Mbs reviews vitamin b12 testing report february 2014 table of contents section Page

4 REVIEW OF GUIDELINES RELEVANT TO VITAMIN B12 TESTING

This Chapter presents the results of the literature search for clinical practice guidelines relevant to vitamin B12 testing.

4.1 Clinical practice guidelines

4.1.1. Australian Guidelines

No Australian guidelines were identified that made recommendations on vitamin B12 testing.

4.1.2 International Guidelines

International guidelines related to the use of vitamin B12 vary widely in their recommendations. While some recommend vitamin B12 testing as a screening tool in commonly encountered illnesses such as dementia, others suggest restricting testing to patients who have already undergone pre-test investigations (such as full blood examinations and blood film examination).
A rapid review from the Division of Evidence Development and Standards at Health Quality Ontario (see Chapter 5.1 for further details) identified three guidelines on the diagnosis of vitamin B12 deficiency.⁽⁷¹⁾ The three guidelines^(72-74) were assessed using the AGREE appraisal tool⁽⁷⁵⁾. The recommendations from each of the guidelines are listed in Table 4.1. Two of the guidelines were systematic reviews with recommendations.^{(72, 73)} The guideline by the British Columbia Medical Association and Ministry of Health was not explicitly based on a systematic review of the literature. In the methods that are reported on the website that published the guideline, the authors state that a full systematic review may not be conducted for all of their guidelines. As a result, it is unclear whether this guideline was based on the results of a systematic review. The three guidelines scored poorly on linking the evidence to the recommendations.⁽⁷¹⁾
A further nine guidelines, eight of which focused on specific clinical conditions or patient populations, were identified in the literature search for clinical practice guidelines. Relevant recommendations from these guidelines are summarised in Table 4.1.
Table 4.1: Guidelines relating to vitamin B12 testing

Title	Author and country	Populations	Frequency	Overall recommendation
Cobalamin (vitamin B12) Deficiency - Investigation and Management (2012)^(74)	British Columbia Medical Association/ Ministry of Health, Canada	Patients with unexplained neurologic symptoms (parasthesia, numbness, poor motor coordination, memory lapses) Patients with macrocytic anaemia or macrocytosis Other populations where testing is considered include: Elderly >75 years Inflammatory bowel disease (of small intestine) Gastric or small intestine resection Prolonged vegan diet (no meat, poultry or dairy products) Long-term use of H2 receptor antagonists or proton pump inhibitors (at least 12 months), or metformin (at least 4 months)	Not reported	Routine screening for vitamin B12 deficiency is not recommended
Best practice in primary care pathology: review 1 (2005)^(73)	Smellie et al, UK	Patients with macrocytic anaemia Patients with macrocytosis Patients with specific neuropsychiatric abnormalities	There is no obvious merit in repeating vitamin B12 measurements unless lack of compliance is suspected or anaemia recurs	Emphasise the importance of attempting to assess whether deficiency is present before requesting vitamin B12 levels... assess medication, family history, diet, alcohol intake and symptoms of malabsorption
Vitamin B12 (cobalamin) deficiency in elderly patients (2004)^(72)	Andres et al, Canada	All elderly who are malnourished All patients in institutions and psychiatric hospitals All patients with haematological or neuropsychiatric manifestations of vitamin B12 deficiency	Not reported	All people over 65 years of age who are malnourished, all people in institutions or psychiatric hospitals, and all people with haematological or neuropsychiatric manifestations of vitamin B12 deficiency should have their serum vitamin B12 levels measured
Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies (1994)^(76)	The British Committee for Standards in Haematology (BCSH) UK	Patients with the following clinical indications: Gastrointestinal disease Neurological disease Psychiatric disorders Malnutrition Alcohol abuse Autoimmune disease of the thyroid, adrenal and parathyroid glands Family history of pernicious anaemia Infertility Haematological diseases associated with vitamin deficiency Drugs that interfere with vitamin absorption Metabolic disease in infants	Not reported	Serum B12 testing (and serum and red cell folate testing) follow the initial investigation of blood count and blood film examination MMA and Hcy measurements are considered as “subsidiary investigations”
Chronic kidney	Disease (CKD)
Clinical Practice Guideline for anaemia in chronic kidney disease (2012)^(77)	Kidney Disease Improving Global Outcomes (KDIGO) International^5	Patients with CKD	Not reported	Vitamin B12 testing should be performed in the initial evaluation of the causes of anaemia in CKD patients
Dementia
Supporting people with dementia and their carers in health and social care (2012)^(78)	National Institute for Health and Care Excellence (NICE) UK	Patients presenting with dementia symptoms	Not reported	Serum vitamin B12 (and folate) is recommended as a basic dementia screen to be performed at the time of presentation, usually within primary care
Practical Guidelines for the Recognition and Diagnosis of Dementia (2012)^(79)	Galvin and Sadowsky US	Patients presenting with dementia symptoms	Not reported	Testing serum vitamin B12 is one of the pre-diagnostic tests to determine coexisting disorders
Cognitive impairment in the elderly-Recognition, diagnosis and management (2007)^(80)	British Columbia Medical Association/ Ministry of Health, Canada	Elderly with cognitive impairment and dementia	Not reported	Vitamin B12 testing is recommended as one of the laboratory tests in the initial work-up of suspected dementia or mild cognitive impairment
A synopsis of the practice parameters on dementia from the American academy of neurology on the diagnosis of dementia (2004)^(81)	Pitner and Bachman	Patients with dementia	Not reported	B12 deficiency should be screened for and treated in patients with dementia
Chronic fatigue	syndrome (CFS)	or myalgic encephalopathy (ME)
Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management of CFS/ME in adults and children (2007)^(82)	NICE UK	People with CFS/ME	Not reported	Tests for vitamin B12 deficiency and folate levels should not be carried out unless a full blood count and mean cell volume show a macrocytosis
Distal symmetric	polyneuropathy
Practice parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory and genetic testing (an evidence –based review) (2009)^(83)	American Academy of Neurology (AAN)	Patients with polyneuropathy	Not reported	Serum B12 with metabolites (methylmalonic acid with or without homocysteine) tests may be considered for all patients with polyneuropathy
Chohn’s disease
Systematic review: managing anaemia in Crohn’s disease (2006)^(84)	Kulnigg and Gasche Austria	Patients with Crohn’s disease or inflammatory bowel disease	Not reported	Routine vitamin B12 measurements are not necessary, only if patients have macrocytic anaemia or do not respond to iron treatment

