Blood & Lymphoreticular

G6PD deficiency: triggers and management

Clinical Overview and When to Suspect G6PD Deficiency

— X-linked recessive: males predominantly affected; heterozygous females can have variable phenotype via lyonization

— Highest prevalence: African, Mediterranean (Italian, Greek, Sephardic Jewish), Middle Eastern, and Southeast Asian ancestry

— Without it, oxidative stress denatures hemoglobin → Heinz bodies → splenic macrophages bite out denatured Hb → bite cells → acute intravascular + extravascular hemolysis

— Sudden hemolytic anemia 24–72 hours after starting a new oxidant drug, eating fava beans, or developing an infection

— Dark "cola-colored" urine, jaundice, fatigue, back/abdominal pain in a male of at-risk ancestry

— Neonatal jaundice without ABO/Rh incompatibility, especially in Mediterranean or Asian newborns

— Unexplained hemolytic episode during DKA, sepsis, or hepatitis A

— G6PD A− (African): milder, self-limited hemolysis (older RBCs lysed, reticulocytes spared)

— G6PD Mediterranean: severe, can hemolyze even reticulocytes; fava bean sensitivity is classic

— G6PD Canton: severe Asian variant

G6PD (glucose-6-phosphate dehydrogenase) deficiency is the most common human enzymopathy, affecting ~400 million people worldwide

Pathophysiology in one line: G6PD generates NADPH via the pentose phosphate pathway → NADPH regenerates glutathione → glutathione neutralizes oxidative stress in RBCs

When to suspect on Step 3:

Variants matter clinically:

Board pearl: A previously healthy young man of Mediterranean descent who develops jaundice and dark urine 2 days after starting TMP-SMX for a UTI or dapsone for PJP prophylaxis → G6PD deficiency until proven otherwise. The hemolysis is episodic and trigger-driven, not chronic — between episodes, the CBC is normal, which is a frequent stem trick.

Step 3 management: Recognition is preventive medicine — screening before high-risk drugs (rasburicase, dapsone, primaquine, tafenoquine) prevents catastrophic hemolysis.

Presentation Patterns and Key History

— Onset 24–72 hours after exposure to an oxidant trigger

— Symptoms: malaise, fatigue, scleral icterus, jaundice, dark/tea-colored urine (hemoglobinuria), flank or abdominal pain, sometimes fever

— Self-limited in A− variant (3–7 days as reticulocytes replace lysed cells); more prolonged in Mediterranean variant

— Drugs: dapsone, primaquine, tafenoquine, methylene blue, rasburicase, nitrofurantoin, sulfonamides (TMP-SMX, sulfasalazine), phenazopyridine, high-dose aspirin, quinolones (moderate risk)

— Foods: fava beans (favism) — most classic, especially in Mediterranean variant

— Infections: any febrile illness; particularly hepatitis (A, B), pneumonia, typhoid, DKA

— Mothballs: naphthalene exposure in infants (crib liners, stored clothing) — pediatric vignette favorite

— Henna (skin application in neonates in some cultures)

— Jaundice peaking at day 2–3, often without anemia

— Risk of kernicterus if untreated — bilirubin can rise rapidly

— Key distinction from physiologic jaundice: timing earlier and bilirubin higher

Classic acute hemolytic episode — the most testable scenario

High-yield trigger history — ask explicitly:

Neonatal presentation:

Chronic non-spherocytic hemolytic anemia (CNSHA): rare class I variants → baseline hemolysis without triggers; lifelong transfusion/folate dependence

Family history: maternal uncles or brothers with "jaundice after antibiotics" or unexplained transfusions

Key distinction: G6PD deficiency causes episodic, trigger-driven hemolysis with normal interval CBC; hereditary spherocytosis causes chronic hemolysis with splenomegaly and family history of cholecystectomy/splenectomy. Both can have negative Coombs, but timing and chronicity separate them.

Step 3 management: Build a written trigger-avoidance list at the index visit — patients should carry it (wallet card or phone note) and show it to every new prescriber, including dentists and ED clinicians.

