EDUCATION PRACTICE EDUCATION PRACTICE

RATIONAL TESTING Interpreting raised serum ferritin levels • Link to this article online for CPD/CME credits Marianna Koperdanova, Jonathan O Cullis

Salisbury District Hospital, Salisbury A 60 year old businessman attended his general practi- Raised ferritin due to iron overload SP2 8BJ, UK tioner after an insurance medical examination at which Iron overload occurs when there is increased absorption Correspondence to: J O Cullis abnormal liver function tests had been noted (alanine of dietary iron, or after administration of iron or via blood [email protected] aminotransferase 70 IU/L (normal range 10-40 IU/L) transfusion. Cite this as: BMJ 2015;351:h3692 doi: 10.1136/bmj.h3692 and γ-glutamyltransferase 120 IU/L (normal range 0-37 Secondary iron overload—This may follow repeated IU/L)). He was otherwise fit and well and not taking blood transfusions, multiple infusions of intravenous iron This series of occasional articles regular medication. His general practitioner noted that (such as in people with renal failure and cancer patients provides an update on the best use of key diagnostic tests in the his full blood count and renal function were normal, and who have been treated with repeated parenteral iron), or initial investigation of common or requested hepatitis B and C serology (which were nega- prolonged ingestion of iron supplements. It may occur in important clinical presentations. tive) and serum ferritin level, which was 567 µg/L (nor- chronic anaemias with ineffective erythropoeisis (such The series advisers are Steve Atkin, professor of medicine, Weill mal range 24-300 µg/L). as thalassaemia intermedia, sideroblastic anaemias, and Cornell Medical College Qatar; chronic haemolytic anaemias). In such cases, those who and Eric Kilpatrick, honorary What is the next investigation? have received >20 transfusions (for example, patients with professor, department of clinical biochemistry, Hull Royal Infirmary, Ferritin is an intracellular iron storage protein and a sickle cell disease, β thalassaemia major, aplastic anae- Hull York Medical School. To marker of iron stores. Normal serum ferritin levels vary mia, or myelodysplasia) are at risk of iron overload and in suggest a topic for this series, between laboratories but generally concentrations the long term may develop cardiac, hepatic, or endocrine please email us at [email protected]. >300 µg/L in men and postmenopausal women and dysfunction. Secondary iron overload may also be due to >200 µg/L in premenopausal women are regarded as porphyria cutanea tarda, a hepatic porphyria presenting elevated.1 Low ferritin values provide absolute evidence with cutaneous photosensitivity and liver dysfunction due of iron deficiency.2 Raised levels often indicate iron to hepatic iron deposition. overload, but they are not specific, as ferritin is an acute Primary iron overload (hereditary haemochromatosis)— phase protein and is also released from damaged hepato- This is iron accumulation due to inheritance of mutations cytes; thus levels are elevated in inflammatory disorders, in the HFE gene on chromosome 6. This autosomal reces- liver disease, alcohol excess, or malignancy.3 4 Raised sive disorder is the commonest single gene disorder in ferritin levels therefore require further investigation in northern European populations (estimated prevalence primary care to determine if they truly represent iron 0.4%), but is far less common in other populations.6 It overload. It is critical to consider two broad categories causes excessive absorption of dietary iron, but is often of causes: asymptomatic and unrecognised in primary care.9 10 • Raised ferritin without iron overload Associated morbidities (hepatic, endocrine, cardiac) are • Raised ferritin due to iron overload. serious and preventable: timely diagnosis and treatment These can usually be distinguished through clinical are important. assessment and measurement of serum transferrin saturation.5 Clinical assessment in primary care Initial clinical assessment of any patient with hyperfer- Raised ferritin without iron overload ritinaemia should first consider reactive causes (box 2); Most patients (90%) with hyperferritinaemia will not have if these are clearly present, further investigation may iron overload.6 7 Many conditions are associated with “reac- be unnecessary. An alcohol history is mandatory, as is tive” high ferritin levels (box 1), and these may coexist assessment for liver disease. Check body mass index and (such as inflammation and hepatitis).8 blood pressure, as elevated ferritin levels in absence of

