Facial Pain

A 64 year old woman presented with a history of "2 years (yes years) of heaviness in her chest (worse over the past 2 weeks), 2 weeks of nausea, intermittent subjective "numbness and tingling" in both hands and feet, and "severe pressure" behind her left ear which felt like someone was "sticking a knitting needle" into her ear. The ear pain radiated into the left side of her jaw. There was no hearing deficit and no tinnitus. There was a background of dysthymia and fatigue. She had seen an ENT specialist who was not able to provide an explanation or any treatment for her pain and she was distressed that he had "taken her money and didn't want to see her again. She had previously been diagnosed as having eustachian tube dysfunction but did not find this diagnosis very satisfactory. Overall she seemed dysthymic with a flavour of "learned helplessness". A bit of a "heart sink" presentation but doesn't mean that she shouldn't have a comprehensive and rational assessment of her presenting complaint (s)

There were no recent bloods to identify cardiac risk factors such as cholesterol or diabetes.
BP was 160/90.
ECG was "normal"
Troponin was negative and other bloods were noncontributory. Auto-immune serology is still pending.
The patients usual GP had arranged an MRI for the following week of her neck and I added a request for brain and left ear imaging/ report.

I can't recall medications etc but here are the questions I particularly wanted to look up:

1. What are the causes of unilateral facial/ ear pain?
2. What is somatisation and what are other similar syndromes?
3. What are the diagnostic criteria of chronic fatigue?

I have taken most of the information below from Up To Date

What are the causes of unilateral facial pain?

"The causes are myriad, and misdiagnosis and mismanagement are common." Up To Date

CENTRAL CAUSES OF FACIAL PAIN

            Anasthesia dolorosa

Persistent, painful anaesthesia in the distribution of the trigeminal or occipital nerve. The patient has sensory loss (decreased sensation to pin-prick testing) but can feel pain. This may be a complication of thermocoagulation used to treat trigeminal neuralgia.

            Central Post Stroke Pain

Pain and altered sensation in any area of the face following a stroke.

            Facial pain cased by Multiple Sclerosis

Can occur unilaterlly or bilaterally

            Persistent idiopathic facial pain

This basically means the patient has facial pain but no one can find a cause.

            Burning Mouth Syndrome

Sensation of burning mouth for which no medical or dental cause can be found. There are a number of Internet sites for patients who have this syndrome. Generally there is a lot of associated distress and fear of not being taken seriously.

NEURALGIAS

Pain is usually severe at onset and is described as lancinating, "electric shocks," or as "jabbing." The pain can last a fraction of a second, or for several seconds. Some neuralgic conditions have trigger zones--areas that when stimulated provoke an attack.

            Glosso-pharyngeal neuralgia

Neuralgic-type pain in the region of the glossopharyngeal nerve (CN IX and X)

Glossopharyngeal nerve (IX)

Causes spasms of severe, stabbing pain of the ear, tonsillar fossa, base of the tongue, or beneath the angle of the jaw. Triggers include chewing, swallowing, coughing, speaking and yawning.
The pain spreads upward from the oropharynx toward the ear. The severe spasms last for seconds to minutes, but there may also be a mild constant background pain. The spasms may awaken the patients from sleep.

There are "idiopathic" and "secondary" forms of glossopharyngeal neuralgia. Secondary causes include demyelinating lesions, cerebellopontine angle tumor, peritonsillar abscess and carotid aneurysm.

The evaluation of a patient suspected of suffering from glossopharyngeal neuralgia includes a careful history, especially enquiring about the presence of trigger factors and nocturnal awakening.

MRA are indicated in virtually all patients to rule out a mass lesion or vascular pathology.

            Nervus intermedius neuralgia

A rare disorder characterized by brief paroxysms of pain felt deeply in the auditory canal. Also called geniculate neuralgia or Hunt neuralgia.

Nervus intermedius anatomy
 

This is a very RARE disorder.
The International Classification of Headache Disorders requires that all three of the following are present:

• Pain (otalgia) not due to another cause such as glossopharyngeal neuralgia.
• Pain paroxysms of intermittent occurrence, lasting for seconds or minutes, in the depth of the ear
• Presence of a trigger area in the posterior wall of the auditory canal

            Occipital neuralgia

Occipital nerve from Brown: Atlas of Regional Anesthesia, 3rd ed., Copyright © 2006 Saunders

 

Cutaneous fields of the head and neck (from Up To Date)

The cause is unknown but may result from occipital nerves getting squashed a bit by neck and scalp muscles.

