Rheumatology & Haematology — MCQs

A 74-year-old woman is investigated for lethargy. Blood tests show: Hb 102 g/L, MCV 88 fL, WCC 5.2 × 10⁹/L, platelets 192 × 10⁹/L, ferritin 420 mcg/L, CRP 48 mg/L, ESR 78 mm/hr, creatinine 142 micromol/L (eGFR 38 mL/min/1.73m²). Blood film shows normochromic normocytic red cells with rouleaux formation. Serum protein electrophoresis demonstrates a monoclonal IgG kappa band of 28 g/L. What is the most important next investigation?

Q45

A 58-year-old man with established seropositive rheumatoid arthritis has been treated with methotrexate, then combination methotrexate-sulfasalazine-hydroxychloroquine, with inadequate response. He was commenced on adalimumab (anti-TNF) with methotrexate 6 months ago. His DAS28 score has improved from 6.1 to 4.8, but he continues to have morning stiffness lasting 2 hours and synovitis in multiple joints. CRP remains elevated at 28 mg/L. What is the most appropriate management strategy according to UK guidelines?

Q46

A 33-year-old woman at 34 weeks gestation presents to the emergency department with sudden onset dyspnoea and pleuritic chest pain. She is haemodynamically stable. CTPA confirms a left lower lobe pulmonary embolism. She has no previous VTE history and pregnancy has been uncomplicated. What is the most appropriate anticoagulation management for the remainder of pregnancy and postpartum period?

Q47

A 41-year-old man presents with acute onset pain and swelling of his right ankle. He has a history of psoriasis affecting his scalp and elbows. Joint aspiration reveals weakly positively birefringent crystals. Plain radiographs show soft tissue swelling and a small erosion at the first metatarsophalangeal joint. Serum urate is 0.38 mmol/L (normal <0.42). What diagnosis best explains the crystal findings in the context of his presentation?

Q48

A 52-year-old woman is admitted with bilateral leg swelling. She has a history of breast cancer treated with mastectomy and chemotherapy 18 months ago, now in remission. Doppler ultrasound confirms bilateral above-knee deep vein thromboses. CT chest-abdomen-pelvis shows no evidence of cancer recurrence but reveals extrinsic compression of the inferior vena cava by enlarged lymph nodes at the level of the renal veins. What is the most appropriate long-term anticoagulation strategy?

Q49

A 67-year-old man with established rheumatoid arthritis on methotrexate 20mg weekly and hydroxychloroquine 200mg twice daily has persistently active disease (DAS28 score 5.2) despite optimal conventional DMARD therapy for 8 months. He has no contraindications to biologics. His rheumatologist is considering adding a biologic agent. Which of the following statements regarding biologic DMARD selection is most accurate?

Q50

A 43-year-old woman presents with a 3-week history of fatigue and dyspnoea on exertion. She follows a strict vegan diet and takes no supplements. Blood tests reveal: Hb 79 g/L, MCV 103 fL, WCC 4.8 × 10⁹/L, platelets 168 × 10⁹/L, reticulocytes 38 × 10⁹/L, serum B12 145 ng/L (normal 200-900), serum folate 2.8 mcg/L (normal >3), LDH 580 U/L. What is the most appropriate next investigation to guide management?

Rheumatology & Haematology UK Medical PG Practice Questions and MCQs

Question 41: A 28-year-old woman presents with recurrent episodes of severe abdominal pain, nausea, and confusion. During episodes, her urine turns dark red. Family history reveals similar episodes in her father. What is the most likely diagnosis?

