Munchausen syndrome and factitious disorder: the role of the laboratory in its detection and diagnosis

Abstract

The term Munchausen syndrome is used to describe the patient who chronically fabricates or induces illness with the sole intention of assuming the patient role. Such persons often have a close association with the medical profession and thus use their knowledge to falsify symptoms and laboratory specimens to mimic disease. Cases of factitious disease have appeared in the literature originating from all medical specialties, and include such rare disorders as phaeochromocytoma and Bartter's syndrome. The laboratory can play a key role in the detection and diagnosis of factitious disorders. Indeed discrepant biochemistry results may provide the first clue to the diagnosis. Laboratory staff should be particularly aware of highly variable test results and extreme abnormalities that are not consistent with the wider biochemical profile, suggesting sample tampering. Factitious disorder should also be included in the clinician's differential diagnosis when disease presentation is unusual or an underlying cause cannot be found. Investigation to exclude or confirm factitious disorder at an early stage can prevent unnecessary testing in the search for increasingly rare diseases. Appropriate analyses may include screening tests for the detection of surreptitious drug administration or replication of a fabricated sample to confirm the method used. In all cases close communication between the clinician and laboratory is essential. This will ensure that appropriate tests are conducted particularly with regard to time critical and repeat tests.

Introduction

Munchausen syndrome is a category of factitious disease, whereby a person fabricates or induces an illness in order to assume the patient role. ¹ The patient involved may feign illness in a number of ways. These include:

Fabrication of a medical history (which may include forgery of laboratory results);

Faking symptoms;

Mimicking bleeding or haematuria via self-inflicted injury;

Creating illness by artificial means (e.g. ingestion of laxatives);

Exploiting stable but abnormal biochemical/physiological findings to mimic illness (e.g. abuse of a known electrocardiogram [ECG] abnormality to gain admission for investigation of acute myocardial infarction);

Tampering with laboratory specimens.

Munchausen syndrome is not considered a discrete diagnosis by the American Psychiatric Association, ² or the World Health Organization. ³ Rather, the syndrome is included under the umbrella term of factitious disorder, which is defined by the following diagnostic criteria: ²

1. The patient intentionally produces or feigns physical or psychological signs or symptoms;

2. The motivation for the behaviour is to assume the sick role;

3. External incentives for the behaviour are absent.

The title of Munchausen syndrome is, however, still commonly used in the literature to describe a subset of patients in which the factitious disorder is particularly severe. The term is usually reserved for patients in whom the disorder is chronic, and for which multiple hospital admissions (often at various locations) have been sought.

The term ‘Munchausen syndrome’ was first coined by Asher in 1951 ¹ after Baron von Munchausen, famous for his vastly exaggerated but engaging stories. In his paper, Asher ¹ described three subcategories of the syndrome in which patients sought repeated admission to hospital via fabrication of signs and symptoms. These were:

Haemorrhagica histronica (bleeding);

Laparatoma migrans (abdominal pain);

Neurological diabolica (neurological symptoms).

Cases of Munchausen syndrome have since been described across all medical specialties. Furthermore, in 1977 Meadow introduced the term ‘Munchausen by proxy’ to describe the perpetrator who fabricates an illness in a child. ⁴ This terminology has, however, since been revised and such cases should now be referred to as ‘Fabricated or Induced Illness by Carers (FII)’. ⁵

Typically, the perpetrators of factitious disorders are women. Interestingly, however, the patients featuring in cases specifically described as ‘Munchausen syndrome’ are more commonly men. With regard to FII, the abuser is most often the biological mother, ⁶ although fathers, grandparents and other carers have been identified as perpetrators. ⁷ Often the person fabricating the illness has a close link to the health-care profession, whether through their own employment or via family members. In one study of FII the perpetrator worked either in health care or childcare in 80% of the cases described. ⁸ While medical knowledge is clearly utilized by the perpetrator to convincingly fabricate the disorder, employment within the health-care setting may also be abused to obtain the means (e.g. prescription drugs) to induce the disorder.

Factitious disorders, including Munchausen syndrome, are estimated to account for around 0.6–1.3% of general hospital admissions. ⁹ However, the true prevalence is difficult to determine as many cases go unrecognized. Recognition of factitious disorder requires a high level of clinical suspicion, and it is not surprising that most clinicians are uncomfortable with making the diagnosis. ¹⁰ Unfortunately, this can lead to years of unnecessary investigations, including invasive surgery with the associated potential for serious consequences. Clearly, the diagnosis of factitious disorder becomes more likely as more tests return results that are negative or within the reference range. For example, it is estimated that 4% of patients presenting for the first time with chronic diarrhoea have a factitious cause, while the prevalence increases to 20% in tertiary centres. ¹¹ The higher proportion of factitious disorders recognized within tertiary centres simply reflects that a number of negative investigations would have already been obtained prior to referral.

