 80% of patients will recover from an acute episode of rheumatic fever within 12 weeks
• Recurrent episode of rheumatic fever can occur – usually, but not always associated with re-infection with streptococcus
  • If these episodes do occur, it is usually within 5 years of the original diagnosis
• Rheumatic heart disease occurs in up to 45% of patients in the long-term
  • Patients need life-long cardiology follow-up
• Recurrent episodes can be triggered by repeat streptococcal infection, pregnancy, or use of the COC pill

Prophylaxis

• Secondary prophylaxis (long-term antibiotic use) is recommended for all patients
• Should be continued for a minimum of 5 years, or until the age of 21 – whichever is longest
• Recommended 10 years for patients with carditis
• In patients with severe valvular disease, life-long prophylaxis may be recommended

Flashcard

References

• Rheumatic fever – patient.info
• Rheumatic fever – BMJ Best Practice
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.

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Thalassaemias are autosomal recessive inherited disorders of haemoglobin, causing structural deficiencies in haemoglobin molecules. As such, they are a type of haemoglobinopathy.

They mainly effect individuals of asian, middle eastern or mediterranean ethnicity.

Heterozygous forms are relatively common and usually minor. Homozygous forms are rare, but cause a severe anaemia of childhood and can be fatal without treatment.

Haemoglobinopathies typically present with a microcytic hypochromic anaemia which will NOT respond to iron. In the most severe cases, thalassaemias can be fatal in utero or in the first few months of life, but most cases are of mixed genetic background and are mild.

Thalassaemia can be broadly classified into α-thalassaemia and β-thalassaemia, depending on the underlying structural haemoglobin changes. β-thalassaemia is more common.

They are also often referred to as thalassaemia major, thalassaemia intermedia and thalassaemia minor – however this classification usually refers to the severity of the disease (usually when referring to β-thalassaemia).

The vast majority of cases are of minor disease and are typically asymptomatic. The most severe forms of the disease (rare) are incompatible with life and can result in miscarriage or death of the newborn. In between these extremes is Thalassaemia major – a serious condition, which often manifests in infancy with failure to thrive, fevers and bony (including facial) deformities. It can be cured with bone marrow transplant (if available) but is usually treated with lifelong recurrent blood transfusions . These patients often become iron overloaded and as a result require iron chelation therapy, and regular cardiac and liver monitoring under the supervision of a multi-disciplinary team.

Epidemiology

• 1.5% of the global population are carriers of β-thalassaemia. Most prevalent in:
  • Mediterranean
  • Middle east
  • Southern China
  • Central, south and southeast Asia
• 5% are carriers of α-thalassaemia. most prevalent in:
  • Southeast Asia
  • Africa
  • India

Pathology

Haemoglobin molecules are made up of 4 “globin” chains. There are 4 types of globin chain; alpha (α), beta (β), gamma (γ) and delta (δ). Usually a haemoglobin molecule is made up of a pair of one type of globin chain (e.g. a pair of α chains) and then two other chains.

• Most commonly, haemoglobin is made up of 2 alpha and 2 beta chains – HbA (α₂/β₂₎
• Mutations in the alpha chains give rise to α-thalassaemia, and mutations in the beta chains give rise to β-thalassaemia

Over 300 mutations have been identified and the clinical severity of the disease varies widely.

• Clinically, severe cases of thalassaemia manifest as haemolytic anaemia with splenomegaly (+/- hepatomegaly) and pallor (pale-looking) – often at birth or within the first few months of life.
• Individuals with thalassaemia traits (either alpha or beta) are often asymptomatic
• The clinically asymptomatic types of α-thalassaemia and β-thalassaemia produce a mild microcytosis – which often can appear like an iron-deficiency anaemia (although will often have normal iron studies). They will not respond to iron therapy.

α thalassaemia

There are two genes that code for α chains. That’s easy to understand. And then thalassaemia starts to get very complicated.

There are 6 possible genotypes. You will definitely NOT be expected to know all of these unless you are a haematologist. But, for completeness – here they are*:

Name	Genotype	Info
Normal	(a,a / a,a)	No thalassaemia
α+ thalassaemia heterozygous	(a,- / a,a)	Clinically asymptomatic / ↓ Hb / ↓ MCV ↓ MCH
α+ thalassaemia homozygous	(a,- / a,-)	Clinically asymptomatic ↓ Hb (slightly) ↓ MCV ↓ MCH
αo thalassaemia heterozygous	(a,a / -,-)	Clinically asymptomatic ↓ Hb (slightly) ↓ MCV ↓ MCH
HbH disease	(a,- / -,-)	Symptomatic ↓ Hb ↓↓ MCV ↓ ↓MCH Splenomegaly Bone changes
α thalassaemia major	(-,- / -,-)	Usually fatal ↓↓ Hb (severe) Severe intrauterine haemolytic anaemia

*I presume the genotype notation was first used before texting smiley faces became “a thing”!

• Severe homozygous α thalassaemia is usually fatal in utero
  • Is one of the two main causes of hydrops fetalis – the other being rhesus incompatibility – which is now rarely seen.
• α-thalasseamia carrier – refers to deletion of one α chain, and is asymptomatic
• α-thalasseamia trait – refers to presentations with deletions of two α chains (a,- / a,-) or (a,a / -,- )
• α-thalasseamia media – refers to HbH disease – whereby beta-haemoglobin chains replace this missing alpha-chains – and hence the predominance of HbH
  • HbH – haemoglobin H chains are an abnormal type of haemoglobin produced when a patient inherits an α+ from one parent and an αo from another
• α-thalasseamia major – as above

Diagnosis

Unlike in β-thalassaemia, haemoglobin electrophoresis is usually normal.

• α-thalasseamia carrier and α-thalasseamia trait – usually undiagnosed, asymptomatic. Can be detected on genetic testing, or with an “α-β chain synthesis ratio”
• α-thalasseamia media – HbH disease – on blood films stained with a supra vital stain, there are tell-tale inclusions in the RBCs known as Heinz Bodies

β thalassaemia

There is only a single gene that codes for the beta chain – which makes β-thalassaemia slightly easier to understand!

Presentation

Newborns are born with large amounts of HbF – the γ chains in HbF are slowly replaced by β chains in the first years of life. This process is highly variable. The typical presentation for β-thalassaemia is around the end of the first year of life, but it can take up to 5 years.

Defective β-chain synthesis usually results in increased alpha-chain synthesis. Excess alpha chains will precipitate in red cells and cause the red cell walls to be weakened. These fragile RBCs will subsequently be destroyed in bone marrow and the spleen. This causes a progressive splenomegaly as well as bone marrow proliferation – which results in bony deformities.

• Homozygous disease usually presents by the age of 3 months, and if untreated can be fatal by the age of 1 year. Some may not present until as old as 5. Presenting features include:
  • Failure to thrive
  • Vomiting
  • Sleepiness
  • Irritability
  • Stunted growth
  • Fevers – due to hyper-metabolic state
• Most neonates with β-thalassaemia major are detected on blood spot screening at birth
• Signs and symptoms are usually absent if Hb >90 g/L

Signs

In milder cases (Hb >90 g/L) there are rarely any signs or symptoms. In more severe cases, signs can include:

• Hepatoslpenomegaly
• Bony deformities
  • Frontal bossing
  • Prominent facial bones
  • Dental deformities
• Jaundice
• Pallor
• Cardiac flow murmur secondary to anaemia
• Poor exercise tolerance

A child with failure to thrive and a microcytic anaemia should be strongly suspected of having a haemoglobinopathy (most commonly thalassaemia).