A. Acute intermittent porphyria (Correct Answer)
B. Hereditary coproporphyria
C. Variegate porphyria
D. Erythropoietic protoporphyria
E. Congenital erythropoietic porphyria

Explanation: ***Acute intermittent porphyria*** - This condition is characterized by acute **neurovisceral attacks** involving severe **abdominal pain**, nausea, and **confusion** (neuropsychiatric symptoms). - The dark red urine observed during episodes is due to the non-enzymatic oxidation of accumulated **porphobilinogen (PBG)** and **delta-aminolevulinic acid (ALA)**. The positive family history also supports its genetic basis. *Hereditary coproporphyria* - While it causes acute **neurovisceral attacks** similar to AIP, hereditary coproporphyria often presents with additional **cutaneous photosensitivity** (blistering skin lesions), which is not described in the patient. - The biochemical hallmark is the elevation of **coproporphyrin** in urine and feces, distinguishing it from AIP where ALA and PBG are predominantly elevated. *Variegate porphyria* - This condition also presents with acute **neurovisceral attacks** (abdominal pain, neurological deficits), but a key differentiating feature is the common presence of prominent **cutaneous photosensitivity** (blistering and skin fragility). - The absence of skin lesions in this case makes Variegate Porphyria less likely compared to AIP. *Erythropoietic protoporphyria* - Erythropoietic protoporphyria primarily causes **non-blistering photosensitivity**, leading to pain, burning, and itching upon sun exposure, typically starting in childhood. - Crucially, it does **not** cause acute neurovisceral attacks or lead to elevated urine PBG/ALA, which are central to the patient's symptoms. *Congenital erythropoietic porphyria* - This is a rare and severe disorder that usually presents in **infancy** with extreme **photosensitivity**, resulting in severe scarring, hemolytic anemia, and **erythrodontia** (reddish-brown teeth). - The patient's presentation as a 28-year-old with neurovisceral symptoms and dark urine, but without these severe infantile features, rules out congenital erythropoietic porphyria.

Question 42: A 54-year-old man presents with progressive muscle weakness, particularly affecting proximal muscles. He has difficulty rising from chairs. CK is 3500 U/L. Muscle biopsy shows inflammatory infiltrates. What is the most likely diagnosis?

A. Polymyalgia rheumatica
B. Polymyositis (Correct Answer)
C. Dermatomyositis
D. Inclusion body myositis
E. Muscular dystrophy

Explanation: ***Polymyositis***- This is an **inflammatory myopathy** characterized by **progressive, symmetric proximal muscle weakness**, which manifests as difficulty rising from chairs.- The significantly elevated **CK (3500 U/L)** and the finding of **inflammatory infiltrates** on muscle biopsy are classic indicators of polymyositis, in the absence of distinguishing skin features.*Polymyalgia rheumatica*- The primary symptoms of PMR are **muscle pain and stiffness**, particularly in the shoulder and hip girdles, rather than profound muscle weakness.- **Creatine Kinase (CK) levels are typically normal** or only minimally elevated, which contradicts the very high CK value in the patient.*Dermatomyositis*- While sharing proximal muscle weakness and elevated CK, dermatomyositis is differentiated by characteristic **cutaneous manifestations**, such as **Gottron’s papules** or a **Heliotrope rash**, which are not described in this case.- Pathologically, dermatomyositis is often associated with **perifascicular atrophy** and humorally mediated damage, distinct from the predominantly cell-mediated inflammation of polymyositis.*Inclusion body myositis*- IBM often affects **distal muscles** (e.g., wrist flexors, ankle dorsiflexors) in addition to the quadriceps, often presenting with an asymmetric pattern, unlike the symmetric proximal weakness presented.- This diagnosis is histologically confirmed by the presence of **rimmed vacuoles** and protein aggregates within muscle fibers, specific findings not generally implied by a generic

Question 43: A 31-year-old man presents with fever, night sweats, and weight loss over 2 months. Chest X-ray shows mediastinal lymphadenopathy. Lymph node biopsy shows Reed-Sternberg cells in a background of inflammatory cells. What is the most likely diagnosis?