Repeat hospital admissions and investigations inevitably also incur a large financial cost. In a study of patients seeking treatment for factitious renal colic in Philadelphia area hospitals between 1989 and 1995, ¹² the average cost of a single hospital visit was calculated as $2914 (approximately equivalent to $5000 ¹³ in 2010). The significance of this financial burden increases substantially when it is considered that, on average, each of the 12 patients studied made 18 hospital admissions over the six years. While it is important that pathology is excluded, an awareness of the possibility of factitious disorder can therefore avoid unnecessary tests, invasive procedures and financial costs.

The prevalence of factitious disorder appears to vary significantly between medical specialties. ¹⁰ This apparent variation may be partly due to differences in awareness of the syndrome, yet certain disorders do appear to hold more appeal. Mehta et al. ¹⁴ believed cardiology is targeted because risk stratification for admission is largely based on medical history, for which a plausible story could be easily invented. A disorder may also be targeted due to publicity associated with recent medical advances, or because of the elaborate and technical medical language used within the specialty. ¹⁴ However, appeal factor may not always apply. In 2002 a case of factitious parasitosis ¹⁵ was described in which a women claimed to have passed a roundworm in her stool. She provided a plausible history consistent with ascariasis – an infection caused by ingestion of ascarid eggs in contaminated food. This disease results in the passing of deceased adult worms months after the initial infection. The worm in the stool was, however, found to be an earthworm. The authors were unable to ascertain whether the worm had been placed in the stool sample, or had been swallowed. ¹⁵

Factitious parasitosis is, not surprisingly, unusual. More often cases of factitious disease encountered in the laboratory stem from nephrology, gastroenterology and endocrinology investigations. Perhaps the most common form of falsification experienced in the laboratory is the submission of stones that do not constitute accepted forms of urinary calculi. One laboratory reported 3.5% of stone submissions to be spurious, with multiple submissions made by single perpetrators of factitious disease. ¹⁶ Many such stone submissions would not fulfil the factitious disorder criteria, and spurious stones can be presented unintentionally. However, multiple spurious stone submissions by the same patient do warrant further investigation.

The laboratory can play a major role in detection and diagnosis of factitious disorders. Indeed discrepant biochemistry results may provide the first clue to the diagnosis when symptoms or medical history alone are fabricated. More substantial laboratory input is, however, likely to be required when sample tampering or illness induction is suspected. In such cases it is the role of the laboratory to either exclude or confirm sample fabrication. This may involve direct detection of the offending substance or replication of manipulated results in order to provide evidence of factitious disease. In cases of FII the laboratory and clinicians should also liaise with appropriate agencies (e.g. the police) so that the medicolegal aspects of the case can be established.

Role of the laboratory

The following section will provide an overview of the role of the laboratory in cases of factitious disorder involving (1) falsified symptoms or result transcripts, (2) sample tampering and (3) induced illness. Case examples are provided throughout to illustrate how factitious disorder may present and the appropriate investigation when sample fabrication is suspected. A suggested laboratory approach will also be provided for the investigation of fabricated disorders that are more commonly encountered in the laboratory.

Falsified symptoms and forged results

In cases of factitious disorders involving fabrication of a medical history or symptoms alone, the first clue to the diagnosis may be consistently normal findings on clinical examination and biochemistry analysis. However, a fabricated medical history may include manipulated result transcripts and it is the clinician's responsibility to ensure that all laboratory results are from reliable sources. Isolated abnormal results, particularly from non-familiar laboratories, should therefore be treated with suspicion. A telephone call to confirm the results and their origin, or repeat analysis by the local laboratory may be all that is required.

Falsified transcripts were used in a case of factitious multiple endocrine neoplasia type 2 (MEN2). In this case, a 33-year-old woman was referred to the endocrine clinic due to ongoing investigation of intermittent palpitations. ¹⁷ Following referral, the patient produced a document describing a positive RET1 gene mutation as well as elevated parathyroid hormone and calcitonin results, consistent with MEN2. However, further clinical and biochemical examinations were normal. The clinician therefore requested repeat analysis of the RET1 gene and no mutation was found. Investigation into the source of the original results revealed that the transcript had been forged.

There were several factors which raised the possibility of factitious disease in this case. Firstly, the patient's presentation is unusual – a classical finding in factitious disorder. ¹⁷ For example, MEN2 typically presents in childhood whereas this woman was referred in her 30s. Secondly, a close inspection of the original RET1 gene analysis revealed two different mutations on the same gene: one mutation associated with MEN type 2A and the other with MEN type 2B. This is a highly unlikely combination. Finally, biochemical tests conducted at the hospital were inconsistent with a diagnosis of MEN2 as calcium, thyroid function, parathyroid hormone and metanephrine analyses were all normal. Investigation into the original results was therefore appropriate, and confirmed the diagnosis of factitious disease.