THE BOTTOM LINE Box 1 | Causes of high ferritin without iron overload • Elevated ferritin levels are usually due to causes such as acute or chronic Common inflammation, chronic alcohol consumption, liver disease, renal failure, • Liver disease (such as non-alcoholic steatohepatitis or viral metabolic syndrome, or malignancy rather than iron overload hepatitis) • Exclude these causes clinically or with initial tests such as full blood count, • Alcohol excess liver and renal function, and inflammatory markers (C reactive protein or • Acute and chronic inflammatory conditions erythrocyte sedimentation rate) • Infections • A normal serum transferrin saturation (ideally fasting) usually excludes iron • Malignancy overload (where it is raised) and suggests a reactive cause for raised ferritin • Renal failure • Unexplained serum ferritin values >1000 μg/L warrant referral for further • Metabolic syndrome investigation Less common • Consider HFE mutation screen for hereditary haemochromatosis in individuals • Thyrotoxicosis with elevated ferritin and a raised transferrin saturation >45% • Acute myocardial infarction the bmj | 8 August 2015 31 EDUCATION PRACTICE

iron overload are increasingly recognised in patients with thebmj.com Box 2 | Causes to be considered at first encounter with a Previous articles in this metabolic syndrome (obesity, type 2 diabetes, dyslipidae- 11 12 patient with raised ferritin series mia, and hypertension). Box 2 outlines other causes ЖЖTests to predict to be excluded. Causes without iron overload imminent delivery in • Recent illness (such as acute infection) threatened preterm First line tests • Alcohol intake These include: labour • Abnormal liver function, chronic liver disease, cirrhosis— • Blood count and inflammatory markers (C reactive (BMJ 2015;350:h2183) Check liver function tests, consider liver ultrasound scan protein or erythrocyte sedimentation rate) to detect • Viral hepatitis—Serology for hepatitis B and C ЖЖInvestigating occult inflammatory disorders • Acute or chronic inflammatory conditions—Erythrocyte intracerebral Serum creatinine and electrolytes for renal function • sedimentation rate or C reactive protein, or both haemorrhage • Liver function tests—Abnormal results should • Metabolic syndrome (obesity, type 2 diabetes, (BMJ 2015;350:h2484) prompt consideration of viral hepatitis screening and ЖScreening tests for dyslipidaemia, hypertension)—Check body mass index, Ж abdominal ultrasonography blood pressure, blood glucose, lipid studies tuberculosis before Blood glucose and lipid studies. • • Renal failure—Check renal function starting biological • Malignancy (for example, weight loss, anorexia)—Imaging Transferrin saturation therapy as appropriate (BMJ 2015;350:h1060) If the cause of hyperferritinaemia is unclear, the most use- ЖЖInvestigating young ful test to aid differentiation of true iron overload from Causes with iron overload adults with chronic other causes is the serum transferrin saturation. • Iron supplements, intravenous iron, transfusion history diarrhoea in primary care • Anaemia or known haematological conditions—Full blood (BMJ 2015;350:h573) Normal transferrin saturation count, blood film, haemoglobinopathy studies ЖЖInvestigating sepsis In patients with unexplained hyperferritinaemia, normal • Hereditary haemochromatosis (fatigue, lethargy, transferrin saturation (<45% in females, <50% in males) with biomarkers arthralgia, diabetes, loss of libido, impotence, usually excludes conditions of iron overload, and reac- amenorrhoea, right upper quadrant abdominal pain, (BMJ 2015;350:h254) 1 4 tive causes should be reconsidered. Ideally, transfer- hepatomegaly, cirrhosis, chondrocalcinosis, skin rin saturation should be measured on a fasting morning hyperpigmentation, heart failure) sample, as serum iron levels undergo diurnal variation, • Family history of iron overload and may rise with recent food ingestion, temporarily • Porphyria cutanea tarda (cutaneous photosensitivity) increasing transferrin saturation.13 Patients should also not be tested during acute illness, when iron levels may ––Refer to a hepatologist, as this degree of elevation fall and misleadingly lower transferrin saturation. is more likely to be due to serious underlying pathology.8 Elevated transferrin saturation • Patients with positive HFE mutation results In healthy adults, transferrin saturation >45% has a sen- ––Refer for further assessment and therapy. sitivity of 94% and a positive predictive value of 6% for Venesection is the mainstay of management hereditary haemochromatosis.6 If the elevation is slight, in patients with iron overload, aiming to reach consider repeating measurement on a fasting sample to and maintain ferritin concentrations <50 µg/L.14 eliminate effects of recent food. Generally, genetic muta- Combined genetic testing and iron studies would tion screening (for C282Y and H63D polymorphisms) also be offered to siblings.15 for hereditary haemochromatosis should be offered • Patients with suspected primary iron overload according to local practice in patients with unexplained (that is, raised transferrin saturation, other clinical increased ferritin and transferrin saturation.14 features suggestive of haemochromatosis) who lack Most (>80%) northern Europeans with hereditary the common HFE genotypes haemochromatosis are C282Y homozygotes,15 with about ––Refer for direct assessment of iron stores, such 5% being C282Y/H63D compound heterozygotes (who as magnetic resonance imaging or liver biopsy.15 are significantly less likely to develop iron overload).15 Screening for other genes implicated in hereditary Clinical penetrance is variable, however,14 with possi- haemochromatosis may be considered in such ble influencing factors including menstruation, blood patients if increased iron stores are confirmed and donation, dietary supplements, alcohol intake, and other hepatic and haematological disorders are hepatitis. A study of primary care requests for labora- excluded. tory estimation of serum ferritin suggests that targeting • Patients with secondary iron overload (for example, blood samples with raised ferritin levels (≥300 μg/L in due to inherited or acquired anaemia) males, ≥200 μg/L in females) and transferrin saturation ––Consider iron chelation. Phlebotomy cannot be levels (>50% males, >40% females) for HFE genotyping used to remove excess iron in secondary iron improves detection of C282Y homozygous hereditary overload except in patients who have received haemochromatosis.10 transfusions during curative therapy for haematological malignancies. What are the next steps? • Patients with mildly increased ferritin levels (300- • Patients with confirmed iron overload with ferritin >1000 1000 µg/L) in whom iron overload is unlikely (that µg/L or abnormal liver function regardless of cause is, normal transferrin saturation) and other causes