Differentials

Thalassaemia can be a differential for any other causes of a microcytic anaemia, such as:

• Iron deficiency anaemia
• Anaemia of chronic disease
• Sideroblastic anaemia

Other differentials include:

• Acute leukaemia
• Rhesus incompatibility

Investigations

Blood

• FBC
  • Microcytic hypochromic anaemia
  • May be confused with iron deficiency – especially β-thalassaemia
  • WCC may be elevated due to haemolysis
  • Platelets may be low due to splenomegaly
• Iron studies
  • Increased ferritin
  • Saturation as high as 80%
• Haemoglobin electrophoresis is diagnostic in β-thalassaemia
  • Checks for the presences of HbA2
    • Normal 1.5 – 3%
    • >3.5% is diagnostic for β-thalassaemia
• DNA testing can be used to establish the underlying carrier status in families and parents

	Iron deficiency anaemia	Anaemia of chronic disease	β-thalassaemia	Haemochromatosis
Serum Iron	↓	↓	↑ or	↑
TIBC – aka Transferrin	↑	↓		↓
Serum Ferritin	↓	↑ or	↑ or	↑↑
MCV	↓	↑ or	↑ or	↑↑

Imaging

• X-ray may show bony changes
  • Skull – “hair on end” deformity
  • Maxilla – overbite and overgrowth
  • Long bones and ribs – may be flat or show other deformities
  • CXR – enlarged heart, signs of heart failure
• CT / MRI
  • Can be used to assess the liver in patient on chelation therapy

Other potential investigations

• ECG and Echo – to monitor cardiac function
• Liver biopsy – to assess iron deposition and the degree of haemochromatosis
• Bone marrow biopsy – may be needed to confirm diagnosis
• HLA typing – in cases where bone marrow transplant is considered
• Monitor of chelation therapy
  • Eye tests
  • Hearing tests
  • Renal function

Management

The aim of treatment is to prevent Hb falling below 95 g/L. Many patients will require life-long blood transfusions, although bone marrow transplant (stem cell transplant) is curative, and likely to have better outcome when performed at an earlier age.

• Blood transfusion prolongs survival but causes iron overload. Aim for Hb >95g/L. Consider using ‘leucocyte poor’ blood to prevention sensitisation – especially if future bone marrow transplant is an option
• Indications for transfusion include:
  • Growth impairment
  • Skeletal deformity
• Iron overload usually occurs as a result of multiple transfusions, but can occur without transfusion. Iron deposits widely in various organs in the body, causing fibrosis and organ failure. It can be treated with chelation
  • Patient still often suffer from restricted growth, and endocrine disorders secondary to iron overload, such as diabetes, thyroid disorders and adrenal and pituitary disorders
    • Diabetes is common
    • Be wary that HbA1c is not a reliable indictor of diabetic control due to the reduced lifespan of RBCs in thalassaemia
  • Hepatitis B and C risk is increase due to multiple transfusions
  • Be wary of ever giving iron supplementation to any thalassaemia patient – unless there is proven iron deficiency
  • Chelation therapy typically with desferrioxamine
    • Dose is variable
    • Not available orally
    • Newer oral agents are now available such as deferasirox and deferiprone
• Overall life-expectancy is reduced
• Consider splenectomy if there is marked hypersplenism – be wary of risks of asplenism (life-threatening infections, VTE, pulmonary hypertension)
• Bone marrow transplant is curative
  • Best outcome if done at earlier age
  • There have been recent cases of subsequent embryo selection by parents to produce a child with compatible but disease free bone marrow – the ethical and legal issues around this are still being debated.
• Offer genetic counselling to all patients with all variants of thalassaemia
• Lifestyle factors:
  • Avoid foods rich in iron
  • Vitamins C+E, folic acid may be beneficial
  • Drinking tea and coffee frequently can reduce the absorption of iron

Prognosis

α thalassaemia

• Excellent if only a carrier
• HbH disease has variable prognosis. Most survive into adulthood, but some suffer many complications
• Hydrops fetalis is incompatible with life

β thalassaemia

• Thalassaemia minor causes an asymptomatic microcytic anaemia with no effect on mortality or morbidity
• Thalassaemia major carries an 80% mortality in the first 5 years of life
• Patients who require transfusions have substantially reduced life expectancy
  • Without chelation – often will not survive teenage years
  • Chelation therapy has improve life-spans
• Stem-cell transplant (bone marrow transplant) is associated with 85-90% survival after 15 years

Flashcard

References

• Thalassaemia – patient.info
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.

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• Menopause is the permanent cessation of the menstrual cycle
• Menopause usually occurs between the ages of 45 and 55
• Typical age is 51.5
• Premature menopause is defined as menopause before the age of 40 – aka premature ovarian insufficiency
• The process of going through the menopause can be split into the premenopause – a time of irregular periods, and menopause – the time when the periods cease. The total time spent passing through these changes varies between 2 and 5 years
• Postmenopause is said to begin at 12 months after the final period
• Menopause has many physiological effects, but one of the main pathological consequences is the predisposition for osteoporosis
• As well as being a physiological process, menopause is induced by surgical removal of the ovaries, or by damage to ovarian function with radiotherapy or chemotherapy

Physiology

• As the menopause approaches, the number of primary follicles declines
• Levels of FSH and LH rise dramatically
• The ovary produces very little oestrogen or progesterone, but continues to produce androgens
• Diseases for which risks increases after menopause:
  • Osteoporosis
  • Cardiovascular disease
  • Diabetes
  • Cancer
    • Breast
    • Ovary
    • Cervix
• Premature menopause occurs in
  • About 1% of women <40 years as a result of genetic or autoimmune disease. These patients require specialist investigation
  • About 5% of women <40 due to oophorectomy or chemotherapy
  • Women age 40-45 have physiologically significant “premature menopause” and don’t necessarily require further work-up

Presentation

The symptoms of menopause are due to tissue sensitivity to lower oestrogen levels. This mainly affects the brain. Symptoms vary widely – some women experience none at all, whilst other are severe debilitated by their symptoms. About 80% of women will experience some symptoms. 50% of women will experience some symptoms for at least 7 years.

• Hot flushes – 80%
• Night sweats – 70%
• Palpitations – 30%
• Dizziness
• Lethargy / tiredness
• Migraine / other headaches
• Psychological
  • Irritability
  • Depression
  • Anxiety
  • Poor short term memory
  • Sleep disturbance
• Urogential
  • Vaginal dryness (45%)
  • Atrophic vaginitis
  • Dyspareunia (pain on sexual intercourse)
  • Reduced libido
  • Bladder dysfunction
  • Stress incontinence (e.g. frequency, dysuria)
  • Prolapse
• Skin
  • Dry skin
  • Sensation of insects crawling on skin (formication)
  • Facial har
  • Breast tissue atrophy

The oestrogen deficiency symptoms are hot flushes and the urogenital symptoms. These are important to elicit in the history, as these are the symptoms most effectively treated with HRT.

• Vasomotor symptoms (hot flushes and night sweats) are at their height in the perimenopause and early post menopausal stage, before resolving with time
• Urogenital atrophy symptoms tend to worsen with age

Investigations

In a typical-age patient (age 45-55), no specific investigations are required – the diagnosis is usually clinical. However, several investigations may be performed to rule out other differentials. Differentials include:

• Thyroid disorders
• Dysfunctional uterine bleeding
• Anaemia
• Depression

Investigations to help discern these differentials would include:

• Urinalysis
• FBC
• TSH
• LFTs
• Iron studies
• B-hCG (!)

Investigations are not necessary to confirm diagnosis of menopause in women aged >45.