Physical Exam Findings and Hemodynamic Assessment

— Pallor of conjunctivae, palms, nail beds — proportional to hemoglobin drop

— Scleral icterus and jaundice — usually mild to moderate; indirect hyperbilirubinemia

— Tachycardia as compensatory response to anemia; tachypnea if Hb <7 g/dL

— Hypotension and orthostasis in severe intravascular hemolysis with hemoglobinuria-induced volume shifts or AKI

— Mild splenomegaly may be present during crisis but is not a hallmark (helps distinguish from hereditary spherocytosis or thalassemia)

— Dark urine visible at bedside — gross hemoglobinuria looks like cola/tea

— HR >120, SBP <90, mental status change, oliguria → suggests severe hemolysis + possible pigment nephropathy or DIC

— Capillary refill >3 sec, cool extremities

— Visible jaundice at <24 hours of life is always pathologic

— Cephalocaudal progression of icterus correlates with bilirubin level

— Neurologic signs (hypotonia, poor feeding, high-pitched cry, opisthotonus) = acute bilirubin encephalopathy — emergency

— Vitals q1h during active hemolysis

— Urine output goal >0.5 mL/kg/hr (>1 mL/kg/hr in children) to protect kidneys from free hemoglobin

— Repeat Hb q6–12h until trend stabilizes; brisk drop of >2 g/dL/day signals ongoing hemolysis

During acute hemolytic crisis:

Hemodynamic red flags requiring escalation:

Pediatric/neonatal exam:

Between episodes: Exam is typically completely normal. This catches students off guard — the stem may say "exam unremarkable today" but the history reveals a recent crisis

Hemodynamic assessment framework (CCS-style):

CCS pearl: On a CCS case of suspected G6PD hemolysis, your first orders are CBC, reticulocyte count, peripheral smear, LDH, haptoglobin, indirect bilirubin, UA with urine hemosiderin, type & screen, BMP, plus IV fluids and continuous monitoring — then identify and remove the trigger before ordering the confirmatory enzyme assay.

Diagnostic Workup — Initial Labs

— Normocytic, normochromic anemia; Hb can drop from 14 → 7 g/dL within 48 hours

— Reticulocytosis appears at day 4–7 (initial retic may be falsely low in first 48 hours — a classic Step 3 trap)

— WBC and platelets usually normal (helps distinguish from TTP/HUS/DIC)

— ↑ LDH (often markedly, >1000)

— ↑ Indirect (unconjugated) bilirubin

— ↓ Haptoglobin (consumed by free Hb)

— ↑ Reticulocyte count (after 3–5 day lag)

— Negative direct Coombs (DAT) — critical, separates from autoimmune hemolytic anemia

— Hemoglobinuria — dipstick positive for blood with no RBCs on microscopy (classic dissociation indicating intravascular hemolysis)

— Urine hemosiderin positive several days after hemolysis (from sloughed renal tubular cells)

— Bite cells (degmacytes) — RBCs with a "bite" taken out where splenic macrophages removed Heinz bodies

— Blister cells — Hb pulled to one side leaving a clear blister

— Heinz bodies — denatured Hb inclusions, visible only with supravital stains (crystal violet, methylene blue), NOT on routine Wright-Giemsa

— Polychromasia, schistocytes generally absent (their presence suggests MAHA instead)

— Check BUN/Cr for pigment nephropathy

— K+ may rise from cell lysis

CBC findings:

Hemolysis panel — all elevated/depleted as expected:

Urinalysis:

Peripheral blood smear — the visual money shot:

BMP:

Key distinction: Bite cells + Heinz bodies + negative Coombs + recent oxidant exposure = G6PD. Spherocytes + positive Coombs = AIHA. Spherocytes + negative Coombs + family history = hereditary spherocytosis. Schistocytes + thrombocytopenia = MAHA (TTP/HUS/DIC).

Board pearl: Order the G6PD enzyme assay AFTER the acute episode resolves (4–6 weeks later) — during hemolysis, older deficient RBCs have already lysed and reticulocytes have higher G6PD activity, causing false-normal results.

Diagnostic Workup — Confirmatory Studies

— Gold standard for diagnosis

— Measures NADPH production rate in RBCs

— Timing matters: defer until ≥3 months after acute hemolysis or transfusion to avoid false negatives from young RBC predominance

— Females with heterozygous status may have intermediate values — consider molecular testing if discordant with clinical picture

— PCR for specific variants (A−, Mediterranean, Canton, Mahidol)

— Useful in:

— Females with equivocal enzyme levels

— Family screening / prenatal counseling

— Determining severity and risk for chronic hemolysis (class I vs III)

— Class I: severe deficiency with chronic non-spherocytic hemolytic anemia

— Class II (e.g., Mediterranean): <10% activity, severe episodic hemolysis, fava bean sensitivity

