7.8 Myelodysplastic Syndrome, Myeloproliferative Neoplasms & Porphyria

1. Myelodysplastic Syndrome

A clonal stem cell disorder producing ineffective hematopoiesis: a hypercellular marrow with peripheral cytopenias, dysplastic morphology, and a variable risk of transformation to acute myeloid leukemia. It is predominantly a disease of older adults.

When to suspect it: an older patient with unexplained macrocytic anemia and a low reticulocyte count. The reticulocyte response is the discriminator — the marrow is cellular but the cells die before release.

Before diagnosing myelodysplastic syndrome, exclude the reversible mimics, and this exclusion list is what exam items test:

Copper deficiency is the classic overlooked cause, producing a myelodysplasia-like marrow picture that is fully reversible with repletion, together with a myeloneuropathy that mimics B12 deficiency. Ask about bariatric surgery and zinc supplementation, including excessive denture adhesive use.

Diagnosis requires bone marrow aspiration and biopsy with cytogenetics. Peripheral clues include hypolobated hypogranular neutrophils (pseudo-Pelger-Huet cells) and dimorphic red cells.

Prognosis is stratified by the Revised International Prognostic Scoring System using blast percentage, cytogenetics and depth of cytopenias. Isolated deletion 5q is a favorable subtype with macrocytic anemia and preserved or elevated platelets that responds to lenalidomide.

Management ranges from transfusion support and erythropoiesis-stimulating agents in lower-risk disease to hypomethylating agents in higher-risk disease. Allogeneic hematopoietic cell transplantation is the only curative therapy, limited by age and comorbidity.

2. Myeloproliferative Neoplasms

Clonal expansion producing too many mature cells, in contrast to the ineffective production of myelodysplasia.

Polycythemia vera

Diagnostic approach: an elevated hemoglobin or hematocrit with a suppressed erythropoietin level points to a primary (autonomous) process; a raised erythropoietin points to a secondary cause such as hypoxemia, obstructive sleep apnea, high altitude, smoking, testosterone therapy, or an erythropoietin-secreting tumor. Confirm with JAK2 V617F, and test JAK2 exon 12 if V617F is negative.

Clinical clues: aquagenic pruritus (itching after a hot shower), erythromelalgia, plethora, splenomegaly, and thrombosis at unusual sites — Budd-Chiari syndrome and splanchnic vein thrombosis should always prompt myeloproliferative evaluation.

Treatment: phlebotomy to a hematocrit below 45% plus low-dose aspirin, with cytoreduction using hydroxyurea or ruxolitinib in high-risk patients (age over 60 or prior thrombosis). The hematocrit target below 45% is supported by randomized data showing fewer cardiovascular deaths and thromboses.

Essential thrombocythemia and primary myelofibrosis

Essential thrombocythemia must be separated from reactive thrombocytosis — infection, inflammation, iron deficiency, post-splenectomy and malignancy are far more common causes of a high platelet count. Paradoxically, extreme thrombocytosis above roughly 1,000,000 per microliter can cause bleeding through acquired von Willebrand syndrome.

Primary myelofibrosis presents with marked splenomegaly, constitutional symptoms, a leukoerythroblastic smear with teardrop cells (dacrocytes), and a dry tap on marrow aspiration. JAK inhibition reduces spleen size and symptoms; transplantation is the only cure.

3. Leukocyte Disorders

The blueprint lists leukopenia, leukocytosis and eosinophilia under leukocyte disorders.

• Neutropenia: distinguish benign ethnic neutropenia (a normal variant, notably in people of African ancestry, without infection risk) from drug-induced, autoimmune and marrow-failure causes.
• Leukocytosis: a leukemoid reaction (usually under 50,000 with a left shift and high leukocyte alkaline phosphatase) versus chronic myeloid leukemia (basophilia, low leukocyte alkaline phosphatase, BCR-ABL1 positive).
• Eosinophilia: the practical mnemonic is NAACP — Neoplasm, Allergy/Asthma, Adrenal insufficiency, Connective tissue disease, Parasites. Strongyloides must be excluded before corticosteroids because of hyperinfection risk. Marked persistent eosinophilia with organ damage defines hypereosinophilic syndrome and requires evaluation for a clonal disorder.

