MBS Review
Vitamin B12 Testing
Protocol
July 2013
CONTENTS
ABBREVIATIONS 1
INTRODUCTION TO MBS REVIEWS 2
Principles to Guide MBS Reviews 3
Objectives of the Review 3
Purpose of the Protocol 3
Stakeholder Consultations 3
Public Consultations 4
Medical Craft Groups / Key Stakeholders 4
Background 5
Mechanism of vitamin B12 absorption 5
Functions of vitamin B12 in the human body 6
Causes of vitamin B12 deficiencies 7
Diseases caused by Vitamin B12 deficiencies 8
Vitamin B12 testing 8
Prevalence of Vitamin B12 deficiencies in Australia 10
Clinical Flow Chart 12
METHODOLOGY 13
Population, Intervention, Comparator, Outcomes (PICO) 13
MBS data 15
Guideline concordance 15
Economic evaluation 15
References 16
APPENDIX A – MBS DATA 19
APPENDIX B - SEARCH TERM STRATEGY 21
APPENDIX C – SEARCH STRATEGY 29
ABBREVIATIONS
µg / Microgram /AD / Alzheimer’s Disease /
AIHW / Australian Institute of Health and Welfare /
ANZFSC / Australia and New Zealand Food Standards Code /
CMFM / Comprehensive Management Framework for the MBS /
CoA / Coenzyme A /
CVD / Cardiovascular disease /
Department / Department of Health and Ageing /
DNA / Deoxyribonucleic acid /
ESC / Evaluation Sub-Committee (of MSAC) /
FDA / Food and Drug Administration /
HPLC / High performance liquid chromatography /
holoTC / Holotranscobalamin II /
IF / Intrinsic factor /
MSAC / Medical Services Advisory Committee /
MBS / Medicare Benefits Schedule /
MMA / Methylmalonic acid /
ng/ml / Nanogram per millilitre /
NTD / Neural Tube Defects /
oz / Ounce /
PA / Pernicious anaemia /
PASC / Protocol Advisory Sub-Committee /
PBS / Pharmaceutical Benefits Scheme /
pg/ml / Picogram per millilitre /
PICO / Population, intervention, comparator, outcome /
Pmol/L / Picomole per Litre /
RBC / Red Blood Cell /
RCC / Review Consultation Committee /
RDA / Recommended Dietary Allowance /
TGA / Therapeutic Goods Administration /
INTRODUCTION TO MBS REVIEWS
In the 2011-12 Budget, the Australian Government committed to continue the systematic review of Medicare Benefits Schedule (MBS) items to ensure that they reflect contemporary evidence, improve health outcomes for patients and represent value for money under the Comprehensive Management Framework for the MBS (CMFM).
Reviews support the public funding of evidence-based, cost-effective clinical practice through the MBS.
The MBS Reviews process includes the consideration of policy issues related to services funded under the MBS and is designed to have flexibility depending on the complexity of the issues pertaining to the particular review. For example, where there is a single MBS item or service the review may be focussed and timeframes may not be as exhaustive as a review that include multiple MBS items with related policy issues or non MBS issues. Non MBS issues that require a different process (such as pharmaceuticals or prostheses), and policy issues that are not appropriately dealt with by the Medical Services Advisory Committee (MSAC) process will be identified and addressed in separate processes which will inform the review.
The first stage of a review is the identification of the scope. Reviews with single MBS services/issues will follow the MBS pathway and will be considered by MSAC using the MSAC process. For reviews with multiple MBS services or a specialty and policy issues, the scope and pathway (MBS pathway and policy pathway) will be confirmed by the Review Consultation Committee (RCC), a time limited committee of nominated experts, determined and chaired by the Department.
The MBS pathway will follow the MSAC process and include the:
· development of a protocol;
· collection and evaluation of evidence; and
· advice and recommendations to the Minister through the Department.
The pathway for policy and other issues depends on the issues identified in the scope. There will be interactions between the MBS and policy pathways and stakeholders will be consulted throughout the review process; ensuring alignment of processes and consistency in deliberations.
The engagement with stakeholders is a critical component of the reviews process and issues will be dealt with in a consultative fashion. The role of the RCC is advising the Department on policy issues and the MSAC and its subcommittees is advising on MBS matters. The review process is flexible, ensuring that new and emerging issues and feedback from the RCC, MSAC or public consultations can be incorporated into the reports.
The advice and recommendations provided by the CRC and MSAC to the Department informs the advice for the Minister.
Principles to Guide MBS Reviews
Reviews will:
· have a primary focus on improving health outcomes and the financial sustainability of the MBS, through consideration of areas potentially representing:
§ patient safety risk;
§ limited health benefit; and/or
§ inappropriate use (under or over use)
· be evidence-based and fit-for-purpose;
· be conducted in consultation with key stakeholders including, but not limited to, the medical profession and consumers;
· include opportunities for public submission;
· be published; and
· use Government resources efficiently.
