Haemachromatosis Flashcards
Haemachromatosis
Haemochromatosis: features
Haemochromatosis is an autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6*. It is often asymptomatic in early disease and initial symptoms often non-specific e.g. lethargy and arthralgia
Epidemiology
1 in 10 people of European descent carry a mutation genes affecting iron metabolism, mainly HFE
prevalence in people of European descent = 1 in 200
Presenting features
early symptoms include fatigue, erectile dysfunction and arthralgia (often of the hands)
‘bronze’ skin pigmentation
diabetes mellitus
liver: stigmata of chronic liver disease, hepatomegaly, cirrhosis, hepatocellular deposition)
cardiac failure (2nd to dilated cardiomyopathy)
hypogonadism (2nd to cirrhosis and pituitary dysfunction - hypogonadotrophic hypogonadism)
arthritis (especially of the hands)
Questions have previously been asked regarding which features are reversible with treatment:
Reversible complications
Cardiomyopathy
Skin pigmentation
Irreversible complications Liver cirrhosis** Diabetes mellitus Hypogonadotrophic hypogonadism Arthropathy
- there are rare cases of families with classic features of genetic haemochromatosis but no mutation in the HFE gene
- *whilst elevated liver function tests and hepatomegaly may be reversible, cirrhosis is not
Haemachromatosis - Reversible Cx: Example Question
A 57-year-old gentleman with presents to gastroenterology clinic for review. He has been investigated for haemochromatosis and is being told that this diagnosis is confirmed. On referral, he had a past medical history of previously unexplained cirrhosis with transaminitis, arthritis causing arthralgia and hypogonadism. He is due to be started on regular venesection. Which of his problems is most likely to improve with treatment?
Cirrhosis Transaminitis Arthritis Arthralgia Hypogonadism
The correct answer is transaminitis. Venesection aims to rapidlly remove the excess iron within the body but does not generally reverse established damage. Removal of one unit per week or two is normally effective to deplete of iron, and then the frequency can be reduced. Chronic damage to liver, joints and heart is normally irreversible, but acute injuries can respond well.
Usually irreversible
Cirrhosis
Arthritis
Improvement in Some Patients
Diabetes mellitus
Arthralgia
Hypogonadism
Usually Reversible
Transaminase Elevation
Fatigue
Source:
Burnett, A. K., D. Milligan, and R. Marcus. ‘Guidelines on Diagnosis and Therapy British Society for Haematology Genetic Haemochromatosis.’ British Committee for Standards in Haematology. Darwin, Feb. 2000
Haemachromatosis Diagnosis and Ix - Example Question
A 52 year-old man presents with a 3 month history of impotence, joint pains and malaise. His past medical history includes type 2 diabetes mellitus and hypertension. His current medication includes metformin, ramipril and amlodipine. He has a 30 pack-year history and drinks 15-20 units per week. His occupation is as a prison warden.
On examination of his abdomen, he has a palpable 2cm non-tender live edge. Otherwise heart sounds 1 and 2 are presents with no added sounds, his pulse in regular and his lung fields are clear.
Blood tests reveal:
Bilirubin 20 µmol/l ALP 462 u/l ALT 79 u/l γGT 98 u/l Albumin 37 g/l
What is the most appropriate diagnostic investigation?
Serum ferritin > Transferrin saturation index Caeruloplasmin Urinary copper MRCP
The most likely diagnosis in this patient is haemochromatosis, an autosomal recessive disease that presents with bronzed pigmentation, joint pain, impotence and fatigue. Late signs can include cirrhosis of the liver and diabetes. A fasting transferrin saturation of greater than 55% indicates iron accumulation and along with genotyping for the HFE gene, this would be the most appropriate investigation to establish the diagnosis of the disease.
Haemachromatosis - Investigation
Haemochromatosis: investigation
Haemochromatosis is an autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6*.