— Class III (e.g., A−): 10–60% activity, episodic hemolysis, self-limited

— Class IV: normal activity (no clinical disease)

— Before rasburicase (tumor lysis syndrome prophylaxis) — quantitative G6PD level mandatory; contraindicated if deficient (causes severe methemoglobinemia + hemolysis)

— Before dapsone for PJP prophylaxis in HIV patients

— Before primaquine or tafenoquine for P. vivax/ovale radical cure — tafenoquine requires ≥70% activity

— Hemoglobin electrophoresis (rule out thalassemia, sickle cell — can coexist)

— Osmotic fragility test (hereditary spherocytosis)

— Flow cytometry for PNH (CD55/CD59) if recurrent hemolysis without clear trigger

Quantitative G6PD enzyme assay (fluorescent spot test or spectrophotometric):

Molecular/genetic testing:

WHO classification of variants (high-yield):

Pre-treatment screening — increasingly Step 3 relevant:

Other workup if diagnosis unclear:

Step 3 management: Document the diagnosis prominently in the EMR problem list and medication allergy list as "G6PD deficiency — avoid oxidant drugs" — this prevents future iatrogenic hemolysis at outside facilities.

Board pearl: A negative enzyme assay during active hemolysis does NOT rule out G6PD deficiency — repeat in 3 months.

Risk Stratification and Management Logic

— Mild: Hb >10, stable vitals, oral intake intact, no AKI → outpatient management with trigger removal, hydration, follow-up in 24–48 hours

— Moderate: Hb 7–10, symptomatic anemia, mild AKI, ongoing hemolysis → admit for IV fluids, serial labs, possible transfusion

— Severe: Hb <7 or rapidly dropping, hemodynamic instability, AKI with rising Cr, oliguria, altered mentation → ICU, transfusion, possible RRT

— Stop the offending drug immediately

— Treat the underlying infection driving oxidative stress (don't withhold needed antibiotics — switch class)

— Correct DKA or other metabolic trigger

— IV crystalloid hydration — maintains renal perfusion, flushes free hemoglobin, prevents pigment nephropathy (target UOP >0.5 mL/kg/hr)

— Urine alkalinization with sodium bicarbonate is controversial — not routinely recommended for G6PD (unlike rhabdomyolysis)

— Folic acid 1 mg daily during recovery to support erythropoiesis

— Transfusion if Hb <7 or symptomatic; use leukoreduced PRBCs

— Don't give methylene blue for methemoglobinemia in G6PD patients — it requires NADPH to work and worsens hemolysis; use ascorbic acid instead

— Don't give rasburicase for tumor lysis prophylaxis — use allopurinol + aggressive hydration

— Avoid vitamin K menadione (synthetic form) in neonates

— Hemoglobinuria + Hb <8 = admit

— Pregnant + active hemolysis = admit regardless of Hb

— Neonate with hyperbilirubinemia = admit for phototherapy ± exchange transfusion

Severity stratification at presentation drives the disposition:

Core management principle: REMOVE THE TRIGGER

Supportive care pillars:

What NOT to do:

Disposition decision tree:

CCS pearl: First five orders for moderate-severe G6PD hemolysis on a CCS case: (1) Stop offending agent, (2) IV NS at 1.5× maintenance, (3) CBC + retic + hemolysis panel q6h, (4) Type & cross 2 units PRBC, (5) Strict I/O with goal UOP >0.5 mL/kg/hr.

Board pearl: Most episodes are self-limited within 7–10 days once the trigger is removed; aggressive intervention is reserved for severe anemia or organ dysfunction.

Pharmacotherapy — Trigger Avoidance and Treatment

— Antimalarials: primaquine, tafenoquine, pamaquine (chloroquine and hydroxychloroquine are generally safe at standard doses)

— Sulfa drugs: dapsone, sulfasalazine, sulfadiazine, TMP-SMX (Bactrim) — the most commonly tested trigger

— Other antibiotics: nitrofurantoin, nalidixic acid; fluoroquinolones (moderate risk)

— Methylene blue (paradoxically used for methemoglobinemia — contraindicated here)

— Rasburicase (urate oxidase)

— Phenazopyridine (Pyridium)

— High-dose aspirin (>3 g/day); low-dose cardioprotective aspirin is generally safe

— Naphthalene mothballs

— Acetaminophen at standard doses

— Ibuprofen at standard doses

— Aspirin at low cardioprotective doses (81 mg)