A. Non-Hodgkin's lymphoma
B. Hodgkin's lymphoma (Correct Answer)
C. Sarcoidosis
D. Tuberculosis
E. Lung cancer

Explanation: ***Hodgkin's lymphoma*** - The presence of large, often binucleated **Reed-Sternberg (RS) cells** within a mixed background of inflammatory cells is the definitive histological hallmark. - The combination of **B symptoms** (fever, night sweats, weight loss) and **mediastinal lymphadenopathy** in a young adult is the classic clinical presentation. *Non-Hodgkin's lymphoma* - While NHL can present with B symptoms and lymphadenopathy, the biopsy would show effacement of the node architecture by monoclonal lymphoid cells and **lacks Reed-Sternberg cells**. - Histologically, NHL is characterized by the predominance of malignant lymphocytes themselves, rather than the mixed reactive inflammatory background seen in HL. *Sarcoidosis* - Sarcoidosis can cause bilateral hilar and mediastinal adenopathy, but the lymph node biopsy is characterized by finding non-caseating **granulomas**. - The biopsy would specifically **lack** the malignant Reed-Sternberg cells that were identified in this patient. *Tuberculosis* - Tuberculosis (TB) can result in constitutional symptoms and lymphadenopathy, but the biopsy typically reveals caseating **granulomas** containing **acid-fast bacilli (AFB)**. - Although TB is a differential for B symptoms and lymphadenopathy, the presence of **Reed-Sternberg cells** excludes TB as the primary diagnosis. *Lung cancer* - Lung cancer is primarily a disease of older individuals, and if presenting with adenopathy, the biopsy would show malignant epithelial cells (e.g., squamous or adeno-carcinoma). - Lung cancer does not produce **Reed-Sternberg cells** or the complex inflammatory background characteristic of HL.

Question 44: A 74-year-old woman is investigated for lethargy. Blood tests show: Hb 102 g/L, MCV 88 fL, WCC 5.2 × 10⁹/L, platelets 192 × 10⁹/L, ferritin 420 mcg/L, CRP 48 mg/L, ESR 78 mm/hr, creatinine 142 micromol/L (eGFR 38 mL/min/1.73m²). Blood film shows normochromic normocytic red cells with rouleaux formation. Serum protein electrophoresis demonstrates a monoclonal IgG kappa band of 28 g/L. What is the most important next investigation?

A. Bone marrow aspiration and trephine to quantify plasma cell percentage
B. Serum free light chains (kappa and lambda) and ratio calculation (Correct Answer)
C. Skeletal survey to assess for lytic bone lesions
D. 24-hour urine collection for Bence Jones protein quantification
E. Repeat blood tests in 3 months to assess for progression of paraprotein

Explanation: ***Serum free light chains (kappa and lambda) and ratio calculation*** - Determining the **serum free light chain (sFLC) ratio** is essential as an involved:uninvolved ratio **≥100** is now a formal **myeloma-defining biomarker**, even in the absence of CRAB symptoms. - This test is highly sensitive for detecting light chain involvement which may contribute to the patient's **renal impairment** (light chain cast nephropathy). *Bone marrow aspiration and trephine to quantify plasma cell percentage* - While necessary to confirm the diagnosis and quantify **clonal plasma cells** (≥ 10%), it is typically preceded by non-invasive biochemical screening like sFLC. - This procedure is invasive and is usually performed once a high clinical suspicion of **Multiple Myeloma** or high-risk disease is established by blood/urine tests. *Skeletal survey to assess for lytic bone lesions* - A **skeletal survey** (or nowadays, whole-body low-dose CT) is vital for identifying **bone destruction**, but it does not clarify the biochemical activity of the monoclonal protein as sFLC does. - The absence of lytic lesions would not exclude a diagnosis of myeloma if other **biomarkers** or CRAB features (like the patient's existing anaemia/renal failure) are present. *24-hour urine collection for Bence Jones protein quantification* - This test has largely been replaced in many protocols by the **Serum Free Light Chain assay**, which is more sensitive and convenient for the patient. - **24-hour collection** is cumbersome and notoriously prone to **collection errors**, making it a less ideal next step than serum-based assays. *Repeat blood tests in 3 months to assess for progression of paraprotein* - Delaying investigation is inappropriate here because the patient already demonstrates potential **end-organ damage** (anaemia and renal impairment). - The presence of a significant **monoclonal IgG kappa band** (28 g/L) requires urgent completion of the diagnostic workup to rule out **active myeloma**.