There is continued debate about the best investigation to screen for haemochromatosis.
general population: transferrin saturation is considered the most useful marker. Ferritin should also be measured but is not usually abnormal in the early stages of iron accumulation
testing family members: genetic testing for HFE mutation
These guidelines may change as HFE gene analysis become less expensive
Diagnostic tests
molecular genetic testing for the C282Y and H63D mutations
liver biopsy: Perl’s stain
Typical iron study profile in patient with haemochromatosis
transferrin saturation > 55% in men or > 50% in women
raised ferritin (e.g. > 500 ug/l) and iron
low TIBC
Monitoring adequacy of venesection
transferrin saturation should be kept below 50% and the serum ferritin concentration below 50 ug/l
Joint x-rays characteristically show chondrocalcinosis
*there are rare cases of families with classic features of genetic haemochromatosis but no mutation in the HFE gene
Mx of Haemochromatosis in Pregnancy - Example Question
A 24-year-old woman who is known to have haemochromatosis comes to the antenatal clinic for review. She is 12 weeks pregnant and wishes to keep the baby. On examination her blood pressure is 105/70 mmHg, her pulse is 67 beats per minute and regular. Cardiac function is normal and a liver biopsy from 6 months earlier shows no evidence of hepatic fibrosis.
Hb 120 g/l
Platelets 191 * 109/l
WBC 7.1 * 109/l
Ferritin 600 mcg/l
Which of the following is the most appropriate way to manage the haemochromatosis in pregnancy?
> Observation only Oral deferiprone Venesection once every two months Iron supplementation Vitamin C supplementation
Where the patient’s cardiac function is within the normal range, and as here there is no evidence of hepatic fibrosis on liver biopsy, there is no need for intervention in pregnancy for haemochromatosis. Once the pregnancy has been completed, both cardiac and liver function should be reassessed.
Deferiprone is an iron chelating agent normally used in the treatment of haemochromatosis.There is limited evidence to support its safe use in pregnancy, and the ferritin is only moderately elevated. In the presence of no significant end-organ damage, chelation therapy isn’t indicated, nor is venesection. Iron supplementation and vitamin C supplementation may risk a potentially damaging further elevation in ferritin.
There is current debate as to whether patients without cirrhosis ever require phlebotomy at all. Discussion points out that the major benefit has been demonstrated in patients with documented cirrhosis, unlike the patient described here. The lack of randomised controlled trial evidence in this regard is unsurprising given the prolonged nature of haemochromatosis with respect to progression. Post pregnancy this patient may be able to manage her ferritin levels with dietary measures alone.
Haemochromatosis - Mx: Example Question
A 42-year-old man attends gastroenterology clinic after being referred by his GP for assessment of deranged liver function tests. The patient denied experiencing any specific symptoms, but on close questioning revealed that he had been feeling increasingly lethargic and sleepy during his daily activities. He also reported suffering from intermittent generalised joint pains. The patient had not drawn a connection between these symptoms, attributing them all to getting older and the demands of his busy life at work and at home. Nevertheless, the patient had attended his GP for a ‘health check’ and abnormalities were noted on a set of screening blood tests.
The patient’s past medical history was generally unremarkable, significant only for a laparoscopic cholecystectomy performed 4 years previously as a treatment for recurrent biliary colic. The patient also stated that he had been told by his GP that his recent of blood tests showed that he suffered from ‘borderline diabetes’, but that he had not started any treatment for this at the present time. The patient took no regular or over the counter medications and had no known drug allergies.
The patient had been adopted as a young child and reported to not having much information about the medical history of his biological relatives. As an adult, he had briefly made contact with his biological father until his father had died as a result of complications of liver disease, but the patient stated he did not know the cause of his father’s condition. The patient was a former cigarette smoker who occasionally consumed moderate amounts of alcohol. He had never injected drugs, had a tattoo or received a blood transfusion. The patient lived with his wife and 3 young children and ran his own building company.