Guidelines from the British Columbia Guidelines and Protocols Advisory Committee (2012)⁽⁷⁴⁾ recommend performing a full blood count, blood film and serum cobalamin in all patients suspected of cobalamin deficiency. The guidelines recommend interpreting serum cobalamin levels in light of clinical symptoms, because the test has the following limitations:⁽⁷¹⁾

• 
  it measures total, not metabolically active cobalamin;
  
• 
  the levels of cobalamin do not correlate well with clinical symptoms; elderly patients may have normal cobalamin levels with clinically significant cobalamin deficiency, while women taking oral contraceptives may have decreased blood cobalamin levels due to a decrease in transcobalamin, a carrier protein, but no clinical symptoms of deficiency;
  
• 
  there is a large ‘gray zone’ between the normal and abnormal levels; and
  
• 
  the reference intervals may vary between laboratories. The guidelines state that the conventional cut-off for serum cobalamin deficiency varies from 150-220 pmol/L.
  

The best practice review by Smellie et al. (2005)⁽⁷³⁾ on the diagnosis and monitoring of vitamin B12 (and folate) deficiency was based on a standardised literature search of national and international guidance notes, consensus statements, health policy documents, and evidence based medicine reviews, supplemented by relevant primary research documents. However, the authors of the best practice review stated that the recommendations were mostly ‘consensus rather than evidence based’. Therefore, the guidance/recommendations were derived from a small number of reviews, supplemented by extrapolations from knowledge of the physiology of vitamin B12 and folate. The best practice review recommended that vitamin B12 (and folate) testing should be performed in patients with macrocytic anaemia, macrocytosis, and specific neuropsychiatric abnormalities (including paraesthesia, ataxia, peripheral neuropathy, and memory loss).⁽⁷³⁾

The systematic review by Andres et al (2004)⁽⁷²⁾ used a flow chart or care pathway to describe recommendations. A notable difference in the guideline by Andres et al (2004) was that the authors recommended screening all patients in institutions or psychiatric hospitals for vitamin B12 deficiency. Andres et al (2004) reported that the prevalence of vitamin B12 deficiency was much higher (30% to 40%) in patients who were sick or institutionalised. As mentioned above for the British Columbia Medical Association guideline, there was a very weak relationship between the recommendations and the evidence presented in all guidelines.
The British Committee for Standards in Haematology (BCSH) published a review entitled "Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies" in 1994⁽⁷⁶⁾. Although now very dated, this publication highlighted that vitamin B12 deficiency was synonymous with macrocytic anaemia, but that many patients with pernicious anaemia may present without either anaemia or macrocytosis.⁽⁷⁶⁾ However, emphasis on haematological indices and blood film examination is strong and the authors did not provide comment on the relative merits of various laboratory and test procedures nor on appropriate testing algorithms.
There are several guidelines that focus on specific clinical conditions, which indicate that serum vitamin B12 levels should be assessed. The clinical conditions include (but not limited to) cognitive impairment^{(79, 80)}, dementia⁽⁸¹⁾, Crohn’s disease⁽⁸⁴⁾ and chronic fatigue syndrome⁽⁸²⁾.
The guideline published by the British Columbia Medical Association and Ministry of Health on cognitive impairment in the elderly stated that data from systematic reviews of RCTs (only one of which was cited, Malouf et al. (2003)⁽⁸⁵⁾ did not provide evidence of improvement in cognition or dementia with vitamin B12 treatment.
In addition, many guidelines recommended the evaluation of vitamin B12 deficiency in the workup for clinical indications without specifying a methodology. An exception is in a practice parameter for peripheral neuropathy by the American Academy of Neurology (AAN) that has specified a methodology (evidence level C): screening for “serum B12 level with metabolites (methylmalonic acid with or without homocysteine)” in the evaluation for vitamin B12 deficiency in all patients with distal symmetric polyneuropathy.⁽⁸³⁾