The above case also highlights the depth of knowledge and complexity of lies that may be involved in factitious disorder. However, the deceit is often more obvious. In one case, a 40-year-old woman presented to an orthopaedic department with a Google image of a dislocated ankle which she attempted to pass as her own radiograph. ¹⁸ Factitious disorder was soon suspected based on various inconsistencies between the radiograph and the woman's own presentation.

Symptoms with or without associated changes in the biochemical profile have also been induced to mimic disease during clinical examination. In cases of factitious phaeochromocytoma, the Valsalva manoeuver (forced exhalation against a closed airway) has been utilised by patients as a means to induce hypertension during blood pressure measurements. ¹⁹ A fractionated metanephrine profile would exclude the diagnosis of phaeochromocytoma in such cases. Benign clinical abnormalities may also be exploited. ¹⁴ In a 1998 case of factitious cardiopathic syndrome, a male beat himself with a wet towel to raise his creatine kinase (CK) before presenting to the accident and emergency department with a plausible history of myocardial infarction. ²⁰ In this instance the patient also abused previous findings of a stable but abnormal ECG to gain hospital admission. The deceit was revealed after the CK failed to rise by 25% following the initial presentation and a second ECG was unchanged from that obtained at admission.

Specimen manipulation in factitious disorder

Numerous cases of factitious disorder have been described that involve sample tampering to generate results that mimic disease. The methods used to alter the biochemistry of samples may be very simple, e.g. spitting into a urine sample to stimulate hyperamylasuria ²¹ or complex, e.g. falsification of sweat test analysis and stool fat samples to mimic cystic fibrosis. ²² Many persons described as suffering with Munchausen syndrome have close links to the medical profession, and thus use their knowledge to fabricate laboratory specimens to mimic the disease profile. Employment within a health-care setting may also provide access to prescription drugs with their potential to induce illness. Often these factors result in extensive laboratory testing prior to the final diagnosis being reached. For example, many laboratory and imaging investigations were undertaken before the appropriate diagnosis was made in a case of factitious Cushing's syndrome. ²³ In this example, a pharmacy student had surreptitiously taken steroids to induce a physical Cushingoid state as well as adding prednisolone to 24 h urine collections to generate elevated urine cortisol results. Discordant serum cortisol and adrenocorticotropic hormone (ACTH) results, plus negative results on imaging finally led to suspicion of factitious disease. Further analysis of the urine sample by high performance liquid chromatography (HPLC) confirmed the presence of prednisolone. ²³

Laboratory awareness of abnormal patterns of results, or results that appear to change erratically, is a useful aid to the detection of sample tampering. In the above case of factitious Cushing's syndrome, the urine cortisol results were highly variable and inconsistent with serum cortisol analysis, and thus further investigations into the cause of the raised urine cortisol were appropriately undertaken. In such cases, HPLC of urine samples compared against standard profiles may be used to identify the glucocorticoid administered. ²⁴ Factitious Cushing's syndrome has also been described whereby hydrocortisone has been added directly to urine samples, generating similarly elevated urine cortisol results. ²⁵ In this instance a normal 17-hydroxycorticosteroid and corticosterone concentrations with an elevated cortisol helped to confirm sample tampering. ²⁵ We recommend obtaining a full urine steroid profile when investigating a possible case of factitious Cushings.

Epinephrine addition to urine samples in an attempt to mimic phaeochromocytoma has also featured in the literature; however, such fabrication can be swiftly detected via metanephrine analysis. ²⁶ Indeed with the transition to metanephrine analysis as a first-line investigation of phaeochromocytoma, it is likely that such sample tampering would go unnoticed and thus would not lead to diagnostic confusion. Nonetheless, it is important to ascertain if and how sample manipulation had occurred. In one such case of factitious phaeochromocytoma, isolated increases of epinephrine were found in three consecutive 24 h urine collections taken during hospital admission. ²⁷ Investigation by the clinician revealed that a prescription for an Anapen had been redeemed by the patient shortly before admission. An Anapen is a device for injection of epinephrine in cases of severe allergic reactions. The laboratory was able to demonstrate that the results could be reproduced by addition of one-third of the contents of an Anapen to each urine collection. ²⁷ This case shows the importance of a thorough medical history and good communication between clinician and laboratory. The clinician in this instance was able to identify the means by which the patient could fabricate the sample, while the laboratory acted to confirm this suspicion.

While factitious endocrine cases may be encountered, the laboratory is more likely to become involved with cases of factitious haematuria or proteinuria resulting from manipulation of urine samples. Below is an account of the possible manifestations of such factitious disorders and also the appropriate investigations.