In possible early menopause (age <45), the following hormonal test may confirm the diagnosis:

• Serum FSH – high – (around 25 U/L))
• Serum oestradiol – low – (<100 pmol/L)
• Two readings should be taken 6 weeks apart (or 3 months apart if has a mirena (IUD))
• These investigations are NOT intended to diagnose menopause in women >45
• FSH is not always elevated early in the perimenopausal period

Other investigations to consider around the perimenopausal period include:

• Fasting lipid profile (for cardiovascular disease risk)
• Mammogram – particularly remember to consider this 3 months after starting HRT
• Hysteroscopy – if abnormal uterine bleeding
• Pap smear and mammography
• Bone density – if risk factors (consider using risk calculator – such as FRAX)

Management

Patient education

• Emphasis that the menopause is a natural physiological process
• Some lifestyle factors can trigger the vasomotor symptoms – including caffeine, alcohol, spicy foods
• Lifestyle factors have been shown to reduce the severity of symptoms
  • Healthy diet
  • Healthy weight
  • Regular exercise
  • Smoking cessation
  • Reduce caffeine intake
  • Alcohol intake within recommended safe limits
  • Stress reduction and relaxation (consider mindfulness)
• Screen for anxiety and depression and treat these if present
• Give advice about bone health
  • 1300mg calcium per day
  • 150 minutes of moderate intensity exercise weekly
  • Vitamin D – either supplementation or sun exposure
  • Smoking cessation
  • Safe drinking limits (alcohol)

Sex

• Advise it is normal to need additional vaginal lubrication
• Advise to continue contraception for 12 months after the last period in women >50 and 2 years in women <50
• The combined oral contraceptive pill (low dose preparations) can be used up to the age of 50 if there are no contraindications (see UKMEC guidelines for contraindications). After the age of 50, condoms and progesterone only preparations are recommended.

Hormone replacement therapy

Hormone replacement therapy (HRT) should be considered for any patient with moderate to severe vasomotor symptoms (hot flushes, night sweats, palpitations).

For patients with urogenital symptoms – consider topical oestrogen preparations:

• e.g. – Oestradiol 1mg/g with applicator
  • Once at night for three weeks, then 2-3x per week thereafter
  • OR
  • Oestradiol 10mg pessary – at night daily for 3 weeks, then x2 per week at night after that

These topical vaginal preparations will:

• Reduce vaginal dryness, itching and pain
• Reduce dyspareunia
• Reduce risk of recurrent UTIs
• Take 6-8 weeks to be effective
• Avoid added progestins – can increase the risk of endometrial cancer
• Contraindicated in undiagnosed vaginal bleeding, endometrial cancer
• Some gynaecologists recommend against their use after a diagnosis of breast cancer

For vasomotor symptoms, consider preparations with systemic effects (e.g. oral medications, patches, implants, gels). Use the smallest dose possible to receive symptoms. 

Examples of oestrogen preparations include:

• Patches – applied weekly – typical dose 50mcg
• Transdermal topical gel applied to the skin
• Implant – 50-100mg – given every 3-12 months
• Oral preparations – no need to stop dosing for one week each month (unlike in pre-menopausal women)
  • Oral oestrogen carries significant VTE risk and should not be used in those with personal history or 1st degree relative history of VTE
  • Non-oral oestrogen does NOT have these contraindications and can still be used in these patients

However – unopposed oestrogen (i.e. without progesterone) therapy causes hypertrophy of the uterus and a 5-10x increased risk of endometrial carcinoma.

• As a result, any woman on HRT who still has her uterus should be on a progestin
• Can be given as a 14 day on-off cyclical regimen – however this often causes withdrawal bleeds which many post-menopausal women would prefer to avoid
• Can also be given continually
• The sole purpose of giving a progestin is to prevent endometrial hypertrophy and reduce risk of endometrial carcinoma
• Examples of progestins include:
  • Dydrogesterone 10-20mg daily
  • Medroxyprogesterone acetate 10 mg daily
  • Norethisterone 1.25mg – 5mg daily

Many preparations come as combined oestrogen and progestin combinations. Some of these are cyclical (best in perimenoapusal women) and other are continuous best in post menopausal women – i.e. >12 months since the last period. The most commonly prescribed method is transdermal patch. These may cause localised skin irritation. Transdermal methods of oestrogen are generally preferred because they have a reduced risk of VTE compared to oral preparations.

HRT improves quality of life in the short term. It has widespread and complicated risks for various disease – some increased and some decreased.

In 2002, the Women’s Health Initiative (WHI) trial results were released. This raised concerns amongst prescribers around the world, as it showed that in women who used oestrogen containing oral HRT preparation for >5 years there is an increased risk of:

• Breast cancer – 1.26x risk
• Coronary heart disease – 1.29x risk
• Stroke – 1.41x risk
• Pulmonary embolus – 2.13x risk

and also reduces the risk of:

• Bowel cancer
• Osteoporosis
• Fractures

Prior to this study, HRT was much more widely used. In the wake of this study, new recommendations advised to:

• Not use HRT solely for osteoporosis prevention in asymptomatic women
• Women using HRT should slowly reduce their dose over 2-3 months when stopping treatment
• It is advisable to limit treatment to <5 years
  • There is no proven associated risk of an increase in breast cancer in women who use HRT <5 years
• Risks are greatest in women >60 using HRT

Principles of HRT

• If perimenopausal – use the combined oral contraceptive pill (if <50) or the IUD
• If menopause – use specific HRT preparations (as above and table below)
  • Combined therapy for all women with a uterus
  • Oestrogen only therapy for women without a uterus
  • Start with a small dose and titrate upwards
• Perform mammography 3 months after starting treatment
• Then, review at 6 monthly intervals
• Duration of treatment
  • Aim to cease treatment at 2 years
  • If unable to tolerate symptoms at this point – continue for up to 5 years. Be aware that up to 50% of patient swill suffer vasomotor symptoms (at least temporarily) on cessation of treatment
  • Balance risk vs benefits if you plan to continue past 5 years – ensure informed consent

• E = Oestrogen
• P = Progesterone
• Patches may be preferred over pills due to lower VTE risk

Contraindications to HRT

• Oestrogen dependent tumours
  • Endometrial carcinoma
  • Breast cancer
  • Ovarian cancer
• VTE
  • Contrainidcation for oral oestrogen preparations only
  • Personal or first degree relative history
• Ischaemic heart disease / coronary artery disease
• Previous TIA / CVA
• Uncontrolled HTN
• Undiagnosed vaginal bleeding
• Liver disease
• SLE
• Pregnancy (!)

Examples of HRT preparations

HRT therapies containing both an oestrogen and progestin are known as ‘combined HRT’. There are two types – cyclical and non-cyclical. Cyclical should be used in those who are perimenopausal (<12 months since last period) and non-cyclical can be used in those who are menopausal.

Some examples include (don’t worry about memorising this table – but perhaps know a couple of options):

NB – based on brands available in Australia in 2020. 

Testosterone

• May be given to relieve reduced libido
• Usually given as a 50mg implant – which lasts 3-12 months
• Should be given with concurrent 50mg oestrogen implant
• Limited data as to its safety

Tibolone

• A synthetic hormone with combined oestrogen, progestin and testosterone effects
• Can be used in post-menopause women – particularly useful in patients without a uterus and those whose last period was >12 months ago
• Useful for vasomotor symptoms (but probably less effective than conventional HRT)
• Useful for low libido (better than conventional HRT)
• Less likely to cause bleeding than conventional HRT
• In perimenopausal women may cause irregular bleeding – so avoid

“Bioidentical hormones”

• Available at some private clinics and unregulated online
• Variable preparations and strengths of oestrogen and progesterone
• Marketed as being “safer” than traditional HRT
• There is no evidence that they are safer – and in fact due their unregulated nature are inherently less safe and not well studied
• No evidence that they are more effective than conventional HRT
• Frequently raised by patients who are struggling with menopausal symptoms

Correcting bleeding problems

• Heavy bleeding – reduce oestrogen
• Breakthrough bleeding – Increase progestrogen
• Irregular bleeding – investigate
• Patient can’t tolerate bleeding – use continual regimen
• No bleeding – normal

SSRIs

• Should be considered as second line – and are particularly effective for treatment of hot flushes (vasomotor symptoms)
  • Contrary to some belief – they are not recommended in menopause because of their mood boosting efects
• More effective than placebo in clinical trials
• E.g.:
  • Venlafaxine 37.5mg increasing to 75mg daily
  • Paroextine 10mg increasing to 20mg daily

Other non-hormonal medications

• Gabapentin 100 – 300mg PO OD, slowly can increase dose to maximum of 300mg TDS
• Clonidine 25mcg PO BD, can increase to 50mg BD after 2 weeks

When to refer

Refer to gynaecology if:

• Patient aged <40 and symptoms of menopause, OR
• Pharmacological treatment is required in menopausal women whose menopause is secondary to cancer or chemotherapy

Flashcard

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Menopause – Health Pathways
• HRT – Health Pathways
• Menopause – patient.info

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Dyslipidaemia (often interchangeably used with hyperlipidaemia) describes raised levels of cholesterol in the blood. This is significant because it is associated with increased risk of cardiovascular disease.