— Chloroquine/hydroxychloroquine at standard doses

— Quinine, quinidine

— IV normal saline as primary therapy; lactated Ringer's acceptable

— Packed RBC transfusion for Hb <7 or symptomatic anemia — typically 1–2 units, reassess

— Folic acid 1 mg PO daily for 2–4 weeks during recovery

— No specific antidote exists — supportive care only

— PJP prophylaxis in HIV with G6PD deficiency: use atovaquone instead of TMP-SMX or dapsone

— Tumor lysis prophylaxis: allopurinol + IV hydration (avoid rasburicase)

— Methemoglobinemia: ascorbic acid (vitamin C) IV instead of methylene blue

— Vivax malaria radical cure: primaquine contraindicated; consult ID — sometimes chloroquine alone with relapse monitoring

The "definitely avoid" drug list (high-yield memorization):

Probably safe (commonly mislabeled as triggers):

Treatment of an acute episode — pharmacology:

Special pharmacology scenarios:

Step 3 management: Before prescribing any new drug to a G6PD-deficient patient, cross-check against the WHO/AAFP G6PD safety list. EMR drug-allergy entry should read "G6PD deficiency" with a hard stop on oxidant drugs.

Board pearl: TMP-SMX prescribed for a simple UTI in a young Mediterranean man, followed by jaundice 48 hours later, is the single most common Step 3 vignette for this topic.

Expanded Pharmacology and Specific Drug Decisions

— UTI in G6PD patient: cephalexin, fosfomycin, or amoxicillin-clavulanate (avoid TMP-SMX, nitrofurantoin)

— Skin/soft tissue infection: clindamycin, cephalexin, doxycycline (avoid TMP-SMX)

— PJP prophylaxis (HIV/transplant): atovaquone (1st alt), inhaled pentamidine (2nd alt)

— P. vivax or P. ovale malaria: chloroquine for acute infection; for radical cure, weekly primaquine for 8 weeks under hematology supervision in mild deficiency, or accept relapse risk in severe deficiency

— Tumor lysis syndrome prophylaxis: allopurinol 300 mg daily + aggressive IV hydration; febuxostat alternative

— Methemoglobinemia: ascorbic acid 1.5–2 g IV (methylene blue contraindicated); consider exchange transfusion or hyperbaric O₂ in severe cases

— Avoid prilocaine and benzocaine (methemoglobinemia risk)

— Avoid sulfonamide-containing preoperative antibiotics

— Generally safe: propofol, sevoflurane, lidocaine, succinylcholine

— Rasburicase contraindicated — confirmed black box warning

— Standard cytotoxic agents typically safe, but monitor closely

— Methotrexate, 5-FU — no specific G6PD contraindication

— Hydroxychloroquine: generally safe at standard doses but use caution

— Remdesivir, paxlovid: no G6PD contraindication

— Phenazopyridine + G6PD = severe hemolysis (common UTI symptom-relief trap)

— Henna (PPD-containing) topical applications in children — pediatric ED scenarios

Drug substitution guide — what to use instead:

Vaccines: all standard vaccines safe; no oxidative trigger concern

Anesthesia considerations:

Chemotherapy:

COVID-era specifics (still tested):

Drug interactions to flag:

Step 3 management: When uncertain whether a drug is safe, consult clinical pharmacy and reference the AAFP G6PD drug list; document the decision rationale. For elective procedures, screen pre-operatively in high-risk ancestry patients if oxidant drugs are anticipated.

Board pearl: Atovaquone is the safe answer for PJP prophylaxis in G6PD-deficient HIV patients — high-yield substitution.

Key distinction: Low-dose aspirin for cardiac prevention is generally safe; high-dose aspirin (>3 g/day for anti-inflammatory use) is the triggering dose.