General examination of the patient indicated a caucasian middle-aged man who appeared tanned and slightly under-weight. Abdominal examination was significant only for 5 possible spider naevi on the patient’s upper chest. There was no palpable hepatomegaly or splenomegaly. Examination of the cardiovascular and respiratory systems was unremarkable. Please see below for investigation results arrange before and after the patient’s clinic attendance.
Haemoglobin 136 g / dL Mean cell volume 89.1 fl White cell count 6.5 x 10>3 / microlitre Platelets 385 x 10>3 / microlitre Urea 6.4 mmol / L Creatinine 91 micromol / L eGFR 89 ml / min / 1.73 m2 Sodium 145 mmol / L Potassium 4.3 mmol / L Albumin 48 g / L (reference 35-50) Alkaline phosphatase 124 U / L (reference 35-100) ALT 275 U / L (reference 3-36) Bilirubin 23 micromol / L (reference < 26) Total protein 68 g / L (reference 60-80) Ferritin 1,290 microgram / L (30-300) Transferrin saturation 87 % (15-45) HbA1C 46 mmol / mol (reference < 42) HFE gene analysis C282Y homozygous
What is the appropriate initial management of the patient’s condition?
Phlebotomy: 500 ml every 2 days > Phlebotomy: 500 ml every 2 week Phlebotomy: 500 ml every 2 months Watchful waiting: phlebotomy once ferritin > 2,000 microgram / L Watchful waiting: phlebotomy once ALT > 1,000 U / L
The patient has a non-specific clinical presentation typical for hereditary haemochromatosis. In particular, note the suggestion of the early stages of classical ‘bronze diabetes’: diabetes, skin pigmentation and liver cirrhosis. The clinical picture is supported by the elevated ferritin levels and elevated transferrin saturation. The diagnosis is confirmed by the patient being homozygous for the C282Y mutation of the HFE gene on chromosome 6 (the most common genotype associated with iron overload). The patient would also require additional investigation to assess for end-organ damage; for example, electrocardiography, echocardiography and liver biopsy or liver MRI.
Phlebotomy is the mainstay of treatment in hereditary haemochromatosis and is indicated in all patients with a ferritin level greater than 1,000 microgram / L. Typical initial phlebotomy regimes are 400-500 ml every 1-2 weeks. Once ferritin level falls to the range 50-100 microgram / L, phlebotomy regime can transition to a maintenance schedule every 2-4 months. Please note, that the incorrect answer of 500 ml phlebotomy every 2 days would lead to the patient becoming dangerously anaemic!
Haemochromatosis - Mx = PHLEBOTOMY
Phlebotomy is the mainstay of treatment in hereditary haemochromatosis and is indicated in all patients with a ferritin level greater than 1,000 microgram / L. Typical initial phlebotomy regimes are 400-500 ml every 1-2 weeks. Once ferritin level falls to the range 50-100 microgram / L, phlebotomy regime can transition to a maintenance schedule every 2-4 months.
Haemochromatosis - Example Question
A 52 year-old woman is seen in the gastroenterology clinic with abnormal liver results discovered on routine blood tests. She feels generally lethargic, and has had to go part time at work. She attributes this to the menopause, which happened 2 years ago.
She denies any alcohol excess and does not smoke. She is unsure of any family history, after being adopted at 3 years of age.
She suffers from osteoarthritis, for which she takes paracetamol and ibuprofen. She is on no other regular medication.
On examination, she has a normal body mass index. She has features of chronic liver disease, including palmar erythema and spider naevi. She has a 3cm tender hepatomegaly, with a palpable splenic tip. There is no shifting dullness.
Cardiorespiratory examination is unremarkable. She has bilateral symmetrical swelling of her distal and proximal interphalangeal joints.
Which investigation would be the most specific to support your likely diagnosis?
Ferritin > Transferrin saturation CEA Alpha-1-antitrypsin Lipid profile
Haemochromatosis is a condition of excessive accumulation of iron. Primary hereditary haemochromatosis is a genetic condition, whereas other conditions requiring regular blood transfusions (haemoglobinopathy) can cause an iatrogenic iron overload.