The lipid hypothesis suggests (and is strongly supported by epidemiological studies) that elevated levels of plasma cholesterol causes coronary artery disease as a result of pathological changes in artery walls.

Lipid lowering therapy reduces the incidence of stroke and coronary artery disease.

In particular, low density lipoprotein (LDL) levels (“bad cholesterol”) are strongly correlated with coronary artery disease, whilst HDL –  high density lipoprotein (“good cholesterol”) is protective.

Elevated cholesterol is typically discovered in screening blood tests. The decision to treat depends on multiple factors, which as usually assessed using a cardiovascualr scoring system, such as QRISK3 (UK) or CVDCHECK (AUS).

Exercise and changes in diet can effectively lower cholesterol. Statins are the mainstay of medical treatment. Other lipid lowering drugs are more controversial – such as fibrates – as although they lower measurable cholesterol levels, they have not been associated with a reduction in cardiovascular disease.

A new class of injectable drugs – known as PCSK9 inhibitors have been around since the last 2010s. These show good results in trials but are expensive and require an injection – but are useful in difficult to treat cases.

The Lipid Hypothesis

Historically the management of raised cholesterol is a controversial topic – “the lipid hypothesis” is still challenged in some quarters even today. The landmark “Scandinavian Simvastatin Survival Study (1994) – aka “4S trial” proved survival benefit for lipid lowering therapies.

• Multiple other studies have also shown this benefit – including the following trials; PLACI, PLACII, ACAPS, KAAPS, REGRESS
• The INTERHEART study suggested that 45% of MIs are due to dyslipidaemia

Classification

Dyslipidaemia refers to a state of an abnormal lipid profile in the blood. Can be:

• Abnormally high triglycerides
• Abnormally high cholesterol. Can be:
  • Total cholesterol – TChol
  • Low-density lipoprotein cholesterol – LDL-C
• Abnormally high triglycerides and cholesterol
• Abnormally low high-density lipoprotein – HDL-C
  • This is a risk factor for cardiovascular disease regardless of total cholesterol

Technically hyperlipidaemia refers only to increased levels of triglycerides and cholesterol and as such does not include reference to HDL-C. However in practice, the terms dyslipidaemia and hyperlipidaemia are often used interchangeably. 

Correlations

• Risk increases with the degree of cholesterol elevation
  • 90% risk of cardiovascular disease in patients with total cholesterol >7.8mmol/L
  • 10% reduction in cholesterol gives a 20% reduction in cardiovascular disease risk after 3 years
• Risk of cardiovascular disease particularly high in patients with high LDL and low HDL
  • LDL:HDL radio of >4, or HDL <1mmol/L indicates high risk
• Triglycerides >10mmol/L associated with pancreatitis
• LDL reduction with statin therapy reduces MI, stroke, death, and need for revascularisation therapies

Epidemiology

• Extremely common in developed nations. In the UK almost two thirds of the adult population has a cholesterol >5.2 mmol/L. Mostly as a result of lifestyle and genetic factors
• Familial hypercholesterolaemia (FH) is a specific genetic disease that causes elevated cholesterol, affecting about 1 in 500 individuals
  • Usually heterozygous
  • Homozygous disease is extremely rare
  • Consider this diagnosis in anyone with a total cholesterol of >7.5 mmol/L
  • Associated with a 4x increased risk of cardiovascular disease

Causes

Most cases are related to a combination of lifestyle and genetic factors. It is also important to consider secondary causes:

• Hypothyroidism
• T2DM
• Cholestasis
• Anorexia nervosa
• Obesity
• Alcohol excess
• Liver disease
• Renal disease
• Medications
  • Thiazide diuretics
  • Corticosteroids
  • Beta-blockers
  • Combined oral contraceptive pill
  • Antipsychotics

Presentation

Usually discovered incidentally on screening.

• Australian guidelines (RACGP red book) recommends that every adult have their cholesterol checked every 5 years from age 45 onwards
  • Every 2 years if CVD risk >10%
  • Every year if CVD risk >15%

Levels are measured with a blood sample. A fasting sample is no longer routinely recommended – triglycerides may be falsely elevated in a non-fasting sample, but levels of total cholesterol, HDL-C and LDL-C are not thought to be significantly affected.

It is recommended to have two separate samples at different times to confirm the diagnosis.

• One of these should be fasting

Consider specialist referral for patients with a total cholesterol >20 mmol/L. Levels of >10 mmol/L are associated with an increased risk of pancreatitis. Patients with these levels often have underlying familial hypercholesterolaemia.

Any patient with raised cholesterol should also have:

• Fasting blood glucose – to exclude diabetes as a cause
• Renal function – to exclude CKD as a cause
• LFTs – to rule out liver disease as a cause, and because statin may be contraindicated if AST is >3x the upper limit of normal
• TSH – to rule out myxoedema (hypothyroidism)

“Normal” cholesterol level

A normal cholesterol level depends on the individual.

• No known cardiovascular disease – LDL <4, total cholesterol <5.5
• Known cardiovascular disease – LDL <2, total cholesterol <4

In individuals with no known cardiovascular disease with a raised cholesterol, if the overall cardiovascular risk remains low, there may not be large benefit from pharmacological management, but these patients should still be encouraged to lower their cholesterol with lifestyle factors.

When to treat

Treatment should not be based purely on lipid levels. Typically, levels are used in association with a cardiovascular disease risk calculator (e.g. QRISK3or cvdcheck.org.au) to know when it is appropriate to treat. These calculators use multiple risk factors, including  age, gender, blood pressure, smoking history, left ventricular function (if known) and history of diabetes. The basic principles of these calculators involve treating patients with:

• Known cardiovascular disease and total cholesterol >4mmol/L
• High risk patients with total cholesterol >6.5mmol/L OR total cholesterol >5.5mmol/L and HDL <1mmol/L. High risk include:
  • T2DM
  • Familial hypercholesterolaemia
  • FHx of significant cardiovascular disease – first degree relative first diagnosed with cardiovascular disease at <60
  • Peripheral vascular disease
• HDL <1mmol/L in ANY patient

In the example above (cvdchech.org.au – recommended in Australia) – patients should be treated phamacologically when their 5-year risk exceeds 15%, and considered for pharmacological treatment between 10-15% if they have failed or are unwilling to engage with lifestyle interventions.

Be aware that the CVDCHECK calculator and many similar alternatives may underestimate risk – particularly as they do not take family history into account – and it may be necessary to make a clinical judgment in cases of a strong family history as described above.

• QRISK3 is more in-depth and includes this amongst other factors

Also be aware that the calculator can overestimate the risk on elderly men with no risk factors (purely based on age and gender) and may lead to over treatment in this age group.

Refer patients with any of the below for investigation for familial hypercholesterolaema:

• Total cholestoler >8mmol/L
• Total cholesterol >6mmol/L with FHx of premature ischaemic heart disease
  • ‘Premature” defined as – age of onset <55 in men or <60 in women
• Known FHx of a genetic lipid disorder

Goals of treatment

• Total cholesterol <4.0 mmol/L
• HDL-C ≥1.0 mmol/L
• LDL-C <2.0 mmol/L
• TG <2.0 mmol/L

In familial hypercholesteolaemia

• Aim to reduce LDL-C by 50%

Cholesterol levels can be re-checked 6 weeks after an intervention.