Question 45: A 58-year-old man with established seropositive rheumatoid arthritis has been treated with methotrexate, then combination methotrexate-sulfasalazine-hydroxychloroquine, with inadequate response. He was commenced on adalimumab (anti-TNF) with methotrexate 6 months ago. His DAS28 score has improved from 6.1 to 4.8, but he continues to have morning stiffness lasting 2 hours and synovitis in multiple joints. CRP remains elevated at 28 mg/L. What is the most appropriate management strategy according to UK guidelines?

A. Continue adalimumab for at least 12 months before assessing treatment failure, as 6 months is insufficient
B. Switch to an alternative anti-TNF agent (e.g., etanercept) as he may respond better to a different TNF inhibitor
C. Add prednisolone to the current regimen to provide additional disease control
D. Switch to a biologic with a different mechanism of action (e.g., rituximab, tocilizumab, or abatacept) (Correct Answer)
E. Increase methotrexate dose to maximum tolerated before changing biologic therapy

Explanation: ***Switch to a biologic with a different mechanism of action (e.g., rituximab, tocilizumab, or abatacept)*** - According to **NICE guidelines**, if a patient has an inadequate response to their first **TNF inhibitor** (adalimumab) after 6 months, the preferred next step is switching to a drug with a **different mechanism of action**. - This patient remains in the **moderate disease activity** category (DAS28 4.8 >3.2) with persistent **morning stiffness**, **synovitis**, and elevated **CRP**, indicating a need for a more effective therapy like a **B-cell depletor** (rituximab) or **IL-6 inhibitor** (tocilizumab). *Continue adalimumab for at least 12 months before assessing treatment failure, as 6 months is insufficient* - The standard timeframe for assessing the efficacy of biologic therapy in rheumatoid arthritis, particularly **TNF inhibitors**, is typically **3-6 months**. - Continuing an ineffective treatment beyond this timeframe would delay appropriate management, potentially leading to further **joint damage** and functional impairment given the persistent signs of active disease. *Switch to an alternative anti-TNF agent (e.g., etanercept) as he may respond better to a different TNF inhibitor* - While switching to a second **TNF inhibitor** is an option, UK **NICE guidelines** often prioritize switching to a biologic with a **different mechanism of action** after failure of a first anti-TNF, especially in seropositive patients where **rituximab** is a strong consideration. - The patient's lack of adequate response to adalimumab suggests that the **TNF pathway** may not be the optimal therapeutic target for this individual, making a switch to a different class more effective. *Add prednisolone to the current regimen to provide additional disease control* - **Corticosteroids** like prednisolone are primarily used for managing **flares** or as a bridging therapy, not as a long-term solution for inadequate response to a biologic DMARD. - Adding prednisolone would provide symptomatic relief but would not address the underlying failure of the **biologic DMARD** to achieve satisfactory disease control, potentially leading to **steroid-related side effects**. *Increase methotrexate dose to maximum tolerated before changing biologic therapy* - The patient has already failed **methotrexate monotherapy** and **triple therapy** (methotrexate-sulfasalazine-hydroxychloroquine), indicating that methotrexate alone is insufficient to control his disease. - While optimizing concomitant conventional DMARDs is important, the primary issue here is the **inadequate response** to the **anti-TNF biologic**; therefore, focusing on a change in biologic strategy is more appropriate at this stage.

Question 46: A 33-year-old woman at 34 weeks gestation presents to the emergency department with sudden onset dyspnoea and pleuritic chest pain. She is haemodynamically stable. CTPA confirms a left lower lobe pulmonary embolism. She has no previous VTE history and pregnancy has been uncomplicated. What is the most appropriate anticoagulation management for the remainder of pregnancy and postpartum period?