Occipital neuralgia causes jabs of electric-shock like pain in the back of the head (usually on one side). the pain starts in the back of the neck (around C3) and spreads to the front of the head. There may be sensitivity/ tenderness over the branches of the nerve.

Occipital neuralgia
Pain starts in the neck and spreads forwards

Other causes of occipital neck pain include:

• Muscular problems (trapezius or sternocleidomastoid)
• C2 and C3 disc pathology (eg cervical discogenic pain from degeneration)
• C2 and C3 facet joint problems (often chronic following "whip-lash" like injury)
• Vertebral artery problems

An occipital nerve block is almost diagnostic. If the pain doesn't go away then there is most likely another diagnosis for the pain.

            Postherpetic neuralgia

Neuropathic pain following an episode of herpes zoster (shingles).

            Trigeminal Neuralgia (Tic douloureux)

A VERY COMMON cause of facial pain characterised by spasms of electric-shock like pain in the trigeminal distribution (V1 or V2 or V3). It is more common in women and is probably caused by the trigeminal nerve getting squashed by an artery. The nerve may also be compressed by an acoustic neuroma (or other tumor) or by an epidermoid cyst.

Secondary causes (such as tumor) are unlikely but may be present even if the neurological examination is normal (one studied found this to be the case 15% of the time).

Carbemazepine is the standard treatment

Baclofen may be useful. the starting dose is 5mg TDS with gradual titration to 50mg a day.

Sedation, dizziness, and dyspepsia can occur with treatment, and the drug should be discontinued slowly.

 

Adjunct therapy with lamotrigine (400 mg daily) may be helpful.

 

Surgical therapy is a possibility in refractory cases.

 

Other casues of unilateral facial pain

• Temporal arteritis (50% have claudication; pain may be in the temporal or occipital region; visual loss is a feared complication)

• Dental pain

• Cancer pain

 

What is somatisation?

The DSMV-IV-TR and ICD 10 both discuss somatisation/ somatiform disorder.
Essentially the patient presents with one or more medically unexplainable symptoms. The symptoms usually lead to significant impairment in functioning. Patients are often preoccupied with their symptoms. It is very common in women, especially those who are poorly educated and marginalised. There is often a history of childhood sexual abuse or violence.

What are the diagnostic criteria of chronic fatigue?

Everyone seems to present differently but there are some commonalities: Onset of fatigue is sudden and may follow a mild infection (such as "the flu" or EBV) Following the infection the patient is overwhelmingly fatigued and suffers from disordered sleep and cognition ("cotton wool brain") Physical activity makes things worse Usually these patients have been very high functioning and not the "heart sink" malingering type with chronic back pain etc. Having said this, there may be a history of psychiatric problems in the past. CFS is defined by the CDC as unexplained, persistent or relapsing fatigue that is of new or definite onset; is not the result of ongoing exertion; is not alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social, or personal activities

and

Four or more of the following symptoms that persist or recur during six or more consecutive months of illness and that do not predate the fatigue:

Self-reported impairment in short term memory or concentration

Sore throat

Tender cervical or axillary nodes

Muscle pain

Multijoint pain without redness or swelling

Headaches of a new pattern or severity

Unrefreshing sleep

Post-exertional malaise lasting ≥24 hours

A complex case

Ankylosing Spondylitis managed with biological therapy (etanercept)--high index of suspicion in a patient presenting with a peri-orbital rash

Mr Smith is a 30 year old man who works full time in local government. His position often requires him to travel to remote communities. He presented with very mild tenderness and slight erythema in an arc under his right eye lid. The rash was not painful to touch but ached at times and his right eye felt dry. The sensation was "completely different" to his previous recurrent outbreaks of "cold sores" on his lips and nasal mucosa. There was no visual disturbance.

PMHx

• Ankylosing Spondylitis
• Psoriasis
• Recurrent HSV1 (herpes labialis/ "cold sore") outbreaks on lips and nasal mucosa

Medications

• Valcyclovir 1g BD (under care of a virologist)
• Etanercept 50mg s/c twice a week

On examination

Mr Smith looked well but anxious. He was afebrile and well hydrated.
Visual acuity was 6/5 in the right eye and 6/6 in the left.
There was no foreign body
Fluroscene staining did not show any ulceration

The skin under the right eye was a salmon pink colour and looked almost like the dry rash of psoriasis. There were no vesicles. There was very slight "puffiness" of the lower eye lid.