Non-pharmacological interventions

Dietary cholesterol accounts for between 10-40% of total cholesterol levels. Specific foods causing elevated cholesterol (e.g. eggs and butter) are probably less important than was previously thought, however the overall quality of the diet is still important.

• Regular exercise
• Smoking cessation
• Alcohol intake <20mg daily (<2 standard drinks, and x2 alcohol-free days per week)
• Weight loss
• Advise of suggest waist measurements for minimising cardiovascular disease risk (<94cm for men and <80cm for women). This risk factor is independent of weight
• Diet advice: aim for plant based, whole food diet. Minimise animal product and processed food intake. “Eat not too much, mostly plants”
  • Reduce animal fat intake – meat AND dairy
  • Diet high in vegetables and other plant based foods
  • Complex carbohydrates
  • Avoid foods high in saturated fat
    • Avoid deep fried food and “fast foods”
  • Steam and grill foods instead of frying
  • Avoid snacks heavy in calories (e.g. biscuits, cakes)
  • Eat fish at least twice per week
  • ”Mediterranean Diet”
• Can have a measurable effect in cholesterol in 6-8 weeks
• Continue for at least 6 months before considering drug therapy, except in high risk patients

Medical Agents

Statins – e.g. atorvastatin, rosuvastatin, simvastatin

• HMG-CoA reductase inhibitors
• Adverse effects
  • Myalgias (most common)
  • GI upset
  • Abnormal LFTs
• Do baseline LFTs and CK
  • Repeat at 4-8 weeks
  • Recommended to repeat every 6 weeks for 6 months after initiation of therapy

Alternative agents

• Ezetimibe 10mg daily
  • Often used if statin not tolerated
  • Ezetemibe binds to cholesterol in the digestive tract and can reduce LDL by up to 15%
• Ezetimibe + statin
  • Often used if statin alone is not achieving control of cholesterol levels
• Bile acid binding agents
  • Cholestyramine 4g daily – added to fruit juice (reduces side effects)
  • Causes GI symptoms including constipation and foul smelling wind!
• Fibrates
  • Consider if above agents not working
  • Poor evidence – they lower cholesterol but studies suggest they do NOT improve cardiovascular outcomes
  • Thought to be more effective for triglyceride elevation
• Nicotinic acid
  • 250mg BD with food
  • Can increase up to 1000mg TDS
  • Can cause gastric irritation, hot flushes and gout

PCKS9 inhibitors

• PCSK9 – propotein convertase subtilisin/kexin type 9 – inhibitors are relatively new (around since late 2010s)
• Require an injection
• Examples are alirocumab (Praluent) and evolocumab (Repatha)
• Extremely expensive – in 2018 the quoted annual price was around $14,000USD per year. This is likely to fall and their use is likely to become more prevalent
• May be indicated in particularly difficult to treat cases – especially those involving familial hypercholesterolaemia
• Proven to reduce heart attack and stroke risk by about 15%

Pregnancy

Pregnancy often causes a transient elevated of LFTs. This is not thought to be of clinical significance and should only be treated if it does not resolve after delivery

Dietary agents affecting cholesterol

Various dietary agents have been suggested to lower cholesterol. These include:

• Fish oils – consuming fish at least twice a week has been shown to lower cholesterol
• Plant sterols – have also been shown to lower cholesterol
• Other compounds, such as vitamin E, garlic and lecithin are not supported by evidence

Familial Hypercholesterolaemia

Familial hypercholesterolaemia – FH (aka familial hyperlipidaemia) is an inherited, autosomal dominant disorder. It is a common, but under diagnosed disorder, often encounter in general practice. It affects about 1 in 250 people, and 50% of all first degree relatives of an affected individual.

• Only about 10% of cases are formally identified

It results in massively elevated cholesterol levels from birth, which leads to the early development of cardiovascular disease.

• Cardiovascular disease risk is up to 25x greater than the general population

Patients may or may not present with the “textbook” signs of:

• Arcus senilis – white / grey / yellow ring around the margin of the cornea. Commonly seen in healthy older individuals, but pathological if found at age <45
• Tendon xanthomata – hard, non-tender lumps in tendons – most commonly the achilles tendon
• Xanethelasma – fatty deposits around the eyes

Occasionally (and I have seen it) when a blood sample is taken is can appear yellow and fatty in the test tube!

There is usually a strong family history of raised cholesterol and early onset cardiovascular disease. Early onset cardiovascular disease is defined as:

• Coronary artery disease in men aged <55
• Coronary artery disease in women aged <60

All FH patients should be follow-up annually to check the cholesterol levels and to investigate for any evidence of cardiovascular disease. Compliance, particularly in young asymptomatic patients can be difficult.

Diagnosing Familial Hypercholesterolaemia

Once other possible causes have been excluded – such as hypothyroidism, corticosteroid use, renal disease (nephrotic syndrome) and diabetes, then you can assess the patient for FH.

The Simon Broom diagnostic criteria suggest a diagnosis can be made with:

• TChol >7.5mmol/L AND
• Tendon xanthomata in patient or first or second degree relative OR
• DNA evidence of LDL receptor mutation

Other scoring systems (such as the Dutch Lipid Clinic Network Criteria – DLCNS) are also used – and are more complex. Online calculators are available. Genetic testing is not always required if a scoring system suggests a diagnosis of FH. If there is doubt over the diagnosis, then offer DNA testing. Also consider offering DNA testing to family members of a patient with confirmed FH particularly children of affected adults.

• Cascade screening is the term used to describe the screening process for relatives on an “index case” of familial hypercholesterolaemia
• It usually involves a genetics specialist, and discussion with family members about the sharing of confidential information, and the legal and ethical implications of sharing genetic information ith asymptomatic family members.

Elevated Triglycerides

Elevated triglycerides, especially with otherwise normal lipid profile is strongly correlated to lifestyle factors. Triglycerides also vary more widely between a fasting and a non-fasting sample.

Elevated triglycerides may falsely alter the result of LDL (often making it appear falsely low)

If elevated to >5 mmol/L:

• Advise lifestyle changes, and re-check, ensuring a fasting sample
• Consider fibrates

Flashcard

References

• Familial Hyperlipidaemia – RACGP
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Hyperlidipaemia – patient.info
• Managing Lipids – NPS MedicineWise

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Epidemiology and Aetiology

• M>F (slightly)
• Increased incidence in Pet Owners
• Genetic susceptibility – increased risk in a family history of the disease
  • Disease also often occurs in local geographical clusters
• Essentially unknown aetiology; environmental factors in a predisposed individual (possibly viral infection is the environmental factor)
• Incidence increases with age
  • Rare under 50

Clinical features

• Chronic progressive disease
• Often asymptomatic, and discovered incidentally with a raised ALP in the blood, or discovered incidentally on x-ray
• Only 15-40% of cases have symptoms
• Bone pain – the most common symptom
  • Occurs in 40% of presentations
    Pain is usually due to impingement on other localised structures
  • Bone pain is a late feature. It is typically a deep constant aching pain, worse with weight bearing, and may persist through the night
  • Consider Paget disease of the bone in elderly patients presenting with persist back pain
  • Bony deformity may cause warm skin overlying the lesion due to increased blood flow
• Deformity – up to 30% of patients
• May affect bones anywhere in the skeleton, but common sites include; pelvis, lumbar spine, femur, thoracic spine, sacrum, skull, tibia, humerus
• Usually only affects one site – it is not ‘systemic’ like osteoporosis, and does not spread to other sites.
• Osteoarthritis
• Fractures – bones are prone to fracture because they become more brittle. Affect 15% of patients
• Deafness / Headaches – occurs in some patients due to compression of the vestibulocochlear nerve, when the skull is affected
  • More rarely there may be other non-specific neurological features – e.g. dizziness, altered gait
• Osteosarcoma – used to be more common, now only affects 1% of patients
• Bowing deformity is seen in Paget disease of the long bones
  • This can cause altered gait, and may result in other joint pains, particularly of the hips and lower back
  • Traumatic fracture are also most likely to occur in Paget disease of the long bones

Pathology

• Increased number of osteoclasts. Osteoclasts also often larger. The osteoblasts are normal, but are often over active, due to increased factors released by osteoclasts.
  • Osteoclasts are also often oversensitive to vitamin D
• Essentially, an accelerated rate of bone turnover – with subsequent rapid new bone formation – and this new bone does not have a normal bone matrix – the matrix is disorganised
• The bones increase in size, but become more brittle, and thus more prone to fracture.
• Unclear why some areas of bone are affected and others are normal

Investigations & Diagnosis

Diagnosis is usually made radiologically. Blood tests and other investigations are suggestive or supportive of the x-ray findings.