Hereditary haemochromatosis is inherited in an autosomal trait. The HFE gene has been localised to chromosome 6.
Features
Liver cirrhosis
Cardiomyopathy
Cutaneous pigmentation- this can vary to bronze to slate-grey
Diabetes mellitus
Hypopituitarism, hypogonadism and testicular atrophy
Joint pain
Transferrin saturations (fasting transferrin saturation of >60% in males and >50% in females is highly specific for iron overload)
Serum ferritin (an acute phase reactant, and can be raised in many other conditions- therefore less specific)
Genetic testing for HFE mutation
Menstruation is a protective feature in females, and presentation in females is often post menopausal.
Secondary Haemachromatosis
= Iatrogenic Iron Overload e.g. 2dry to haemoglobinopathy requiring regular blood transfusions
Eg Regular Blood Transfusion
> Iatrogenic iron overload
Presentation e.g. Elderly lady with fortnightly blood transfusions (due to myelodysplasia), presents with new onset DM and ‘bronzed skin’
Haemochromatosis and HFE Gene Mutation
- iron absorption is regulated in the duodenal crypts
- HFE is a protein that regulates iron absorption
- it forms a complex at basolateral membrane of duodenal crypt cells - when bound to transferrin + iron, prevents maturation and consequently absorption of iron in the bowel
- most common form of hereditary haemochromatosis is assoc w mutation in HFE gene leading to failure of complex formation and constant maturation of duodenal crypt cells and subsequent unregulated uptake of iron
Haemochromatosis - Non specific Presentation
LETHARGY + ARTHRALGIA + DM (polyuria, polydipsia)
Screening for Haemochromatosis
General Population = Transferring sats > Ferritin
Family Members = HFE gene testing
Haemochromatosis Pseudogout - Example Question
A 45-year-old Caucasian man presents with an acutely painful left knee. He is unable to mobilise due to the pain and swelling. Prior to this episode, the patient states that he is generally active, often enjoying a round of golf every Sunday. Last week he had a minor fall onto both knees whilst clearing out the garage. He puts his current symptoms down to general aches and pain of ‘old age’.
The patient has also noticed that he is waking up more often in the night to pass urine. His wife has noticed that he is looking more ‘tanned’ despite them not going abroad on holiday this year. On further questioning, he admits to drinking 5-6 pints of ale per week. He is a non-smoker.
On examination on the Medical Assessment Unit you note significant left sided knee swelling. The joint is hot and tender to touch. There is no evidence of any surrounding skin changes.
His random glucose is measured at 18mmol/L.
Further blood tests are shown below:
Hb 138 g/l
Platelets 120 * 109/l
WBC 7.0 * 109/l
Na+ 138 mmol/l K+ 4.0 mmol/l Urea 6.2 mmol/l Creatinine 88 µmol/l CRP 72 mg/L
What is the most likely cause of his acutely swollen knee?
Pseudogout Ruptured Baker's cyst Septic arthritis Gout Haemarthrosis
This gentleman presents with arthralgia, polyuria and skin colour changes. These symptoms in a gentleman of this age and ethnicity suggest hereditary haemochromatosis. Polyuria and significantly elevated random blood glucose suggest diabetes. Pseudogout secondary to calcium pyrophosphate crystal deposition in large joints is a well-known complication of haemochromatosis. Radiological manifestations of pseudogout show a classical chondrocalcinosis picture
Haemochromatosis - Example Question
A 30-year-old woman is referred to haematology clinic by her GP for assessment for possible hereditary haemochromatosis. The patient reports that her 37-year-old brother has recently been diagnosed with the condition after developing progressive fatigue and joint pains over the previous few months. The patient is very concerned that she too may have inherited the condition, especially as at the time of his diagnosis her brother has been found to have significant damage to his liver and diabetes secondary to iron overload. With her brother’s consent, the patient had brought a copy of his medical records to the clinic appointment and details of his investigations are given below.