A. Commence treatment-dose LMWH, continue for 6 weeks postpartum, total minimum duration 3 months (Correct Answer)
B. Commence treatment-dose LMWH, continue throughout pregnancy, switch to warfarin after delivery for 6 weeks
C. Commence treatment-dose LMWH, continue for 3 months from diagnosis regardless of delivery timing
D. Commence treatment-dose LMWH, switch to DOAC after delivery, continue for 6 weeks postpartum
E. Commence treatment-dose LMWH, continue for remainder of pregnancy only, cease postpartum if asymptomatic

Explanation: ***Commence treatment-dose LMWH, continue for 6 weeks postpartum, total minimum duration 3 months*** - For pregnancy-associated **venous thromboembolism (VTE)**, treatment with **low-molecular-weight heparin (LMWH)** is required for the remainder of the pregnancy and at least **6 weeks postpartum**. - Guidelines specify that the total duration of anticoagulation must be a **minimum of 3 months**, ensuring the high-risk postpartum period is fully covered. *Commence treatment-dose LMWH, continue throughout pregnancy, switch to warfarin after delivery for 6 weeks* - While **warfarin** is safe for use during breastfeeding, it requires frequent **INR monitoring** and is generally less convenient than continuing LMWH postpartum for the remaining treatment window. - **LMWH** remains the preferred first-line agent throughout the entire management period due to its predictable pharmacokinetics and safety profile. *Commence treatment-dose LMWH, continue for 3 months from diagnosis regardless of delivery timing* - This approach is incorrect because it may lead to cessation of therapy early in the **postpartum period**, which is the time of highest physiological VTE risk. - Clinical guidelines mandate that anticoagulation must continue for at least **6 weeks after delivery**, even if the 3-month total duration has already been met. *Commence treatment-dose LMWH, switch to DOAC after delivery, continue for 6 weeks postpartum* - **Direct Oral Anticoagulants (DOACs)** are currently not recommended for women who are **breastfeeding** due to a lack of safety data and potential excretion into breast milk. - **LMWH** or **Warfarin** are the validated options for postpartum anticoagulation in patients who wish to breastfeed. *Commence treatment-dose LMWH, continue for remainder of pregnancy only, cease postpartum if asymptomatic* - Ceasing anticoagulation immediately after delivery is dangerous as the **postpartum state** is significantly more **prothrombotic** than pregnancy itself. - Management must always include a minimum of **6 weeks postpartum prophylaxis/treatment** to prevent recurrent pulmonary embolism or deep vein thrombosis.

Question 47: A 41-year-old man presents with acute onset pain and swelling of his right ankle. He has a history of psoriasis affecting his scalp and elbows. Joint aspiration reveals weakly positively birefringent crystals. Plain radiographs show soft tissue swelling and a small erosion at the first metatarsophalangeal joint. Serum urate is 0.38 mmol/L (normal <0.42). What diagnosis best explains the crystal findings in the context of his presentation?

A. Acute gout with normal serum urate due to increased renal excretion during acute attack
B. Calcium pyrophosphate deposition disease (pseudogout) coinciding with underlying psoriatic arthropathy (Correct Answer)
C. Psoriatic arthritis with secondary calcium pyrophosphate crystal deposition
D. Basic calcium phosphate crystal arthropathy associated with psoriatic joint damage
E. Laboratory error in crystal identification; negatively birefringent crystals more likely given clinical context

Explanation: ***Calcium pyrophosphate deposition disease (pseudogout) coinciding with underlying psoriatic arthropathy*** - The presence of **weakly positively birefringent crystals** in joint fluid is the hallmark diagnostic feature of **calcium pyrophosphate deposition disease (CPPD)**, also known as pseudogout. - This diagnosis directly explains the acute inflammatory episode, and its coexistence with the patient's **psoriasis** highlights that multiple arthropathies can occur in the same individual. *Acute gout with normal serum urate due to increased renal excretion during acute attack* - Gout is definitively diagnosed by the presence of **strongly negatively birefringent** needle-shaped monosodium urate crystals, which contradicts the

Question 48: A 52-year-old woman is admitted with bilateral leg swelling. She has a history of breast cancer treated with mastectomy and chemotherapy 18 months ago, now in remission. Doppler ultrasound confirms bilateral above-knee deep vein thromboses. CT chest-abdomen-pelvis shows no evidence of cancer recurrence but reveals extrinsic compression of the inferior vena cava by enlarged lymph nodes at the level of the renal veins. What is the most appropriate long-term anticoagulation strategy?