Objectives of the Review
To ensure the clinical and financial sustainability of the MBS, reviews will assess specific services or MBS item(s) and associated policy issues in a focused, fit-for-purpose, evidence based process. Findings will recognise that MBS funding should align with contemporary evidence, reflecting appropriate patient groups and best clinical practice.
Purpose of the Protocol
This document outlines the methodology for providing evidence based analysis to support the review of services for vitamin B12 testing, specifically the frequency of testing and the appropriate patient population for testing. The Protocol outlines the review methodology, clinical research questions the review will focus on, methods to identify and appraise the evidence and key stakeholder groups and experts to be consulted during the conduct of the review.
Stakeholder Consultations
The Department is responsible for the review process including documents developed for policy and MBS issues and contractual arrangements for the development of the protocol and other report documents for the review. This includes ensuring that the relevant documents are available online for public consultation at the appropriate time and that comments are incorporated into informing the review process.
The Department’s management of stakeholder engagement and negotiations with the relevant medical craft groups and key stakeholders will ensure the review findings are informed by consultations.
Following the finalisation of the review process, the advice to the Minister for Health on the findings of the review will be informed by the review reports, advice and recommendations from MSAC and RCC, public consultations and also other information that is relevant to the review including budgetary considerations.
Questions to be delivered to the RCC include, but are not limited to the following:
(1) Is vitamin B12 testing appropriate for MBS reimbursement?
(2) What are the expected patient health outcomes with regard to patient groups, type of intervention and practitioners ordering and performing (accreditation and training) the vitamin B12 testing?
(3) What are the clinical indications for medically necessary vitamin B12 testing?
(4) Are current assays used for the detection of serum vitamin B12 levels accurate and reflect the true status of vitamin B12 in the Australian population?
(5) What are the safety, efficacy, effectiveness of the tests and the effect that the results of the test have on treatment?
Public Consultations
The invitations to the general public (which include all stakeholders - patients, consumer groups, individual service providers, health professionals and manufacturers) to provide comment on the draft documents during the review process are critical to the review process. The documents will be available on the MSAC website (www.msac.gov.au) inviting the public to submit written comments over a four week period. The purpose of the feedback is to inform the final reports and recommendations to the Minister.
Medical Craft Groups / Key Stakeholders
The following clinical craft groups and key stakeholders have been identified as having an interest in this review:
· Osteoporosis Australia;
· IVD Australia;
· Australia and New Zealand Bone and Mineral Society;
· Endocrine Society of Australia;
· National Prescribing Network;
· Australian Association of Pathology Practices;
· Australian Medical Association;
· Consumers Health Forum of Australia;
· National Coalition of Public Pathology;
· Royal Australian College of General Practitioners; and
· Royal College of Pathologists of Australasia.
Background
Mechanism of vitamin B12 absorption
Vitamin B12, also called cobalamin, is a water soluble vitamin that plays a fundamental role in the normal functioning of the brain and nervous system, and for the formation of blood. Dietary vitamin B12, obtained from animal food, is bound to animal protein. The acid and pepsin in the stomach breakdown these protein and release vitamin B12. The free vitamin B12 then binds a protein called haptocorrin (previously known as Transcobalamin I or R-Factor or R-protein), which is produced by the salivary glands and parietal cells of the stomach whose essential function is to protect vitamin B12 from degradation from the acidic environment of the stomach. In the duodenum, the pancreatic enzymes degrade the haptocorrin, and vitamin B12 is released again which then binds to the intrinsic factor (IF) produced by parietal cells. Absorption of vitamin B12 occurs in the terminal ileum (i.e. most distal part of the small intestine) and is aided by binding the complex to the IF receptor on the mucosal surface (Figure 1). In addition to this method of absorption, evidence supports the existence of an alternate pathway that is independent of the IF. This pathway is important in relation to oral supplementation (approximately 1% of a large oral dose of vitamin B12 is absorbed by this second mechanism)(1) Once absorbed, vitamin B12 is bound to two carrier-proteins in blood: haptocorrin and transcobalamin .The majority of vitamin B12 (70-80%) is bound to haptocorrin (named as holo-haptocorrin) and is not biologically active. Only less than 30% of the B12 is bound to trascobalamin II (named as holo-transcobalamin (HoloTC)) which is the active fraction that enters cells for metabolic reactions. Details of these carrier proteins will be discussed later. The interruption of one or any combination of these steps places a person at risk of developing vitamin B12 deficiencies.(2)
Figure 1: Vitamin B12 absorption and transport (2)
Functions of vitamin B12 in the human body
In humans, vitamin B12 and folate are linked by two enzymatic reactions where they function as cofactors (i.e. a cofactor is a component, other than the protein portion, of many enzymes to facilitate the catalytic activity of the enzyme)(3). Vitamin B12 is required as a cofactor in both reactions, whereas folate is required in only one of the reactions (see Figure 2).(2)
Figure 2: The enzymatic reactions that require vitamin B12 and folate (folic acid) as cofactors (4)
In the first reaction, vitamin B12 is required for the conversion of methylmalonic acid (MMA) to succinyl-CoA. MMA is a substance produced when proteins in the body are broken down.(5) Folate does not play any role in this reaction. Deficiency in vitamin B12 can lead to increased levels of serum MMA.(2)
In the second reaction, both vitamin B12 (in the form of methylcobalamin) and folic acid act as cofactors in the conversion of the substrate homocysteine (a homologue of the amino acids cysteine and methionine) to methionine (an amino acid and one of the 20 building blocks of proteins) by the enzyme methionine synthase.(2, 6) More importantly, this pathway is closely linked to the generation of thymidine which is vital for deoxyribonucleic acid (DNA, i.e. the building block of the human body which carries genetic information) synthesis. A deficiency in either vitamin B12 or folic acid or both can lead to increased homocysteine levels in plasma.(2) In addition, deficiency of either vitamins can result in perturbation of these two key pathways with consequent disruption of DNA synthesis caused by thymidine lack and resulting in megaloblastic anaemia, as well as other adverse effects on the nervous system and other organs.(2) It is this metabolic reaction that clearly links the two vitamins and is responsible for the common or shared neuropsychiatric and haematologic disorders discussed in the following sections.