Once diagnosis is confirmed, radionuclide bone scan is often performed to check for any other areas of involvement.

Bone biopsy is not usually required.

Blood tests

• Raised alkaline phosphatase – ALP can be an indicator of osteoblastic activity
  • Remember to ask for bone specific ALP – increased ALP can also be of liver origin
  • Consider checking gamma-GT – to rule out a liver cause if bone specific ALP is not available
  • The level of ALP is correlated to the severity of the Paget disease
• Serum calcium and phosphates are usually normal
  • Abnormal levels may be an indicator of unrelated parathyroid disease  (hyperparathyroidism)
• Vitamin D levels are normal tested. This is for two reasons:
  • To help rule out another cause of raised ALP
  • To ensure levels are sufficient to undertake bisphosphonate therapy

X-ray

• Widening of the cortical region – i.e. the hollow cortex at the centre of the bone (where marrow is produced) is wider
• Mixed areas of sclerosis and lysis – on the x-ray will look like lots of opaque dark splodges in the bone
  • Seen in early disease
  • This can make differentiation between Paget Disease and malignancy difficult in the early stages of the disease
• Bone thickening and enlargement
  • Seen in later disease
  • Easier to differentiate
• Bone deformities
  • Bone bends anteriorly in the tibia
  • Bone bends laterally in the femur
• May also show what appears to be localised osteoporosis in areas of very high osteoclast activity – called osteoporosis circumscripta – this is particularly apparent in the skull
• MRI or CT may also be used to better define unusual bone lesions

Bone scan

• Increased isotope uptake in affected bones
• Often performed after the initial lesions has been diagnosed to assess the extend of the disease
• Any areas that appear to show ‘uptake’ on a bone scan should then be further investigated with x-ray to confirm if there is Paget’s disease at these sites

Urine

May contain collagen due to very high bone resorption

Differentials

• Bone malignancy
• Osteoarthritis
• Osteoporosis

Treatment

• Severe pain
• Nerve compression from expanding bone, or other neurological complications
• Fractures
• Asymptomatic disease with significant biochemical abnormalities, e.g.
  • ALP >2x normal
  • Raised ALP and Paget Disease at a site that commonly results in fracture (e.g. long bones, vertebrae or base of skull)
• In some cases it can be difficult to detainee if pain is arising from Paget Disease or osteoarthritis. In these patients, I trial of bisphosphonates may be indicated.

Bisphosphonates are the ‘mainstay’ of treatment. They inhibit osteoclast activity, and cause osteoclast apoptosis. They damage the cytoskeleton of the osteoclast, so the cell is then unable to bind to bone, and to perform its bone resorption duties.

Serum calcium and vitamin D levels should be checked before therapy is initiated and all patient should be started on supplemental vitamin D (1,000 international units daily) and calcium (this often comes combined).

Bisphosphonates are often able to induce disease remission. Typical regimen will last 2 months. The agents described below are sometimes called the “newer” bisphosphonates, or the “nitrogen containing bisphosphontes”. Older agents are less effective and rarely used.  Options include:

• Zolendronic acid
  • Given via IV infusion – e.g. 5mg given on 15 minutes
  • Induces remission for up to 2-3 years after a single dose
  • Usually first line choice – more effective than oral agents
  • Up to 90% remission rate, <1% relapse rate
  • Resistance can develop after multiple doses
  • Can cause flu-like symptoms after first dose
  • Pamidronate is an alternative IV bisphosphonate but is less effective (“older” bisphosphonate). It may be considered if resistance has developed to zolendronate
• Oral therapy – e.g. risedronate, alendronate
  • May be considered in younger patients or those with less severe disease
  • About 60% remission rate, 20% relapse rate
  • Usually oral doses are given daily for a limited period – e.g.:
    • Risedronate 30mg daily for 2 months
    • Allendronate 40mg daily for 3-6 months
  • Much more cumbersome dosing than the IV preparations:
    • Must be taken with water
    • No food should be taken for at least 30 minutes afterwards
    • Patients should not lie down for 2 hours after taking them to avoid oesophageal irritation and gastroesophageal reflux
  • Any required dental work should be performed before initiation of therapy as this reduces the risk of a rare but serious side effect of bisphosphonates – oestonecrosis of the jaw
• Calictonin
  • Can be used in patents who do not tolerate bisphosphonates
  • Does not induce remission but can reduce disease progression
• Adverse effects of bisphosphonates
  • Osteonecrosis of the jaw – extremely rare in the short durations of therapy used in Paget Disease. Approximate risk is 1 in 100 000
  • Bone Pain
  • Flu-like symptoms – transient, occurs in 25% of patients

• Simple analgesia – e.g. paracetamol 1g QID, ibuprofen 400mg TDS PRN
• Orthoses – braces, usually plastic that support and protect a bone
• Orthotics – show inserts that help to correct deformity and altered gait
• Analgesia
• Education
• Treat the complications – e.g. joint replacement, hearing aids, physiotherapy

Ongoing Management

• Consider repeating ALP at 3-6 months to assess the effectiveness of treatment
• Repeat annually
• Initiate treatment again when ALP starts to rise or patient becomes symptomatic again

Complications

• Increased risk of bone tumours – particularly osteosarcoma
  • Incidence of up to 1% of PBD patients
  • Consider this in lesions that do not respond to medical therapy – particularly pain
  • If osteosarcoma develops it is often advanced and fatal
  • More common in long standing disease

Flashcard

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Paget Disease of the Bone – UpToDate
• Paget Disease of bone – AFP

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Epidemiology

• Mean age of onset between 45-60
• Prevalence is 0.5-1% of the over 60’s in the UK
• 2nd most common neurodegenerative disease (after Alzheimer’s)

Aetiology

Pathology

Clinical features

• Tremor – usually of the hands @ 4-7Hz. Disappears with deliberate activity.
• Bradykinesia – slow movements. Fine motor movements are particularly badly affected
• Rigidity – increased resistance to passive movement. Sometimes called ‘lead pipe rigidity’. Rigidity is equal throughout the range of movement (unlike spasticity – which is velocity dependent ). Rigidity is also equal in both extensors and flexors – unlike spasticity.
  • Sometimes called cogwheel rigidity – as the rigidity temporarily gives in certain ranges of movement – as if you are moving a cog (the result of tremor plus rigidity).
  • Note that power remains normal, and there is no sensory loss.
• Posture and Gait – slow shuffling steps gait. Often stooped, with reduced arm swinging. Narrow based.
• Speech – may be slow and monotonous. In late stage disease may be slurred, or even lost.
• Plain face / facial stare. This effect is exaggerated by a reduced blinking rate.
• Depression – many Parkinson’s patients also suffer from depression. If this is present in the early stages, then the plain face symptom of Parkinson’s may be confused with a withdrawn emotional state often seen in depression.
• Dementia – is also often associated with PD – probably because in many cases, the degeneration seen in the basal ganglia is also found in other areas of the brain.
• Hallucinations are common, and are thought to be a combination of both the disease and the drugs used to treat it. Often they are not unpleasant.