32 8 August 2015 | the bmj EDUCATION PRACTICE

(such as liver disease, inflammatory disorders) are Outcome not evident The patient’s fasting serum transferrin saturation was 40%, ––Consider interventions as deemed appropriate and an abdominal ultrasound scan showed fatty change to reduce ferritin concentrations (alcohol within the liver. He admitted to drinking 35 units of alcohol abstinence, improved glycaemic control, a week. The chronic alcohol consumption was believed to weight reduction, and lowering triglyceride be the cause of the hyperferritinaemia, and there was no concentrations). We suggest re-checking serum evidence of iron overload. Lifestyle advice and alcohol absti- ferritin (and other relevant tests) three to four nence were advised, and liver function and ferritin measure- months after these interventions. ments had normalised on repeat testing three months later.

10-MINUTE CONSULTATION Bariatric surgery Y Oskrochi, A Majeed, G Easton

Department of Primary Care and An obese 34 year old man with a body mass index of Bariatric surgery eligibility criteria in England (as defined by Public Health, Imperial College 37.4, type 2 diabetes, and hypertension presents want- NICE guideline)1 London, Charing Cross Hospital, ing advice on weight loss. He is concerned about his lack London W6 8RF, UK Body mass 6 month NSI index Extra eligibility criteria requirement* Correspondence to: Y Oskrochi of progress despite adhering to a six month primary care [email protected] led weight loss regime. He has heard of weight loss sur- ≥27.5 Asian origin and recent onset T2DM No Cite this as: BMJ 2015;351:h3802 gery being offered by the NHS and wants to know if he ≥30 Recent onset T2DM No doi: 10.1136/bmj.h3802 is eligible. ≥35 Obesity related comorbidity† Yes ≥40 None Yes This is part of a series of occasional ≥50 None No articles on common problems in What you should cover primary care. The BMJ welcomes • Ask the patient about what weight loss measures he contributions from GPs. has tried so far. For example: • Check that he does not have uncontrolled alcohol or thebmj.com ––How has he modified his diet and physical drug dependency—ask about alcohol and drug use, activity? check medical records, and administer AUDIT-C Previous articles in this ––Has he tried weight support or management questionnaire to screen for alcohol misuse if series 2 programmes? concerns exist. ЖЖNipple discharge • Check dates of any prescriptions issued for drug (BMJ 2015;351:h3123) interventions. What you should do ЖЖGradual loss of vision • Check attendance (current or future) at a tier 3 • Outline the available surgical options: in adults weight management service, which may affect ––There are two main types of surgery, almost (BMJ 2015;350:h2093) eligibility for bariatric surgery in England (table).1 always done via keyhole (laparoscopic) surgery: ЖЖFoot drop • Assess whether any clinically beneficial weight one that restricts how much can be eaten (BMJ 2015;350:h1736) loss has been achieved. As this is not defined in the (restrictive) and one that limits absorption from ЖЖHigh INR on warfarin guidelines, we suggest the following: the gut (malabsorptive). (BMJ 2015;350:h1282) ––Objective improvements—Body mass index, waist ––Commonly offered procedures include sleeve ЖЖTeenagers with back circumference, improved blood pressure control, gastrectomy (restrictive), gastric banding pain better glycaemic control. (restrictive), and gastric bypass (combination of (BMJ 2015;350:h1275) ––Subjective improvements—Energy levels, mobility, restrictive and malabsorptive). general health and wellbeing. ––Surgery may involve a stay in hospital of up to a • Assess eligibility for surgery (table). few days. • Assess the patient for comorbidities that may affect ––Each type of surgery has its own specific his eligibility for surgery, including cardiovascular, complications, and the surgical team