Initial management

I treated him with oral antibiotics for early peri-orbital cellulitis and asked him to return for review in 1 to 2 days if there was no improvement.

Follow up Mx

He returned for review and described that the area was becoming more painful but lacked the neuropathic pain and tingling associated with his usual HSV1 outbreaks.

On examination this time there was the appearance of dry raised areas/ ? early vesicles under the right eyelid. The medial aspect of the eye appeared slightly inflamed.

I took a viral swab. and contacted the opthalmology registrar who said it wasn't his field and to talk to a dermatologist!.. After some convincing he was able to say he agreed with the management plan of continuing the antibiotics and changing the antiviral to aciclovir 800mg orally 5x a day for 7 days.
A few days later he presented on the weekend and saw a colleague who was concerned about the appearance of his eye and the increasing pain. Another discussion with the reluctant ophthalmology registrar led to the initiation of aciclovir 5% cream being added.

When I phoned the patient after the weekend to advise that the viral swab had come back positive for HSV1 and to see how he was going he reported that the lesions were improving and there were no concerning eye symptoms.

Questions

1. What is the role of biologic therapies in ankylosing spondylitis?
2. What precautions must be taken with a patient on biological therapies?
3. What is the difference in presentation and pathophysiology of herpes simplex, herpes zoster and varicella zoster?
4. What is the recommended treatment for each (adults, children, pregnancy)?
5. Explain briefly the presentation, investigation ad management of ankylosing spondylitis?

Answers below come from Australian Doctor 2008 Managing Ankylosing Spondylitis, and RACGP Australian Family Physician.

What is the role of biologic therapies in ankylosing spondylitis?

There are a range of "biologic therapies" but those listed in Australia for the treatment of ankylosing spondylitis are:

1. Infliximab (Remicade. IV)
2. Adalimumab (Humira. Sub cut) 
3. Etanercept (Enbrel)

The are drugs which are directed against tumor necrosis factor (TNF) alpha. TNF alpha is a pro-inflammatory cytokine responsible for inflammation in a number of chronic disease states.

Both infliximab and adalimumab are anti TNF α monoclonal antibodies that bind specifically to human TNF α and nuetralise the biological activity of TNF-α by in stopping it binding to its receptors. They do not bind to TNF-Beta.

Etanercept works differently--it acts as a "decoy receptor" to competitively inhibit the binding of TNF to its genuine receptor. Etanercept binds to both TNF-alpha and to TNF-beta rendering them biologically inactive by inhibiting their interaction with cell surface TNF receptors.
 As a group, all of the anti-TNF therapies are effective for treating the symptoms of ankylosing spondylitis, with dramatic improvements in spinal pain, spinal stiffness, fatigue, peripheral joint inflammation, physical function and quality of life. Anti-TNF alpha therapy also reduces the occurrence of uveitis flares associated with ankylosing spondylitis

How do patients qualify for anti TNF alpha therapies?

• These medications can ONLY be prescribed by specialists
• Patients must have severe active ankylosing spondylitis with a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of at least four.
• They must fulfil the modified New York classification criteria* for ankylosing spondylitis, which includes at least grade 2 bilateral or grade 3 unilateral sacroiliitis on X-ray.
• Patients must also have documented failure of at least two NSAIDs and an appropriate exercise program for the entire three months before assessment.
• C-reactive protein and/or ESR must be elevated no more than four weeks before assessment.
• Once therapy has been established, the patient needs to show a significant improvement in both BASDAI and inflammatory markers to be able to continue on the drug. 

* Modified New York criteria for classification [9]

Definite AS if criterion 4 and any one of the other criteria are fulfilled.

1. Low back pain of at least 3 months' duration that is improved by exercise and not relieved by rest.
2. Limited lumbar spinal motion in sagittal and frontal planes.
3. Chest expansion decreased relative to normal values for sex and age.
4. Bilateral sacroiliitis grade 2 to 4, or unilateral sacroiliitis grade 3 or 4.

 

Table 2 (above) is from the RACGP AFP article Clinical use of anti-TNF-α biological agents

What precautions must be taken with a patient on biological therapies?