Differentials and other causes of Parkinsonism

• Alzheimers
• Multi-infarct dementia
• Repeated head injury e.g. in boxers
• The VODKA signs:
  • V – vascular events – e.g. stroke, MI
  • O – orthostatic hypotension with atonic bladder – can be caused by multi-system strophy (MSA)
  • D – Dementia with vertical gaze paralysis – could be a supranuclear palsy.
  • K – Kayser-Fleisher rings – Wilson’s disease (causes cerebellar dysfunction)
  •  A – apraxic gait – communicating hydrocephalus

Investigations and Diagnosis

Treatment

Drugs

• Efficacy decreases over time
• ‘On-off effect’ at the end of the dose
• Nausea / GI Upset
• Dyskinesias
• Psychosis
• Compulsive behaviours – often related to gambling, money or sexual behaviour.

• Nausea
• Hallucinations
• Drowsiness

• Postural hypotension
• AF

Other treatments

Surgery

Tissue transplant

More Information

Epidemiology

• Usual onset between the age of 45 and 60
• Affects 0.5-1% of the population over the age of 60.

Aetiology

Pathology

• Lewy bodies are occasionally widespread throughout the brain – in which case they are associated with dementia – diffuse Lewy body disease.

• In rare circumstances, often times of great emotion, patients report that their symptoms disappear for a very short time – for a few seconds or minutes.

• Bradykinesia – this sign of PD is directly related to the lack of dopamine
• Other signs of PD – e.g. tremor and rigidity – these are more complex, and complex mechanisms involving other NTs are involved. For example, neurons in the corpus striatum release ACh, whose release is normally inhibited by dopamine. In PD, there is not this inhibition, so these neurons release too much ACh.

Clinical features

• Tremor
  • Usually most and first apparent in the hands. Usually rolling tremor of about 4-7Hz. Disappears with activity. Most apparent as the thumb rolls over the forefinger (pill rolling tremor)
• Bradykinesia
  • Rapid, fine motor movements (e.g. picking up/using tools, playing the piano) are particularly badly affected.
• Rigidity
  • Increased resistance to passive movement. Sometimes called lead pipe. Rigidity is equal throughout the range of movement (unlike spasticity – which is velocity dependent ). Rigidity is also equal in both extensors and flexors – unlike spasticity.
  • Sometimes called cogwheel rigidity – as the rigidity temporarily gives in certain ranges of movement – as if you are moving a cog.
  • Note that power remains normal, and there is no sensory loss.
• Posture and gait:
  • Shuffling gait
  • Stoop
  • Reduced arm swigning
  • Narrow base
  • Often the signs are unilateral initially, but as the disease progresses, will become bilateral.
• Speech – normal tone is lost. Becomes monotonous, and may lose normal scanning quality. Later in the disease, there may be slurring, and even complete loss of speech.
  • Plain face / facial stare. This effect is exaggerated by a reduced blinking rate.
  • Skin – may become greasy and sweaty
  • GI problems – heartburn, dribbling, dysphagia, weight loss and constipation.
  • Depression – many Parkinson’s patients also suffer from depression. If this is present in the early stages, then the plain face symptom of Parkinson’s may be confused with a withdrawn emotional state often seen in depression.
  • Dementia – is also often associated with PD – probably because in many cases, the degeneration seen in the basal ganglia is also found in other areas of the brain.
  • Hallucinations are common, and are thought to be a combination of both the disease and the drugs used to treat it. Often they are not unpleasant.

Questions to ask in the history

• General lethargy and tiredness
• Problems using tools
  • General problems with dexterity
• ‘Freezing’ – often whilst walking the patient may suddenly stop. This is particularly apparent at times when hesitation is normal, e.g. when turning, or when going through a doorway
• Difficulty rolling over in bed
• Ask them about their handwriting
  • Typically it becomes smaller, and more spidery (micrographia). You may want to ask them to write their name and address to show you their writing, or draw a spiral. Keep in the notes to compare at future visits.
• Anosmia – start by asking if they have noticed any changes in their sense of smell. See below for how to examine
• Violent dreams – patients with PD may act out their dreams whilst laid in bed – particularly violent ones. This may involve arm swinging and legs kicking (REM behaviour disorder). Often their partner will sleep in a different bed.
• Visual hallucinations – usually these are not distressing, and many patients find them intriguing. For example, may involve seeing animals walking around the room, or seeing a hat stand, and thinking it is a person.

Differentials

• Alzheimers
• Multi-infarct dementia
• Repeated head injury e.g. in boxers
• Drugs
  • Neuroleptic drugs – haloperidol, chloropromazine – these drugs block dopamine receptors.
  • Dopamine reducing drugs – e.g. reserpine
• The VODKA signs:
  • V – vascular events – e.g. stroke, MI
  • O – orthostatic hypotension with atonic bladder – can be caused by multi-system strophy (MSA)
  • D – Dementia with vertical gaze paralysis – could be a supranuclear palsy.
  • K – Kayser-Fleisher rings – Wilson’s disease (causes cerebellar dysfunction)
  • A – apraxic gait – communicating hydrocephalus

Investigations

• MRI – is usually normal
• Dopamine transporter imaging – is a fancy new test (not available in many places) is not very useful

Treatment

Drug treatments

• L-Dopa is naturally very short acting
• Take with food to avoid nausea vomiting
• Usual dose is around 800mg/24hr in divided doses, but get up to this level gradually
• Usually, L-Dopa is given with carbidopa (cobeneldopa), entacapone or benserazide. These are agents that decrease L-dopa metabolism and thus prolong the half-life of L-dopa.
  • These also reduce the dose needed by about 90%!

• Nausea  /GI upset / diarrhoea
• Unwanted movements – dyskinesias
  • These usually occur in the face and limbs, and occur at the peak therapeutic effect, thus the line between therapeutic and high dose is fine.
• Hypotension
• Arrhythmia
• Psychosis and other psychological effects. These are a direct result of increased dopamine levels in the brain. More common psychological effects include:
  • Confusion
  • Disorientation
  • Insomnia
  • Nightmares
• Compulsive behvaiour
  • Gambling
  • Spending
  • Inappropriate sexual behaviour
• On-off effect – related to the fluctuating plasma concentration of L-Dopa. The effect is seen more often the longer the drug has been used. It is also seen in untreated patients. This leads to occasions where the drug is effective, and periods where it is not effective at all, and the symptoms of PD dramatically return. This usually occurs at the ‘end of dose’  – i.e. in the hours as the drug is wearing off, but before it is time to take the next dose. You can try to reduce the on-off effect with slow release L-dopa (poor evidence). Often the on-off effect can never be eliminated once it has occurred.

• They are also now often used as adjuncts to L-DOPA in patients of any age.

• Drowsiness
• Hallucinations
• Nausea

• Hallucinations
• Hypotension
• Nausea / vomiting
• Fibrosis (rare)
• Drowsiness

• In the early stages of PD it may help to slow the progression of the disease (controversial). If given at diagnosis, the mean time at which patients start L-DOPA is 18 months (normal 10-12). Long-term outcome is not altered.
• Used widely as an adjunct to L-DOPA, helps to reduce the dose of L-DOPA, which in turn reduces the side-effects, and increases the long-term effectiveness of L-DOPA.
• As it is selective for MAO-B, it lacks many of the side effects seen in the MAO inhibitors used to treat depression. It does not cause the ‘cheese-effect’ or cause many drug interactions.