4. Porphyria

A separately named blueprint subsection. The porphyrias are disorders of heme biosynthesis, and they are tested because they masquerade as common problems.

Acute intermittent porphyria

The classic acute hepatic porphyria. Presentation:

• Severe, poorly localized abdominal pain that is out of proportion to a benign abdominal examination, with normal imaging and often normal laboratory studies apart from hyponatremia
• Autonomic features — tachycardia, hypertension, vomiting, constipation
• Neuropsychiatric features — motor neuropathy (which can progress to quadriparesis), seizures, anxiety, psychosis
• Reddish or port-wine urine that darkens on standing in light
• No cutaneous photosensitivity — a key discriminator

Attacks are precipitated by cytochrome P450-inducing drugs (barbiturates, sulfonamides, rifampin, phenytoin, carbamazepine, progesterone), fasting or crash dieting, alcohol, infection, surgery, and the luteal phase of the menstrual cycle. A young woman with recurrent unexplained abdominal pain who has had a negative laparotomy is the archetypal vignette.

Diagnosis: urinary porphobilinogen and delta-aminolevulinic acid measured on a spot sample obtained during the attack. Testing between attacks may be normal.

Treatment: stop the offending drug, provide intravenous glucose and, for severe attacks, intravenous hemin, which suppresses ALA synthase and aborts the attack. Pain is treated with opioids; many common analgesics and sedatives are unsafe, so a porphyria-safe drug list must be consulted.

Porphyria cutanea tarda

The most common porphyria overall, and clinically the opposite of the acute hepatic porphyrias: cutaneous, not neurovisceral.

• Painless blistering and skin fragility on sun-exposed skin, especially the dorsa of the hands
• Hypertrichosis, hyperpigmentation, scarring and milia
• No abdominal pain and no neuropathy

It is strongly associated with hepatitis C, HIV, alcohol, estrogen therapy, smoking and iron overload including HFE mutations — so a new diagnosis obliges testing for hepatitis C, HIV and iron studies. Urinary uroporphyrins are elevated. Treatment is repeated phlebotomy or low-dose hydroxychloroquine, plus sun protection and removal of the precipitant. Curing hepatitis C frequently resolves it.

Erythropoietic protoporphyria

Presents in childhood with immediate painful burning of sun-exposed skin without blistering — a distinctive history because the pain begins within minutes and the skin often looks normal, leading to years of misdiagnosis. It can cause protoporphyric liver disease.

5. Aplastic Anemia

Enumerated under hypoproliferative anemia and worth contrasting with myelodysplasia. Pancytopenia with a hypocellular marrow and no dysplasia or fibrosis, reflecting immune-mediated destruction of hematopoietic stem cells.

Causes include idiopathic autoimmune disease, drugs (chloramphenicol, carbamazepine, gold, sulfonamides), viruses (parvovirus B19 in the immunocompromised, seronegative hepatitis, Epstein-Barr virus), radiation, benzene, and inherited marrow failure syndromes such as Fanconi anemia and telomere biology disorders. Paroxysmal nocturnal hemoglobinuria clones coexist in a substantial minority, and flow cytometry should be sent.

Treatment: allogeneic transplantation for younger patients with a matched donor; immunosuppression with antithymocyte globulin and cyclosporine, increasingly with eltrombopag, for others.

The contrast that generates exam points: aplastic anemia gives a hypocellular marrow without dysplasia; myelodysplastic syndrome gives a hypercellular marrow with dysplasia — although a hypocellular variant of myelodysplasia exists and blurs the distinction.