• Reactivation of TB has been reported so  pre-treatment screening with CXR and QuantiFERON-TB Gold assay is essential.
• The most important adverse effect is the increased risk of severe infection: patients on these medications are immunosuppressed. Be especially vigilant in patients already at increased risk of infection such as those with diabetes.
• The GP sould have a lower threshold for initiating antibiotic therapy when managing patients on anti TNF-alpha medications.
• Live attenuated vaccines must not be given.

Table 4 (above) is from the RACGP AFP article Clinical use of anti-TNF-α biological agents

What is the difference in presentation and pathophysiology of herpes simplex and varicella zoster?

            Herpes simplex virus type 1 (HSV-1)

Note most of this section uses information from Up To Date

Also called herpes labialis, is the cause of vesicular lesions "cold sores" of the mouth. HSV-1 can cause clinical disease in the genitals, liver, lung, eye, and central nervous system. These infections can be severe, particularly in the setting of immunosuppression.
Once the patient has been infected (this primary infection may not cause any symptoms) the virus lives dormant in nerve cell bodies until reactivated (by stress or another trigger factor).
The reactivation of the infection is usually preceded by pain, burning, itching and tingling. The outbreak may spread to other sites (near or far from the original infection) but recurrences are usually less severe each time.
Immunocompromised people are at risk of viral dissemination to the lungs or GI tract or CNS.

            OCULAR INFECTIONS

Primary ocular HSV infections occur in less than 5 percent of patients, but can cause significant morbidity due to keratitis and acute retinal necrosis.

            Keratitis

Recurrent HSV-1 keratitis is a leading cause of corneal blindness. HSV keratitis has an acute onset with pain, visual blurring, and discharge. Physical examination is notable for chemosis, conjunctivitis, decreased corneal sensation, and characteristic dendritic lesions of the cornea.

swollen conjunctiva (chemosis)

HSV Keratitis and dendritic ulcer

            Conjunctivitis and blepharitis

HSV-1 can present as a unilateral conjunctivitis and/or blepharitis with the development of vesicles on the lid margin. Associated symptoms include chemosis, edema of the eyelids, and tearing.

            MEDICAL TREATMENT of HSV KERATITIS

Topical glucocorticoids should not be used!!

Topical antiviral therapy has been the standard for treatment although oral antivirals are equally effective and may be more convenient.
When topical antivirals are used, a randomized trial found that concomitant treatment with oral agents does not improve the outcomes.
Improvement usually occurs within a week and no agent is better to any other.

Varicella Zoster

Primary infection is called varicella or chicken pox.
The reactivation of latent varicella is called shingles or "herpes zoster". This reactivation causes a painful, unilateral, vesicular eruption and happens mostly in adults over age 60.
Onset of varicella (ie chickenpox) during pregnancy can be a disaster for the foetus, but herpes zoster (shingles) had not been shown to cause congenital varicella.
The treatment of shingles (herpes zoster) is with standard antiviral therapy.
Aciclovir is thought to be safe during pregnancy if required.
Antiviral therapy should be initiated in all immunocompromised patients, even if they present after 72 hours.

Herpes zoster opthalmicus (shingles in the eye)

This is a serious sight-threatening condition, and is due to VZV reactivation within the trigeminal ganglion. An opthalmologist should be consulted.

Patients can develop conjunctivitis, episcleritis, keratitis, and/or iritis. Early diagnosis and treatment is critical to prevent progressive corneal involvement and potential loss of vision.

The standard approach to herpes zoster ophthalmicus is to initiate antiviral therapy (acyclovir, valacyclovir or famciclovir) to limit pain, corneal damage and anterior uveitis.
Intravenous acyclovir (10 mg/kg three times daily for seven days) is suggested in the patient whose sight is threatened or who is immunocompromised.
the Australian Therapeutic guidelines (antibiotic) suggest that the oral antibiotics can be supplemented with 3% aciclovir eye ointment 5 times a day.
 

Explain briefly the presentation, investigation and management of ankylosing spondylitis?