Factitious haematuria

Reich et al. ¹² found that 0.6% of patients presenting to their renal clinic had tampered with their urine specimen to generate false haematuria. Such sample manipulation may involve addition of finger prick blood to the urine collection, ²⁸ resulting in apparently gross haematuria. Suspicion should be raised if the extent of haematuria varies significantly between samples, and if all other urinalysis results are normal. Ideally, supervised urine collections should be analysed and if normal would be diagnostic of factitious disease. However, patient compliance is likely to be an issue. Analysis showing normal red cell shape and absence of red cell casts will narrow the diagnosis but cannot exclude other postrenal causes. ²⁹

Less frequently, haematuria may be induced via trauma to the urethra or insertion of foreign bodies such as pins into the bladder. ³⁰ Kenedi et al. ⁹ suggest obtaining a ‘three tube’ urine collection to exclude urethral trauma. For this test a single episode of micturition should be collected into three separate containers, and each part of the collection analysed for red blood cells. If urethral trauma is the cause then the first container (i.e. urine collected at the start of micturition) would contain a larger number of red blood cells than the second and third containers (i.e. urine collected in the later stages of micturition). Unfortunately, however, imaging studies or more invasive exploration may be required before the diagnosis of factitious haematuria can be made in cases of foreign body insertion.

Factitious proteinuria

Fabricated proteinuria alone or in combination with haematuria has also been described. ³⁰ The laboratory should be suspicious if the protein content varies widely between urine collections, and if gross proteinuria is detected in the absence of any other clinical/biochemical signs of nephrotic syndrome. Additionally, gross proteinuria associated with either very low or very high urine albumin concentrations warrants further investigation. If proteinuria is not demonstrated in samples obtained via catheterization or under supervision then this would obviously aid the diagnosis of factitious disease; however, the patient may refuse to co-operate with such procedures. Furthermore, cases have been described whereby proteinuria has been induced by injection of egg protein directly into the bladder. ³¹

Urine protein electrophoresis should be conducted in all cases of suspicious proteinuria. A large albumin band without an associated increase in transferrin indicates surreptitious addition of albumin. However, before pursuing any further investigation, it is important to exclude atransferrinaemia by ensuring that a transferrin band is visible in the serum electrophoresis strip.^32,33 Albumin rarely constitutes greater than 75% of the total urine protein, but profiles of almost pure albumin may be obtained via factitious causes. ³² Antibodies directed against albumin are available and hence can be used to determine whether the albumin detected is of human or non-human origin.

If bands are detected in the urine within the alpha, beta or gamma region then immunofixation should be conducted to exclude Bence-Jones proteins and immunoglobulins. Unusual bands that are negative by immunofixation may indicate the presence of non-human protein. Further investigation of the bands is then necessary to positively identify the abnormal protein for medicolegal reasons. If surreptitious addition of protein is suspected then profiles for comparison may be generated using easily obtainable protein, e.g. protein powder supplements. However, isoelectric focusing may be more useful in instances where the protein substance is unknown. ³⁴ Isoelectric focusing produces several bands, and thus multiple points for comparison. This method can also still be used when there is underlying disease. ³⁴ If available, labelled antibodies should then be used to positively identify the protein.

Manipulations of non-urine specimens

Urine samples are more likely to be tampered with than blood samples, simply because the opportunity to do so is much greater. However, sample tampering has been described for blood, ³⁵ stool^22,36 and cerebrospinal fluid samples. ³⁷ In a case of FII, ³⁵ a woman added urine to blood specimens taken from her child to generate elevated potassium and creatinine results upon analysis. The suspicion of sample tampering was quickly raised as the potassium concentrations generated were incompatible with life, while the child appeared happy and well. In this case the opportunity to tamper with the blood sample was provided as delivery of specimens to the laboratory was commonly done by family members. Sample manipulation was confirmed as specimens taken to the laboratory by hospital staff were normal. The method used to modify the biochemistry was established via reproduction of the results within the laboratory following dilution of blood samples with urine. ³⁵

Stool samples may also be manipulated. In cases of factitious chronic diarrhoea dilution of stool collections with water may be used to increase sample volume. ³⁶ However, such tampering can be detected by measurement of the stool osmolality. Stool osmolality should be similar to that of serum (approximately 290 mosmol/kg), as the body is unable to physiologically dilute faeces. Therefore, a stool osmolality that is significantly lower than 290 mosmol/kg indicates dilution of the sample in water. ³⁶

Factitious disease via induction of illness

When substances are added directly to sample collections suspicion of factitious disease may arise based on the absence of clinical signs on examination, despite the classical collection of symptoms likely described by the patient. However, when the illness has been induced via surreptitious drug intake, both symptoms and biochemical analysis may on first look correspond to the simulated disease. In these instances a thorough history is invaluable – particularly with regard to previous admissions, employment and family history. As previously described, patients presenting with a factitious disorder will often have significant medical knowledge and tend to describe a harrowing list of previous medical investigations. Furthermore, disease presentation may be extreme, take an unusual course upon initiation of investigation, or be refractory to treatment.