Vitamin B12: dietary sources, fortification, and supplements
Vitamin B12 is present in animal products such as meat, poultry, fish (including shell fish), and to a lesser extent milk, cheese and eggs, and it is not present in plant products.(7) The recommended dietary allowance for vitamin B12 is 2.4 µg/day (8) and most individuals can meet this level through dietary intake.(9) Table 1 lists some of the foods with substantial amounts of vitamin B12 along with their vitamin B12 content. Individuals over the age of 50 who have reduced protease secretions in the stomach (as well as strict vegetarians)(10) obtain their vitamin B12 from supplements or fortified foods (e.g. fortified cereal) because of the increased likelihood of food-bound vitamin B12 malabsorption.
Table 1: Examples of dietary sources of vitamin B12 and folate (7, 11)
Type of food / Estimated vitamin B12 content (micrograms µg) /Clams, 3 oz (85 grams) / 84.0 /
Mussels, 3 oz / 20.4 /
Crab, 3 oz / 8.8 /
Salmon, 3 oz / 2.4 /
Beef, 3 oz / 2.1 /
Chicken / 0.3 /
Egg (whole) / 0.6 /
Milk (8 oz, 1 glass) / 0.9 /
Food fortification is defined as the process of adding micronutrients (such as vitamins and minerals) to food as permitted by the Australian and New Zealand Food Standards Code (ANZFSC).(12) Regulations regarding the fortification of foods with vitamin B12 vary between countries. ANZFSC permits only a limited number of foods to be fortified with vitamin B12. This includes selected soy milks, yeast spread, and vegetarian meat analogues.(13)
The risk of toxicity from vitamin B12 intake from supplements and/or fortified foods is low.(14) Vitamin B12 is a water soluble vitamin, and therefore any excess intake is usually excreted in the urine.
Causes of vitamin B12 deficiencies
Table 2 describes causes of vitamin B12 deficiencies which can be divided into four categories: nutritional deficiency, increased requirements, impaired absorption, and other gastrointestinal causes.(6, 15)
Table 2: Causes of vitamin B12 deficiencies
Nutritional deficiency / Increased requirements / Impaired absorption / Other gastrointestinal causes· Poor intake of meats and dairy products in the elderly population (aged 65 and above) (16)
· Alcoholism (17, 18)
· Strict vegan diets (16)
· Malnutrition (19) and avoidance of fortified bread due to coeliac disease (20, 21) / · Due to pregnancy and lactation (22) / · Autoimmune disease with autoantibodies against the intrinsic factor (pernicious anaemia) (23) (24)
· Atrophic body gastritis (due to autoantibodies to gastric parietal cells)(25)
· Gastrectomy (26)
· Prolonged use of acid-suppression therapy or drugs (27) / · Chronic gastrointestinal symptoms e.g. dyspepsia, recurrent peptic ulcer, diarrhoea (2)
· Coeliac disease (28)
· Crohn’s disease (29)
· Patients with intestinal surgery gastric resection, sleeve or banding surgery) (30)
· Tapeworms and other intestinal parasites (26)
· Ileocystoplasty (i.e. a surgical reconstruction of the bladder involving the use of an isolated segment of ileum to augment bladder capacity) (31)
Vitamin B12 deficiency is usually the result of dietary insufficiency and is common in individuals who are strict vegetarians because vitamin B12 is only present in foods from animal origin. Because of the complex mechanism of vitamin B12 absorption, causes of malabsorption may also arise at several levels in the gastrointestinal tract.(24) At the gastric level, the most frequent cause of significant vitamin B12 malabsorption leading to deficiency is pernicious anaemia (PA), which is an autoimmune disorder caused by the frequent presence of gastric autoantibodies directed against IF and the parietal cells.(32) PA can affect both the elderly and young individuals.(33, 34)