            Definition
Ankylosing spondylitis is a chronic, systemic, inflammatory rheumatic condition primarily affecting the spine and sacroiliac joints.
            Incidence
It affects up to 1.4% of the population and affects three times more males than females.
            Presentation
It typically presents as insidious chronic pain in the lower back and buttocks in a young man, along with morning stiffness that improves with exercise.
            Later features
These include extraspinal joint pain and enthesitis (inflammation at sites where tendons or ligaments insert into bone), increasing stiffness and altered posture, and other organ involvement: acute anterior uveitis (iritis), cardiac abnormalities, chest symptoms (apical pulmonary fibrosis), renal symptoms (analgesic abuse nephropathy, IgA nephritis and secondary amyloidosis), GI symptoms (ileal and colonic mucosal ulcers).
            Diagnosis
Clinical:
Reduced range of low back movement, increased occiput to wall distance, reduced chest expansion, sacroiliac joint tenderness and signs of other joint involvement.
Laboratory:
Positive HLA-B27, raised ESR and C-reactive protein, and normocytic normochromic anaemia.
Radiological:
Sacroiliac joint changes on plain films, sacroiliitis on CT or MRI scan, spinal changes.
Trial of therapy:
Marked response to NSAIDs.
            Differential
(Rheumatoid arthritis in different joints [not HLA-B27 positive]), reactive and psoriatic arthritis, spondyloarthropathy with inflammatory bowel disease, diffuse idiopathic skeletal hyperostosis.
            Treatment
Exercise and physiotherapy; simple analgesics; NSAIDs including aspirin; anti-TNF therapy (eg, infliximab, adulimumab and etanercept); other drugs (eg, methotrexate, sulfasalazine and glucocorticoids).

A note on anterior uveitis (Iritis)

The causes can be

1. infectious (herpes simplex; herpes zoster; Syphilis; TB)
2. autoimmune (eg ankylosing spondylitis)
3. idiopathic

Clinical presentation

1. pain
2. photophobia
3. redness (ciliary flush, in a deeper level than conjunctivitis)

Iritis

Not all red eyes are conjunctivitis!!! (although this is the most common).

Causes of red eye may be from inflammation of any area in the anterior segment and include:

1. Conjunctivitis
2. Keratitis/ episcleritis/ anterior scleritis
3. Iritis (anterior uveitis)
4. Acute angle closure glaucoma

These can be differentiated by looking at the location and colour of the inflammation, as well as considering associated symptoms.

A patient with anterior uveitis will have an inflamed iris and ciliary body. The pupil may be irregular because parts of the iris can be "stuck down" with inflammation. refer for specialist slit-lamp examination.

Here is a proforma for examination of the unilateral red eye:

Unilateral red eye  

Patient name________            Date________ 

Medical history
	Yes	No
Visual deterioration
Trauma
Discharge and type
Photophobia
Contact lens wearer
Previous eye surgery

Tick points covered in examination:

­­­__General inspection of the cornea, sclera and lids

 __Lids everted to look for sub-tarsal foreign bodies

__Examine for pre-auricular nodes

__Check the visual acuity in both eyes with glasses and/or pinhole

__Examine the pupils. Check the shape and the light reflex, look for a relative afferent papillary  

    defect (RAPD)

__Examine the cornea using fluorescein 1% drops looking for corneal ulcers/abrasions

Warning features present?

•       Contact lens wearer                                                                                       yes/ no

•       Previous eye surgery or refractive surgery                                                    yes/ no

•       Decreased vision                                                                                           yes/ no

•       Severe pain                                                                                                    yes/ no

•       Nausea and vomiting                                                                                     yes/ no

•       Cloudy or opaque cornea                                                                               yes/ no

•       Dendritic ulcer                                                                                                 yes/ no

•       Hypopyon (pus in the anterior chamber)                                                        yes/ no

•       Nonreactive pupils or RAPD                                                                           yes/ no

•       Ocular trauma                                                                                                 yes/ no

•       Persisting or worsening symptoms                                                                 yes/ no