A. Low molecular weight heparin indefinitely as first-line due to cancer history
B. Warfarin with target INR 2-3 for 3 months, then reassess based on node resolution
C. Apixaban for 6 months as provoked VTE by mechanical obstruction
D. Inferior vena cava filter insertion followed by 3 months anticoagulation
E. Extended duration anticoagulation (indefinite or until IVC obstruction resolves) due to ongoing provoking factor (Correct Answer)

Explanation: ***Extended duration anticoagulation (indefinite or until IVC obstruction resolves) due to ongoing provoking factor*** - Anticoagulation must be maintained as long as a **persistent provoking factor** is present; mechanical compression of the **inferior vena cava (IVC)** by lymph nodes constitutes an ongoing high-risk state for recurrence. - Unlike transient risk factors (e.g., surgery), this **extrinsic obstruction** continues to promote venous stasis and thrombosis until the mechanical cause is surgically or medically resolved. *Low molecular weight heparin indefinitely as first-line due to cancer history* - While **LMWH** was historically preferred for **cancer-associated thrombosis (CAT)**, this patient is in remission, and the lymphadenopathy may not represent active malignancy. - **DOACs** are now generally preferred or equivalent to LMWH for CAT and would be more appropriate for long-term use in this patient if she has no gastrointestinal contraindications. *Warfarin with target INR 2-3 for 3 months, then reassess based on node resolution* - A **3-month duration** is typically reserved for VTE provoked by **transient** risk factors; it is insufficient while a major mechanical obstruction remains active. - Stopping treatment at 3 months while the **IVC is still compressed** would result in an unacceptably high risk of recurrent deep vein thrombosis. *Apixaban for 6 months as provoked VTE by mechanical obstruction* - Although **provoked VTE** is often treated for a fixed duration, the duration depends on the **reversibility** of the provoking factor. - A **6-month limit** is arbitrary in this context; anticoagulation should be "extended" or "indefinite" until the **mechanical stasis** is actually eliminated. *Inferior vena cava filter insertion followed by 3 months anticoagulation* - **IVC filters** are generally indicated only when anticoagulation is **contraindicated** or has failed despite therapeutic levels. - Filters do not treat the underlying thrombus and can actually **increase the risk** of long-term DVT; they are not a substitute for pharmacological anticoagulation in this hemodynamically stable patient.

Question 49: A 67-year-old man with established rheumatoid arthritis on methotrexate 20mg weekly and hydroxychloroquine 200mg twice daily has persistently active disease (DAS28 score 5.2) despite optimal conventional DMARD therapy for 8 months. He has no contraindications to biologics. His rheumatologist is considering adding a biologic agent. Which of the following statements regarding biologic DMARD selection is most accurate?

A. Anti-TNF agents are more effective than other biologic classes and should always be first-line
B. Patients with positive rheumatoid factor and anti-CCP antibodies have better response rates to rituximab compared to seronegative patients (Correct Answer)
C. Tocilizumab is contraindicated as monotherapy and must be combined with methotrexate
D. Abatacept is only licensed for use after failure of anti-TNF therapy
E. All biologic DMARDs have equal efficacy in clinical trials, so selection is based primarily on safety profile and patient preference