• Postural hypotension
• AF

• Urinary retention
• Angle-closure glaucoma, GI obstruction
• Prostate problems

• Dry mouth
• Dizziness
• Urinary retention
• Anxiety
• Confusion
• Tachycardia
• Hallucinations
• Insomnia
• Memory problems

Other treatments

Surgery

Tissue transplant

Other causes of Parkinsonism

Flashcard

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy

Read more about our sources

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Presentation

• Abdominal pain in the epigastric region. For DU’s, the pain is when you are hungry, and GU’s the pain is when you eat. This is because when you are hungry, you produce acid in anticipation of food (the cephalic phase), which is then washed straight into the duodenum and isn’t buffered. When you eat, the food buffers the acid, and so the pain is reduced. In GU, the pain is greater when you eat due to the physical pressure of food on the ulcer. DU pain is present at night as well as in the day.
• Nausea may accompany the pain, and although vomiting is infrequent, it will often relieve the pain.
• Weight loss may be present, particularly in gastric ulcers.
• Left untreated, the symptoms of DU follow a spontaneous relapse and remission course
• Examination is not always that helpful, as there is nearly always general tenderness in all dyspepsia’s.
• History of NSAID’s / alcohol / steroids

Investigations

• Urea breath test to test for presence of H. Pylori
  • Patients will swallow urea that is labelled with an uncommon isotope – i.e. carbon 13 or 14. Usually Carbon 113 is used as it is non-radioactive. Then 10-30 minutes later, a breath sample is taken to measure the amounts of exhaled carbon dioxide containing the labelling isotope. The sample is measured using a mass-spectrometer, which is expensive, but is highly sensitive (97%) and specific (96%). This indicates that the urea has been split up and the carbon absorbed by the body. The urea is split by the enzyme urease which is present in H. Pylori, and thus this indicates the presence of H. Pylori.
  • Often a baseline sample of carbon dioxide is taken before the labelling isotope is given and then the two results compared.
  • There are also urea splitting bacteria in the colon that will cause the labelled carbon to be present in exhaled air about 5 hours after ingesting the urea.
• Serological tests for IgG. These are useful for confirming the presence of H. Pylori, but not as accurate as the breath test. It is about 90% specific. It can take over a year for IgG levels to fall below 50% of their original value even after H. Pylori eradication, so this is not a useful test to see if the infection has been eradicated. Antibodies can also be found in the saliva, but these are nowhere near as accurate as serology.
• Stool test. This is a highly sensitive (96%) and specific (97%) immunoassay that will detect the presence of H Pylori, and can also be used to see if H Pylori has been eradicated. PPI’s must be stopped one week before the test for eradication. This is now often the first line test.

Invasive

• Endoscopy. (OGD) This will confirm the presence of an ulcer by sight, but a sample of gastric mucosa may also be taken. This can be tested in three ways:
  • Put in a urea solution containing Phenol red. If H. Pylori is present, then the urea will be rapidly split to release ammonia, and the solution will increase in pH and change colour. This is known as the rapid urease test.
  • Cultured and tests against various antibiotics
  • Looked at histologically.
• FBC – to check for anaemia
• U+E – rarely shows up Zollinger-Ellison syndrome
• Faecal occult blood
• Barium meal test – sometimes used in patients who are unable to tolerate endoscopy.

Causes

Pathology

• These are usually held responsible for the ulcers where H pylori infection is absent (about 25%). They inhibit cyclo-oxygenases (COX), which are enzymes that enable the production of prostanoids (prostaglandins and thromboxanes). There are 3 variants of COX, 1,,& 3. COX-1 is involved with protection of the gastric mucosa, and it is sometimes called the ‘housekeeping’ enzyme, due to its role in every day wear and tear repair.
• Ultimately, NSAID’s inhibit prostaglandin formation and so reduce the ability of the stomach to heal itself. Small abrasions to the lining of the stomach that occur all the time, and would normally heal are now less likely to heal. Pepsin may also act on these abrasions, and ulceration may possibly occur.
• The major repair pathways that prostaglandins affect are:
  • Bicarbonate secretion into the mucous layer
  • Tight junction maintenance between gastric cells to prevent lumen contents getting between the cells
  • Gastric bloodflow – delivering lots of bicarbonate ions to buffer to acid to the gastric cells.
• Taking long term aspirin makes you 3x as more likely to get an ulcer, and other NSAID’s have a similar effect. Take them both together and your risk is 10x greater!

Treatment

• The patient is under 55 and has tested positive for H. Pylori
• The patient is over 55 and testes have confirmed a gastric ulcer is responsible for their symptoms.
• The patient has no significant underlying pathologies (e.g. cancer) but H. Pylori is present. This is slightly controversial as it has been implicated in GORD, but it is still recommended.

• First line therapy – Triple therapy – patients will be treated with a proton pump inhibitor, and two antibiotics. An example would be:
• Omeprazole 20mg + metronidazole 400mg + clarithromycin 400mg  All twice daily.
• Omeprazole 20mg + metronidazole 400mg + amoxicillin 1g  All twice daily.
• There is very high resistance for metronidazole (25%) and that is why another antibiotic is taken.  This regimen should be followed for 7 days, and then a PPI taken for a further 3-4 weeks.

Complications

• Perforation
• Haemorrhage – this is a result of an ulcer being in an ‘unlucky’ place, and as it gets deeper, it comes across a blood vessel. This can be quite serious if it is a relatively major vessel, and result in anaemia.
• Penetration of adjacent organs
• Anaemia
• Malignancy

Perforation

• Sudden onset severe abdominal pain. At first pain may be localised to the upper abdomen, but it quickly spreads and becomes generalised.
• If the pain radiates to the back, then it is likely to be a posterior duodenal ulcer.
• Localised or generalised peritonitis. Very tender to the touch. You can tell if someone has peritonitis as opposed to a different cause of abdominal pain because if they have peritonitis they will want to lie very still, but with other causes of pain, they may ‘writhe’ around in pain.
• Signs of SIRS (systemic inflammatory response syndrome).
• Breathing will be shallow due to diaphragmatic pain and shock.
• The abdomen will be immobile with board like rigidity.
• Bowel sounds are absent, and the dullness over the liver may not be there due to the prescence of gas in the abdominal cavity
• After a few hours, the initial symptoms may die down, but there will still be the rigidity. Over a longer period of time, the patien’s condition will deteriorate due to peritonitis.
• Perforation has a mortality rate of 25% – this is dependent on the patient’s age and other factors.
• The main problem with a perforated ulcer is that it will cause peritonitis.

Investigations

• X-ray may show gas under the diaphragm (in about 50% of cases)– pneumoperitoneum – shown below by the distinctive lines underneath the diaphragm. Don’t get this confused with air in the stomach, which is perfectly normal and most commonly seen after a recent meal. It is important when taking an x-ray like this that the patient has been sat upright for at least 10 minutes beforehand and is sat upright when the x-ray is taken Otherwise you will not be able to see any air! Sitting like this may be uncomfortable for the patient.

Management

• After resuscitation then the perforation will be treated surgically – it will be closed by being sewn up, and then part of the greater omentum may also be sewn over the affected area – the omentum is still attached to the rest of itself! If this is not possible, then a pyloroplasty may be made from the perforation.
• A pyloroplasty is where the pyloric sphincter of the stomach is widened. It allows quicker emptying of the stomach in people at high risk of PUD and is sometimes performed before an ulcer has perforated. In this case it is performed because sealing up the perforation is too difficult, and it is a treatment that may have beneficial effects for the patient by reducing the risk of future ulcers.

Complications (of surgery)

• Peritonitis

• Chest infection from aspiration during intubation
• Wound infection

• Adhesions. These can occur years after surgery and will ofte4n cause obstruction of the bowel. They are much lea common with key hole surgery than with open surgery – probably due to the reduces physical moving of the bowel by this type of surgery.
• Keyloid scarring – this is where a big thick scar develops over the site of the incision and is virtually impossible to get rid of. You can get rid of it by cutting it off, but it is very likely to grow back again just the same.

Flashcard

References

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