 Sight-threatening conditions presenting with painful red eye

Condition	Clinical clues	Interim management	Urgency (ophthalmological review)
corneal foreign body	history (especially high velocity) pain on lid movements photophobia visual acuity impaired	check for indication of penetrating injury immobilise head remove visible foreign body under slit-lamp examination and topical anaesthesia antibiotic drops and cycloplegic if required for pain review next day unless symptoms completely resolved	refer if suspicion of penetrating eye injury, inadequate removal, especially rust-ring, or if symptoms persist more than 2 to 3 days despite apparently full removal
bacterial infectious keratitis (inflammation of the cornea)	risk factors: contact lens wear or corneal trauma mucopurulent discharge foreign body sensation photophobia white spots on cornea spots stain with fluorescein	swab for culture (but debridement required for adequate specimen) commence antibiotics in consultation with ophthalmologist withhold antibiotics if same-day ophthalmological review possible, as may mask culture results from later debridement	same day—emergent (implies potential to change or worsen rapidly)
viral     infectious keratitis (inflammation of  the cornea)	dendritic ulcer seen with fluorescein stain foreign body sensation photophobia watery discharge	commence topical antivirals see Herpes simplex keratitis or Ophthalmic herpes zoster	within 1 to 2 days
scleritis	severe boring pain, often waking patient from sleep may have history of inflammatory rheumatological disease sclera thickened, bluish-red discoloration globe tender to palpation	an oral NSAID, see Table 1.2 consultation with ophthalmologist	within 1 day
iritis (anterior uveitis)	photophobia and pain constricted pupil injection of radial vessels around limbus cells and flare in the anterior chamber adhesions of pupil to lens hypopyon, fibrin in chamber	pupillary dilatation and cycloplegia, see Table 14.25 commence topical prednisolone if advised by ophthalmologist	same day
hyphaema	blood 'level' in anterior chamber usually history of trauma: if not, consider non-accidental injury in child or blood dyscrasia	discuss with ophthalmologist rest, eye shield avoid aspirin, NSAIDs	same day (if advised by ophthalmologist)
hypopyon	visible pus or white blood cell 'level' in anterior chamber	dilate pupil and cycloplegia, see Table 14.25 obtain blood cultures if sepsis likely check for systemic factors related to sepsis (cause or complication)	same day—emergent
acute angle-closure glaucoma	severe eye pain and tenderness to palpation haloes around lights and reduced vision eye feels hard to palpation compared to contralateral eye severe vomiting and headache photophobia fixed, irregular mid-dilated pupil	immediate referral systemic analgesics and antiemetics commence treatment in consultation with ophthalmologist while awaiting transfer (see Acute angle-closure glaucoma)	same day—emergent

Haemachromatosis

Haemachromatosis

A new female patient presented with a history of recently diagnosed haemachromatosis. She is a 32 year old single woman who had initially presented to a 24 hour medical centre last year for investigation of fatigue. She was confused about venesection and the management of her disease. She did not know what genotype she was and had been told different things by various doctors ranging from advice to have venesection performed every 3 months to only having it done when her "iron levels" were high. Her last venesection was about 3 months earlier.
When I saw her she described 6 weeks of intense fatigue/ asthenia and left knee pain. She wanted to know if she could have a venesection to help with her fatigue and she had been reading about "something else that was given IV after the venesection" and wondered what this was.

PMHx

Bilateral ACL reconstructions following a skiing accident 5 years earlier.
Depression. currently well managed.
Menses age 8. regular but light periods.

Medications

Trifeme

Allergies

NKAD

Clinical questions this case raised for me...

1. What is haemachromatosis?
2. How does haemachromatosis affect women?
3. What is the difference between the gene types?
4. Is iron loading a likely cause for her fatigue?
5. Will venesection alleviate her fatigue?
6. what level of "iron" should we aim for?
7. What physical symptoms should I be looking for?
8. What is the likely course of the disease?
9. What was the "something else given IV" she had been reading about?
10. Can I perform a venesection and how do I do it?
11. What is the pathophysiology/ genetic abnormality that gives rise to HC?

These questions have been answered using Australian Family Physician and doi: 10.1182/asheducation-2006.1.36 ASH Education Book January 1, 2006 vol. 2006 no. 1 36-41                                   

What is haemachromatosis (HC)?

HC is iron overload leading to end organ damage through the interaction of environmental and genetic factors and not the presence of genetic predisposition. Only about 70% of C282Y homozygotes ever develop abnormal iron stores.
Only about 30% of men and less than 1% of women develop significant iron overload related disease (ie actual haemachromatosis).
You can be a C282Y homozygote without having haemachromatosis.

How does haemachromatosis affect women?

Clinically severe disease is less common in females because of menstrual blood loss and blood loss from pregnancy. Women usually present after menopause with symptoms of iron overloading where as men present from their early 30's.

What is the difference between the gene types?

HC is autosomal recessive. Genetic predisposition leads to disease in some but not all cases. More than 90% of hereditary haemachromatosis (HH) are due to homozygosity of C282Y. But not everyone who carries two copies of the C282Y gene will develop significant clinical morbidity. There are actually 4 types of genetic iron overload conditions and HFE haemachromatosis is only one of them.