Aside from the anxiety induced by her brother’s recent illness, the patient reported being in generally good health. She reported leading a busy life, working full time as a primary school teacher in addition to raising her 4-year-old daughter. In the context of these commitments and activities, the patient did not feel she was unreasonably tired or lethargic and did not experience significant joint pains.
The patient had a history of psoriasis that was well controlled with topical treatments. The pregnancy and delivery of her daughter had been uncomplicated. The patient reported a tendency to a heavy menstrual flow and had previously been prescribed tranexamic acid for this by her GP although she had not found significant benefit from this treatment. Aside from topical treatments for her psoriasis, the patient took no regular, prescribed medications and had no known allergies to medications.
Physical examination of the patient was unremarkable; in particular, no signs of chronic liver disease were identified on gastrointestinal system examination.
A summary of the patient’s brothers investigations for hereditary haemochromatosis at the time of his diagnosis is given below.
Ferritin 1,527 microgram / L (30-300)
Transferrin saturation 78 % (15-45)
HFE gene analysis homozygous for C282Y mutation
HbA1C 53 mmol / mol (reference < 42)
Liver magnetic resonance imaging Generalised cirrhosis; low signal seen on all sequences, especially T2 weighted
The patient had undergone basic blood tests arranged by her GP at the time of referral, with results given below.
Haemoglobin 136 g / dL
Mean cell volume 84.1 fl
Ferritin 190 microgram / L (30-300)
Transferrin saturation 43 % / (15-45)
What is the appropriate next investigation to confirm or exclude the patient suffering from hereditary haemochromatosis?
Pituitary hormone panel >HFE gene analysis Liver magnetic resonance imaging (T2 weighted) Patient asymptomatic and normal iron studies, no further investigations indicated Liver biopsy
Hereditary haemochromatosis presents with nonspecific and insidious symptoms, with the result that in some cases, the diagnosis is not suspected until after damage to end-organs has occurred. In such individuals, the risk of death from liver cancer, cirrhosis, cardiomyopathy and diabetes are increased compared to the general population. However, detection and treatment of the condition in a susceptible individual prior to the development of cirrhosis or diabetes results in normal survival. Therefore, genetic testing for HFE gene mutations (specifically, the C282Y and H63D mutations) is indicated for an individuals meeting one of the following criteria:
Elevated serum ferritin (> 300 microgram / L in males; > 200 microgram / L in females)
Elevated transferrin saturation (> 45 %)
First degree relative with haemochromatosis
Therefore, in the case of this patient, HFE gene analysis should be requested to confirm or exclude hereditary haemochromatosis. The patient’s iron studies are at the upper end of normal, which is surprising for this patient in the context of her menorrhagia and raises suspicion of iron overload developing in the future. Women with haemochromatosis do not normally develop significant iron overload until after their menopause. In addition, the clinical penetrance of C282Y homozygosity is variable, with haemochromatosis associated morbidity developing in only 10-33 % of individuals with this genotype. Therefore, even in the absence of iron overload, it is helpful to be aware of the presence of HFE mutations to enable informed testing of an individual’s children.
The other available answers are investigations to assess damage to end-organs that may be appropriate for an individual with a confirmed diagnosis of haemochromatosis. Of note, liver MRI is the most useful imaging technique for assessing hepatic iron overload and can quantify the degree of iron overload to guide phlebotomy regimes and avoid repeated liver biopsies.
Haemochromatosis Reversible vs Irreversible Cx again
Venesection aims to rapidlly remove the excess iron within the body but does not generally reverse established damage. Removal of one unit per week or two is normally effective to deplete of iron, and then the frequency can be reduced. Chronic damage to liver, joints and heart is normally irreversible, but acute injuries can respond well.
Usually irreversible
Cirrhosis
Arthritis
Improvement in Some Patients
Diabetes mellitus
Arthralgia
Hypogonadism
Usually Reversible
Transaminase Elevation
Fatigue