A number of cases have been described whereby illness has been induced by surreptitious drug intake. For example, Ipecac, an over-the-counter cough mixture and emetic, can be used to induce vomiting. Both chronic diarrhoea following laxative abuse and induced hypoglycaemia have been reported in multiple cases of factitious disorder and FII. A description of typical presentations and appropriate laboratory investigation of these factitious diseases are given below. The key investigations of hypernatraemia in infants required to exclude salt poisoning will also be discussed. Sections on factitious presentations of thyrotoxicosis, phaeochromocytoma, Cushing's syndrome and Bartter's disease have also been included as there are multiple publications featuring these disorders in the context of factitious disorder.

Ipecacuanha induced vomiting

Investigation of factitious causes of vomiting should be instigated in any situation in which a cause of the disorder cannot be found. Ipecacuanha toxicity can cause cardiac or skeletal myopathy resulting in elevated CK and transaminases, and therefore such biochemical abnormalities may also provide a clue to the diagnosis. ³⁸ Measurement of emetine concentrations in serum or urine by HPLC has been previously recommended as a means to detect ipecacuanha abuse. ³⁹ However, access to this assay may now be limited.

Factitious chronic diarrhoea

Factitious disease accounts for approximately 20% of tertiary centre referrals for chronic diarrhoea. ¹¹ The disorder may be fabricated by presentation of watered down stool samples, ³⁶ as previously described, or induced via purposeful laxative abuse. ⁴⁰ Stool analysis and laxative screening is therefore recommended in all cases of chronic diarrhoea of uncertain origin. ⁴¹

Stool analysis involves measurement of sodium, potassium and magnesium concentrations as well as stool osmolality of the faecal water. The faecal osmotic gap can then be calculated using the formula: (290–2× [faecal sodium + potassium]). An aliquot suitable for analysis is obtained via homogenization of the liquid stool sample (by manual stirring or a mechanical blender) followed by centrifugation. Only liquid stool collections can be processed and the laboratory must not add water to the specimen. It is also important that the stool sample should be brought to the laboratory as soon as possible and analysed immediately. Bacterial breakdown of carbohydrates to osmotically active sugars will occur if analysis is delayed, resulting in a very high osmolar gap. A large osmolar gap will also occur if the stool sample is contaminated with urine. A measured faecal osmolality that is lower than serum osmolality indicates that the stool collection has been diluted with water. ³⁶

Laxatives contain osmotically active ingredients such as sorbitol, lactose, lactulose or magnesium, which when taken in excess cause an osmotic diarrhoea. This type of diarrhoea is associated with an osmolar gap in excess of 125 mosmol/kg. ¹¹ Secretory diarrhoeas, on the other hand, are caused by unabsorbed electrolytes in the lumen and are associated with an osmotic gap of less than 50 mmol/kg. ¹¹ If the osmolar gap indicates the presence of a laxative agent then this should be confirmed via a laxative screening test.

Laxative screening is available at various referral laboratories across the UK (Assay Finder Ltd at www.assayfinder.com revealed five different sites in April 2012). The assay is generally conducted on urine samples as laxative concentrations tend to be much higher in urine than in serum. However, serum and faecal screens are available. The screen is conducted by either mass spectrometry or gas chromatography, and should include detection of anthraquinones, biscadoyl and phenolphthalein. ¹¹ Thin-layer chromatography methods must be avoided as they have a high false-negative rate for senna based products and a high false-positive rate for bisacodyl. ⁴²

Repeat screening may be necessary to identify intermittent intake. ¹¹ In addition, broad screening is recommended for all laxative testing, even if a previous positive result for a particular agent has been obtained. This is because patients may alternate the type of agent used between tests. Magnesium would not be identified on a laxative screen, and therefore should be measured separately along with every laxative screen request. ¹¹ A stool magnesium concentration of greater than 45 mmol/L strongly indicates magnesium induced diarrhoea. ¹¹

Induced hypernatraemia

There are multiple reports of hypernatraemia that have been induced via the intake of large quantities of salt. ⁴³ Such hypernatraemia from salt overload tends only to be described in infants and young children, rather than older children and adults. In part this is due the inability of the immature kidney to excrete a large sodium load, but is also due to the lack of capability of a young child to satisfy their thirst without help. ⁴³

Hypernatraemia in an infant of any cause is rare. In any child presenting with hypernatraemia, a urine osmolality should be conducted to exclude a defect in the concentrating ability of the renal tubules. ⁴⁴ There is no UK estimate available of the prevalence of hypernatraemia in infants that are not exclusively breast fed; an annual incidence of only two in 100,000 babies was approximated following review of a large Texas study. ⁴⁵ Most cases are the result of dehydration, whether due to lack of water intake (e.g. inadequate provision of breast milk) or excessive loss of water (e.g. diarrhoea). Unintentional salt overload has also been described, for example, following incorrect preparation of feeds by parents or carers. ⁴⁶ Non-accidental salt overload, including cases of FII, accounts for only a minority of cases of hypernatraemia (approximately 1 in 200). ⁴⁵