Is iron loading a likely cause for her fatigue?

One of the main complications of iron overload is severe fatigue.

Will venesection alleviate her fatigue?

Probably...especially if there are no other comorbidities. However in the first 24 hours following venesection, patients can feel worse.

What do the iron studies mean?

• Anyone whom you suspect may have HC should have a fasting serum ferritin (SF) and transferrin saturation (TS).
• Increased transferrin reflects increased absorption and increased serum ferritin reflects increased body iron stores. Serum transferrin is often raised before ferritin becomes raised. Serum ferritin is also an acute phase reactant.
• If SF is high but TS is normal, hereditary haemachromatosis is unlikely...more likely SF is high due to inflammation/ infection.
• If SF is in the normal range in a person with HC, they may have some arthritis but are unlikely to have other symptoms.
• Mild iron excess corresponds to SF values < 500 μg/L, medium to 500–1000, and severe > 1000. This threshold of 1000 should be kept in mind since, beyond this value, severe clinical complications become very likely.
• If serum ferritin is >1000 mcg/ L you must refer to a liver specialist for mx to avoid cirrhosis.

NB there are three main confounding situation situations which make raised plasma ferritin difficult to interpret:

1. Alcholism
2. Metabolic syndrome and NASH
3. Inflammation

If any of these are present then consider MRI Ferrascan to estimate level of iron loading.

What level of "iron" should we aim for?

There are differences in the guidelines but aiming at getting serum ferritin between 50ug/ L to 200ug/ L is reasonable. Patients who present with serum ferritin >1000ug/L are at risk of cirrhosis and so the aim is for a lower serum ferritin to try and deplete the liver. They should see a specialist.

What physical symptoms should I be looking for?

Beware of HC in anyone who presents with marked lethargy and/ or arthralgia and/ or loss of libido. Physical examination may be normal if diagnosed early. If iron loading has progressed you may find liver cirrhosis, testicular atrophy and sore/ tender, swollen joints. (ND common causes of cirrhosis in Australia include NASH, alcoholic cirrhosis and hepatitis...HC is NOT a common cause of liver cirrhosis).

What is the likely course of the disease?

The potential sequaele of untreated iron overload include fatigue, arthritis, impotence, diabetes, fibrosis, cirrhosis and cardiomyopathy. Early diagnosis and Mx prevents complications and results in a normal life expectancy.

What was the "something else given IV" she had been reading about?

An alternative to venesection is desferrioxamine, a chelating agent, but this is expensive and so rarely used.

What do I need to know about venesection?

The Red Cross Blood Bank will do this if you ask them to. Note that the referring doctor remains responsible for the patients overall management.

Hb should be monitored every 2 weeks initially and serum ferritin every month when venesections are first started.

Management of venesections

Venesections should be commenced (even without symptoms) if ferritin > 300 μg/L in men; > 200 μg/L in women.

Induction Phase                          

• The venesections are usually performed on a weekly basis, although their frequency can be adapted to both the initial levels of hyperferritinemia and to the patient’s tolerance. The volume should be adapted to body weight: 7 mL/kg body weight, not exceeding 550 mL per phlebotomy.
• The goal is to obtain ferritinemia ≤ 50-200 μg/L.
• Efficiency is based on serum ferritin, checked on a monthly basis as long as ferritin levels remain above the upper normal limits (300 μg/L in men, 200 μg/L in women). Thereafter, testing should be performed every two venesections.
• Venesections should be held whenever hemoglobin values are < 11 g/dL. 

Maintenance therapy

• Maintenance treatment is based on phlebotomy every 1–4 months, according to the patient’s needs, and aims at maintaining the serum ferritin level ≤ 50 μg/L. The patient should understand that the management is based on ferritin values, which reflect the amount of stored iron, and that transferrin saturation levels can fluctuate and (probably) be acceptable as long as values remain < 75% (when the TS is below this threshold, no potentially toxic iron species are expected to be present in the circulation). This addresses a common misconception that transferrin saturation reflects the degree of saturation of the overall body in iron.
• Serum ferritin levels should be checked at least every two venesections
• hemoglobin monitored within the 8 days preceding each phlebotomy (checking this parameter immediately prior to the venesection may be of course the most simple procedure).

What is the pathophysiology/ genetic abnormality that gives rise to HC?