will explain respiratory, kidney, or liver disease. these in greater detail, but direct the patient to appropriate online resources.3 4 THE BOTTOM LINE • Discuss possible benefits of surgery5: • Refer patients for bariatric surgery if they have ––Weight loss—On average 25% loss of body weight, body mass index >35 with associated obesity depending on the procedure (bypass ~30%, conditions (type 2 diabetes, hypertension, banding ~18%). Warn that weight loss may be obstructive sleep apnoea) and have failed to transient, with some weight gain recurring after control their weight with non-surgical efforts two years. • Consider referral at a lower body mass index if ––Some comorbidities may improve—However, this the patient is of Asian origin, has new onset type is not inevitable. For example, type 2 diabetes 2 diabetes, or both may require less or no insulin, obstructive sleep apnoea may not require nocturnal continuous the bmj | 8 August 2015 33 EDUCATION PRACTICE LIFE IN VIEW/SPL IN LIFE

positive airway pressure, lipid profile may ––For gastric banding, failure rates of 30-50% are improve (although patients may still need a statin common and revision surgery is not routinely if they have concurrent ischaemic heart disease), offered on the NHS. and hypertension may be better controlled. ––Warn patients who have had or are having ––Lower mortality—29-40% lower risk of death from bypass about the risk of dumping syndrome any cause compared with no surgery. (postprandial feeling of faintness, sweating, ––Better quality of life—Studies show overall and palpitations that may be accompanied by improvement, with greater improvement in bloating, nausea, and diarrhoea caused by rapid physical functioning than in mental state. movement of food, especially sugar, from the • Discuss the short term postoperative risks: stomach into the duodenum), hypoglycaemic ––Perioperative mortality is low (<0.3%) and events, and lower alcohol tolerances. depends on the type of operation (bypass ––Excess skin can result from weight loss, and its > banding) and patient related factors removal is not offered on the NHS. (comorbidities, age). ––The surgical team will discuss operation type ––Complication (4-25%) and reoperation rates specific complications with them. (22-26%) vary depending on operation • Impress on the patient the need for long term type and patient related factors (history of follow-up. This includes regular follow-up for thromboembolism, obstructive sleep apnoea, at least two years with the surgical team and a extremes of body mass index, or impaired lifelong commitment to annual monitoring with the functional status).5 GP, with review of symptoms and complications, ––Encourage the patient to find out more himself weight, nutrition, and mineral and vitamin and offer sources of information. concentrations, with replacement treatment if • Discuss long term postoperative complications: necessary. ––Following a successful operation and recovery, • If potentially eligible, and the patient remains keen, patients may still experience complications refer him for bariatric surgery. The patient has the including nutritional deficiencies (iron, vitamin ultimate responsibility to decide about his care, but

B12, folic acid, vitamin D), which require lifelong remind him that eligibility decisions also lie with monitoring and replacement when needed. the surgical team. In this case, the patient would be ––Patients will not be able to eat the same amount eligible as he meets all the criteria and type of food as before. This is difficult to • Provide written information. The Patient.co.uk and predict. They will have to see what works best NHS Choices websites offer detailed information for for them, although they will be given advice and patients about the entire process,3 4 empowering support by the specialist team. them to make informed treatment decisions.

34 8 August 2015 | the bmj