The fractional sodium excretion is a useful indicator of the cause of hypernatraemia and should be used to distinguish salt overload (of any cause) from hypernatraemia of dehydration. This distinction is important for both medical and legal reasons. Calculation of fractional sodium excretion requires analysis of sodium and creatinine in paired urine and serum samples. In an infant with normal renal function, the fractional sodium excretion should be less than 1% during hypernatraemia of dehydration but greater than 2% in volume replete patients with salt overload. ⁴⁴ Indeed, much higher fractional excretion rates have been encountered during investigation of hypernatraemia due to excessive salt intake.

Fractional sodium excretion should be calculated at frequent intervals during the child's recovery. ⁴⁵ If sodium and water provision during treatment is known, then fractional excretion data may be used to determine the pattern of change in sodium and water balance – thus aiding the diagnosis. For example, in hypernatraemia of dehydration sodium balance would be approximately neutral, while fluids would be avidly retained by the patient. In contrast, sodium excretion would be expected to be in excess of intake in a patient recovering from salt overload.

It is important to note that urinary sodium concentrations may be elevated in cases of salt overload and in dehydration. Meadows et al. ⁴³ found that urine sodium concentrations following salt overload were usually in the range of 200–230 mmol/L. Although, the urine sodium concentrations associated with hypernatraemia of dehydration are generally lower, ⁴⁷ there is significant overlap in the values and thus this measure cannot be used to distinguish the two conditions. ⁴⁵

A sample of gastric aspirate should also be obtained at the earliest opportunity in all infants admitted with hypernatraemia. ⁴⁵ Gastric aspirates usually contain 50–60 mmol/L sodium; ⁴³ sodium concentrations exceeding 200 mmol/L are therefore highly suggestive of salt ingestion. ⁴³ Serum analysis of bicarbonate, chloride, phosphate and calcium may also be useful to determine the nature of the sodium salt administered. ⁴⁵ Typically, sodium chloride (table salt) is implicated, but sodium bicarbonate and sodium phosphate have been recorded as causes of hypernatraemia.^43,48,49

Induced hypoglycaemia

Surreptitious administration of exogenous insulin or insulin secretagogues such as sulphonylureas has been used to induce hypoglycaemia.^50–52 Hyperinsulinaemia is suspected based on the large glucose requirements needed to obtain normoglycaemia, and a positive response to glucagon administration, if tested. Unfortunately, partial pancreatomy for a suspected insulinoma may be conducted prior to the true cause of the hypoglycaemia being identified. ⁵¹

A clinician's awareness for factitious disorder combined with appropriate application of laboratory tests can be used to avoid unnecessary surgery. In particular, factitious causes of hypoglycaemia should be excluded early if the episodes occur in an apparently random fashion. Unlike true hyperinsulinism, the hypoglycaemia of factitious disease typically occurs at random intervals with no relationship to food intake nor fasting. ⁵²

A diagnosis of induced hypoglycaemia can usually be established via simultaneous measurement of insulin, C-peptide, (pro-insulin) and insulin secretagogues. All samples for analysis should be obtained at the time of hypoglycaemia, as useful information can only be yielded from measurements made on simultaneous collections. In patients with hypoglycaemia due to an insulinoma or via secretagogue administration, the plasma insulin, C-peptide and pro-insulin concentrations can be raised or within the normal fasting range, but always inappropriate for the degree of hypoglycaemia. Analysis of C-peptide and insulin alone will not differentiate between these two causes, and therefore the diagnosis of induced hypoglycaemia may be missed.

Direct analysis of secretagogues is available, and can be conducted on a small volume of plasma. Their measurement should therefore be considered in any case of suspected insulinoma prior to surgical intervention, particularly when hypoglycaemia appears to occur in a random fashion. In one study, positive sulphonylurea screens were found on 31 out of 94 samples previously obtained during hyperinsulinaemic hypoglycaemic episodes. ⁵³ Of these samples, 10 were identified as relating to possible cases of factitious drug ingestion – a diagnosis which had not been considered at the time. ⁵³