There is increased iron absorption across the intestinal mucosa. Humans don't have any compensatory mechanisms of iron excretion that can be activated: Normally iron is simply lost when intestinal cells shed away, and through blood loss like menstruation. HFE is the short-hand name for the gene (High Fe) that normally regulates iron uptake in healthy people. The protein encoded by this gene is called the HFE protein. This HFE protein normally forms a complex with beta-2 microglobulin and transferrin receptor 1 (TfR1). The C282Y mutation means that instead of this complex forming on the intestinal cells, the HFE gene gets trapped inside the cell--consequently, no iron is taken up by the TfR1. The body recognises this as a problem and so up regulates the "divalent metal transporter" on the brush border of the intestinal villus cells. The metal transporter then absorbes stacks of iron (way too much). There are other problems that the C282Y mutation cases including messing up the body's ability to monitor and regulate iron.

How is iron overload assessed and managed?

In the past assessment of iron overload was done using a liver biopsy but now there is new non- invasive MRI technology called Ferriscan which does the same job.
An initial course of 1 to 2 venesections per week should be done until excess iron is removed...and then once about 3 to 4 times a year to maintain normal iron stores.

NB 500mls blood contains 250mg iron.

How is the severity of haemachromatosis classified?

• Stage 0 = C282Y homozygosity without biochemical (normal plasma transferrin saturation and ferritin) or clinical symptoms.
• Stage 1 = C282Y homozygosity with increased transferrin saturation (> 45%) but normal serum ferritin values and no clinical symptoms.          
• Stage 2 = C282Y homozygosity with both increased transferrin saturation and ferritin (> 300 μg/L in men; > 200 μg/L in women) but no clinical symptoms. (Start Venesection)
• Stage 3 = C282Y homozygosity with increased transferrin saturation, increased ferritin, and clinical symptoms affecting the quality of life (asthenia, impotence, arthropathies, etc.).  
• Stage 4 = C282Y homozygosity with increased transferrin saturation, increased ferritin, and clinical symptoms manifesting organ damage predisposing to early mortality (cirrhosis with the risk of hepatocellular carcinoma, insulin-dependent diabetes, cardiomyopathy).

Other points:

• This patient had a number of family members who were found to have assymptomatic C282Y homozygotes. To prevent haemachromatosis in these family members, life-long venesection is recommended at 3 x per year.
• Patients should avoid alcohol while serum ferritin is raised
• Patients should avoid vitamin C supplements
• Patients can consider eating less red meat and this might decrease the number of venesections they require.
• Cirrhotic patients should undergo HCC surveillance every six months with hepatic ultrasound and serum alpha-fetoprotein measurement.
• In cirrhotic patients endoscopy should be considered to determine if varices or other evidence of portal hypertension that might require therapy are present.
• Arthralgia can sometimes get worse when venesections are initiated.

Clinical Guidelines

HAEMOCHROMATOSIS (Third edition) 2007

Clinical guidelines for the diagnosis and management of haemochromatosis published by the Digestive Health Foundation (Gastroenterological Society of Australia).

 

 

Hereditary haemochromatosis

Genetics in Family Medicine: The Australian Handbook for General Practitioners (2007)
National Health and Medical Research Council

Fact sheets

Ferriscan and haemochromatosis

Ferriscan is an MRI-based method of measuring liver iron concentration. It provides an accurate, accessible and safe method of assessing the presence and severity of iron overload.

Brochures and Information for Patients

Haemochromatosis (Haemochromatosis Australia)

Brochure published by Haemochromatosis Australia with brief information for patients about haemochromatosis and contact details for Haemochromatosis Australia.

You can order free copies of this brochure at publications@haemochromatosis.org.au.

Haemochromatosis Your Questions Answered

Booklet published by Haemochromatosis Australia with comprehensive consumer focussed information for patients about haemochromatosis. Co-authors include Professor Martin Delatycki, Professor Lawrie Powell, Professor John Olynyk and Dr Barbara Bell (ARCBS). 28 pages A5.

You can order free copies of this brochure at publications@haemochromatosis.org.au .

Hereditary Haemochromatosis

Fact sheet with particular emphasis on genetics of haemochromatosis published by the Centre for Genetics Information (Australia). 2007.

Iron Overload Fact Sheet

Fact sheet published by the Iron Disorders Institute (USA). 2 pages.

Online Training

Hemochromatosis (Iron Storage Disease)

Online training module produced by the Centre for Disease Control and Prevention (USA).