Explanation: ***Patients with positive rheumatoid factor and anti-CCP antibodies have better response rates to rituximab compared to seronegative patients*** - **Rituximab**, an anti-CD20 B-cell depleting therapy, demonstrates superior clinical response in patients who are **seropositive** for **rheumatoid factor (RF)** or **anti-CCP antibodies**. - This enhanced response is attributed to the central role of **B-cells** in producing these autoantibodies, which drive the inflammatory process in seropositive rheumatoid arthritis. *Anti-TNF agents are more effective than other biologic classes and should always be first-line* - Current guidelines suggest that **Anti-TNF**, **IL-6 inhibitors**, and **T-cell costimulation blockers** have comparable efficacy as first-line biologics after conventional DMARD failure. - The choice of agent is individualized based on **comorbidities**, patient preferences, and specific disease characteristics, rather than a universal hierarchy of efficacy for anti-TNF agents. *Tocilizumab is contraindicated as monotherapy and must be combined with methotrexate* - **Tocilizumab**, an **IL-6 receptor antagonist**, is unique among biologics for having demonstrated significant efficacy and approval as **monotherapy** in clinical trials for rheumatoid arthritis. - It is often utilized as monotherapy in patients who are **intolerant** of or have contraindications to methotrexate or other conventional synthetic DMARDs. *Abatacept is only licensed for use after failure of anti-TNF therapy* - **Abatacept**, a selective T-cell costimulation modulator, is licensed for use in RA patients who have had an inadequate response to **conventional DMARDs**. - It is **not restricted** to use only after failure of anti-TNF therapy and can be considered as a **first-line biologic** after cDMARDs. *All biologic DMARDs have equal efficacy in clinical trials, so selection is based primarily on safety profile and patient preference* - While many biologic classes achieve similar primary endpoints in broad clinical trials, **individual patient characteristics** such as serostatus, disease phenotype, and comorbidities can influence specific drug success rates. - Selection is a complex process considering **efficacy in specific patient subsets**, **safety profile**, administration route, **comorbidities** (e.g., risk of infection or heart failure), and patient preference.

Question 50: A 43-year-old woman presents with a 3-week history of fatigue and dyspnoea on exertion. She follows a strict vegan diet and takes no supplements. Blood tests reveal: Hb 79 g/L, MCV 103 fL, WCC 4.8 × 10⁹/L, platelets 168 × 10⁹/L, reticulocytes 38 × 10⁹/L, serum B12 145 ng/L (normal 200-900), serum folate 2.8 mcg/L (normal >3), LDH 580 U/L. What is the most appropriate next investigation to guide management?

A. Bone marrow aspiration and trephine to assess for megaloblastic changes
B. Intrinsic factor antibodies and gastric parietal cell antibodies to diagnose pernicious anaemia
C. Red cell folate level as this is more sensitive than serum folate for tissue deficiency
D. Methylmalonic acid and homocysteine levels to distinguish B12 from folate deficiency (Correct Answer)
E. Anti-tissue transglutaminase antibodies to screen for coeliac disease

Explanation: ***Methylmalonic acid and homocysteine levels to distinguish B12 from folate deficiency*** - The patient presents with **macrocytic anemia**, low **serum B12**, and low **serum folate**, along with elevated **LDH**, strongly suggesting a megaloblastic process. - Measuring **methylmalonic acid (MMA)** and **homocysteine** is essential: MMA is specifically elevated in **B12 deficiency**, while homocysteine is elevated in both **B12 and folate deficiencies**, allowing for definitive differentiation of the primary deficiency. *Bone marrow aspiration and trephine to assess for megaloblastic changes* - While a bone marrow biopsy would show characteristic **megaloblastic changes** such as hypersegmented neutrophils and megaloblasts, it is an invasive procedure. - Given the clear biochemical evidence of **vitamin B12** and **folate deficiency** and the patient's **vegan diet**, a bone marrow biopsy is generally not required for initial diagnosis. *Intrinsic factor antibodies and gastric parietal cell antibodies to diagnose pernicious anaemia* - These antibodies are specific for **pernicious anemia**, an autoimmune condition causing **B12 malabsorption**. - The patient's **strict vegan diet** without supplementation provides a direct and highly probable explanation for B12 deficiency (dietary), making autoimmune causes less likely as the immediate primary concern. *Red cell folate level as this is more sensitive than serum folate for tissue deficiency* - **Red cell folate** reflects long-term folate status and is less affected by recent dietary intake than serum folate. - However, its diagnostic utility is limited as it can be falsely low in **B12 deficiency** and is generally not preferred over **serum folate** and **homocysteine** levels for assessing folate status. *Anti-tissue transglutaminase antibodies to screen for coeliac disease* - **Coeliac disease** can cause malabsorption of various nutrients, including **folate** and **vitamin B12**, leading to anemia. - However, the most direct and evident cause for the patient's deficiencies, given her history, is her **strict vegan diet**, making other malabsorption syndromes a secondary consideration without other gastrointestinal symptoms.

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