When exogenous insulin has been administered to induce hypoglycaemia, the insulin concentration is high whereas C-peptide and pro-insulin concentrations are low. Furthermore, the plasma insulin concentration is typically >100 mU/L following exogenous administration, while in fasted insulinoma patients the insulin concentration does not tend to exceed 20 mU/L. ²⁹ However, immunoassays for insulin have various degrees of cross-reactivity with insulin analogues. The insulin result obtained will therefore depend on (i) the insulin analogue present and (ii) the cross-reactivity of the assay with that analogue. ⁵² It is the laboratory's responsibility to ensure that they are aware of the specificity of the insulin assay in use, so that appropriate interpretation is made. For example, potentially misleading results were obtained in a case of induced hypoglycaemia when the insulin analogue ‘Humalog’ was administered. ⁵² In this instance, the assay used had low cross-reactivity to Humalog, and therefore low insulin concentrations were recorded. Fortunately further investigation was conducted using alternative immunoassays with higher cross-reactivity, and by liquid chromatography tandem mass spectrometry (LC-MS/MS). Humalog was subsequently positively identified. ⁵²

Factitious thyrotoxicosis

Surreptitious intake of thyroxine will cause symptoms and basic thyroid biochemistry diagnostic of thyrotoxicosis; however, suspicion of a factitious cause should be raised if thyroid results do not respond to treatment. ²⁷ As well as clinical examination for goitre and ophthalmic signs, investigations to exclude thyroxine-induced thyrotoxicosis should include TSH, free T4 assays and radio-isotope uptake studies. Thyroglobulin analysis has also proved useful in the past. ⁵⁴ Radio-isotope uptake studies are used to exclude hyperthyroidism and ectopic thyroid hormone production; a low uptake will occur in cases of thyroiditis or factitious thyrotoxicosis. Thyroglobulin analysis is then useful to exclude thyroiditis. Thyroglobulin should be low-normal in cases of factitious disease, due to suppression of endogenous thyroid hormone production, while in thyroiditis, the thyroglobulin concentration is elevated. However, the laboratory should be aware that falsely low thyroglobulin results may occur due to interference in the assay for persons with antithyroglobulin antibodies. ⁵⁵ In such cases, analysis of antithyroglobulin antibody status may be useful to validate the thyroglobulin result.

Factitious Cushing's syndrome

Steroid administration to purposefully induce a Cushingoid state has been described; however, the abnormality in the blood results will depend on the glucocorticoid taken and its cross-reactivity within the cortisol assay. ²³ Physical evidence of Cushing's syndrome presenting with low cortisol and ACTH concentrations indicates possible surreptitious intake of a glucocorticosteroid that has low cross-reactivity within the cortisol assay. In this instance, HPLC may be used to distinguish the presence of endogenous and exogenous steroids. ²⁴ Self-administration of hydrocortisone, on the other hand, is harder to detect, and suspicion may only be raised if cortisol results are extreme or highly variable. This is because exogenous ‘natural’ glucocorticoids are difficult to discriminate from endogenous sources. A method developed for the detection of doping offences within sport utilizes isotope ratio mass spectrometry to identify exogenous steroid abuse. ⁵⁶ In this technique, the higher proportion of the carbon-13 isotope within endogenous steroids compared with their synthetic analogue is used to determine the presence of exogenous steroids. ⁵⁶ A similar approach could potentially be utilized in the future for the detection of factitious Cushing's syndrome.

Factitious phaeochromocytoma

Multiple publications have described factitious phaeochromocytoma presenting either via injection of epinephrine to induce symptoms or direct addition of epinephrine to urine samples.^57–59 On each occasion isolated increases in urine epinephrine concentrations were identified. However, catecholamine analysis revealing isolated epinephrine elevations would be highly unusual for a true phaeochromocytoma. ²⁶

Catecholamines are metabolized to metanephrines within tumour cells of a phaeochromocytoma. This process occurs continuously, and independently of catecholamine release so that in phaeochromocytoma metanephrine concentrations remain high even between symptomatic episodes. The condition can therefore be practically excluded by normal metanephrine concentrations. Indeed, following the transition to the use of urine metanephrine as a first line screen for phaeochromocytoma, use of epinephrine to induce disease may go undetected. ²⁶

Analysis of Chromogranin A may be a useful adjunct to the diagnosis. This protein is synthesized and secreted with catecholamines, and so a high level of Chromogranin A will therefore indicate an endogenous source. However, Chromogranin A is not specific to phaeochromocytoma and may be raised in other conditions including liver disease, renal insufficiency and stress.

Factitious Bartter's syndrome

Bartter's syndrome is a rare genetic disorder affecting the ascending loop of Henle. The disorder is associated with a hypokalaemic alkalosis, hyperaldosteronism and hypercalciuria. Typically the disorder presents in childhood and a renal biopsy of the kidney will show hyperplasia of the juxtaglomerular apparatus.

A few cases of factitious presentations of the diseases have appeared in the literature, including one of FII.^60,61 The biochemical abnormalities are mimicked by surreptitious intake of loop diuretics, and it is likely that many such cases go undetected. Furthermore, hyperplasia of the juxtaglomerular apparatus may be caused by prolonged diuretic ingestion. ⁶⁰ Therefore, due to the rarity of the disorder, surreptitious intake of diuretics should be excluded in any patient presenting with signs and symptoms of Bartter's syndrome. A diuretic screen can be conducted using HPLC of urine samples, although, several samples may need to be tested to improve sensitivity. Urinary chloride analysis will show large variability if diuretic intake is intermittent.

Surreptitious vomiting may also generate serum biochemistry typical of Bartter's syndrome – however, this cause can be excluded via analysis of the urine chloride. Urine chloride will be low if hypokalaemia is caused by vomiting, due to renal conservation, whereas Bartter's syndrome is associated with increased chloride excretion.

Other considerations for the laboratory

The laboratory should be aware of results that appear highly variable over a period of time and/or incompatible with the rest of the biochemical profile. Errors occurring during analysis or possible sources of interference should always be excluded, but it is important to consider sample manipulation if no obvious cause can be found. Indeed, discrepant biochemical results relating to factitious disease may initially be regarded by the clinician as analytical error. ⁶² For example, a negative pregnancy test was ignored when a women presenting to an emergency centre was subsequently found to have elevated serum beta HCG. ⁶² However, no intrauterine pregnancy was observed via sonogram and an ectopic pregnancy was subsequently excluded by surgery. The elevation in serum beta HCG had been caused via self-injection of HCG and evaluation of the patient's medical history revealed 30 previous surgical procedures for alleged gynaecological reasons. ⁶² This case shows that discrepant biochemical results should not be dismissed as laboratory error without further investigation (which may only involve a repeat analysis).

When any investigation of factitious disease is initiated, direct communication by the laboratory with the clinician is essential. This will ensure that the most appropriate tests are conducted to enable confirmation or exclusion of the diagnosis without unnecessary delay. The clinician should provide the laboratory with details of the patient's medical and family history. This information may identify the source of any drugs used to induce illness, and thus direct what should be tested for as a priority. Discussion of biochemical results may also help the clinician proceed with non-laboratory based investigations. For example, raised CK concentrations in combination with a suspicious presentation of myocardial infarction should prompt the clinician to question the patient regarding any muscular trauma. In addition, the laboratory should be available to advise clinicians on the importance of time critical samples, for example collection of simultaneous samples for insulin, C-peptide and secretagogues during hypoglycaemic episodes investigation. Frequent repeat investigations to assess dynamic changes should be encouraged, such as monitoring of fractional sodium excretion during the investigation of hypernatraemia.

When factitious disease is induced in a child, laboratory evidence may be required at any future trial. A chain of custody form must therefore be kept with any samples obtained from a child with suspected factitious illness, and signed by all persons involved with processing of the sample. This documentation, along with full details of the case, should be provided to any referral centre utilized for sample analysis. Indeed, direct discussion with the referral laboratory prior to sending any sample under investigation will also ensure that the most appropriate tests will be conducted.

Finally, it is always important to remember that factitious disorder is not a diagnosis of exclusion. Early investigation to confirm or exclude factitious disease should be conducted if it features within the differential diagnosis. Equally, rare disorders should not be forgotten, and equivalent effort should be put into the investigation of true disease. However, continued exploration into increasingly rare disorders without consideration of factitious disease can lead to harm of the patient.

Management of the patient diagnosed with a factitious disorder

There appears to be little concensus on the appropriate management and follow-up of patients diagnosed with a factitious disorder, and the general prognosis for such patients is poor.^63–66 The Royal College of Paediatrics and Child health offers advice specific to cases of FII; ⁵ however, there is currently no evidence based guideline to advise on patient management in cases of factitious disorder. The laboratory should therefore liaise closely with local clinicians to aid appropriate laboratory based follow-up on a case-by-case basis.

Conclusion

Factitious disorder can present with a fascinating array of fabricated diseases from within all medical specialties. Although an uncommon diagnosis, its early detection is important in order to prevent unnecessary and prolonged investigation. Exclusion of factitious disorder should therefore be conducted before complex tests for rare disorders are initiated – particularly when such investigations involve invasive procedures.

Often the patients own medical knowledge is used to manipulate samples and symptoms to mimic a disease profile. A diagnosis can therefore be very difficult to make, as is reflected by the number of investigations that a patient may undergo before the true cause of disease is discovered. However, there may be clues to the diagnosis early on. For example, the clinician should be aware of unusual presentations or illnesses that take on an unusual course following initiation of treatment. The laboratory can also aid the clinician by highlighting highly variable results, or even results that together do not make biochemical sense.

Good communication between the laboratory and clinician can significantly aid a rapid diagnosis of factitious disorder. When abnormal biochemical results are the first clue to the diagnosis, the laboratory may be called upon to help identify the means by which the fabricated results were obtained. This can be extremely important for medicolegal reasons. If investigation of factitious disease is requested then the clinician must provide as much information to the laboratory as possible in terms of clinical signs and symptoms, so that appropriate tests can be advised. The role of the laboratory in this group of patients is crucial to their management.