Special Populations — Elderly and Organ Impairment

— G6PD deficiency may be diagnosed late in life when an oxidant drug is started for a new comorbidity (e.g., dapsone for bullous pemphigoid, sulfasalazine for IBD, nitrofurantoin prophylaxis for recurrent UTI)

— Baseline anemia of chronic disease or CKD-related anemia can mask subtle hemolysis — watch for unexplained Hb drops after new prescriptions

— Polypharmacy increases trigger exposure risk; perform medication reconciliation at every visit

— Recovery from hemolysis is slower due to blunted erythropoietic response

— Patients with CKD are at higher risk of pigment-induced AKI during hemolysis

— Avoid nephrotoxic adjuncts (NSAIDs) during acute episodes

— Dose-adjust antibiotics carefully when substituting around triggers

— Patients on erythropoiesis-stimulating agents (ESAs) for CKD anemia may have falsely elevated reticulocyte counts, complicating diagnosis

— Hemodialysis itself is not a trigger but check dialysate composition; some sterilization agents historically caused hemolysis (no longer used)

— Indirect hyperbilirubinemia from hemolysis can decompensate chronic liver disease

— Hepatitis A and B are known triggers — vaccinate G6PD-deficient patients against hepatitis A and B if not immune

— Avoid hepatotoxic drugs that compound oxidative stress

— Repeated hemolysis can paradoxically cause iron overload (from heme catabolism + transfusions), not deficiency

— Don't reflexively give iron — check ferritin and transferrin saturation first

— Hemolysis-associated hemoglobinuria can mimic gross hematuria in anticoagulated elderly patients — don't stop anticoagulation reflexively; check UA microscopy

Elderly patients:

Renal impairment:

Hepatic impairment:

Iron status considerations:

Anticoagulation overlap:

Step 3 management: In any elderly G6PD patient starting a new chronic medication, schedule a CBC + reticulocyte count 1–2 weeks after initiation as a safety check, even if the drug is on the "probably safe" list. Document G6PD status in the EMR as a drug allergy to trigger automated alerts.

Board pearl: Sulfasalazine for newly diagnosed ulcerative colitis in an older patient is an underrecognized hemolytic trigger — screen for G6PD in patients of at-risk ancestry before initiation.

Special Populations — Pregnancy and Pediatrics

— Heterozygous female carriers may be asymptomatic but can hemolyze with severe oxidant exposure

— Avoid nitrofurantoin in 3rd trimester and at term — both for fetal hemolysis risk and maternal G6PD risk if mother is heterozygous

— Avoid sulfa drugs near term (kernicterus risk + maternal hemolysis)

— Safe UTI options: cephalexin, amoxicillin-clavulanate, fosfomycin

— Folic acid supplementation continues; consider higher dose (5 mg) if recurrent hemolysis history

— Genetic counseling: 50% of sons of carrier mothers will be hemizygous affected

— Neonatal jaundice typically appears day 2–3, can progress rapidly

— Higher risk in Mediterranean and Asian variants

— Triggers in newborns: naphthalene mothballs in stored clothing, henna application, maternal ingestion of triggers transferred via breast milk (fava beans, certain drugs), vitamin K menadione (synthetic, not phytonadione)

— Phototherapy is first-line for hyperbilirubinemia

— Exchange transfusion if bilirubin approaches kernicterus threshold (use Bhutani nomogram)

— IVIG sometimes used in severe hemolytic hyperbilirubinemia

— Several states include G6PD on expanded newborn screening panels; not universal in the US

— High prevalence regions (some Mediterranean countries, Asia) have routine universal screening

— Classic vignette: 4-year-old Italian or Greek boy presents with jaundice, dark urine, pallor 24 hours after eating fresh fava beans at a family gathering

— Severe rapid-onset hemolysis; transfusion often required

— Counsel families to avoid fava beans, broad beans, and possibly soy and legumes (variable individual sensitivity)

— Mothers should avoid fava beans and oxidant drugs if infant is G6PD deficient

— TMP-SMX in lactating mother is contraindicated if infant has G6PD deficiency

Pregnancy:

Neonatal G6PD deficiency:

Newborn screening:

Pediatric favism:

Breastfeeding considerations:

Step 3 management: For any neonate with jaundice + at-risk ancestry + no ABO/Rh incompatibility, order G6PD enzyme assay as part of the workup; coordinate with pediatric hematology for follow-up and family screening.

Board pearl: Maternal fava bean ingestion can trigger hemolysis in a breastfed G6PD-deficient infant — a high-yield, easily-missed pediatric scenario.

Complications and Adverse Outcomes

— Pigment nephropathy / AKI — free hemoglobin precipitates in renal tubules; risk highest with intravascular hemolysis and dehydration

— Prevention: aggressive IV hydration to maintain UOP >0.5 mL/kg/hr

— Treatment: continued hydration, RRT if oliguric AKI fails to resolve

— Severe anemia with cardiovascular compromise — high-output failure, demand ischemia, syncope

— Hyperkalemia from cellular lysis — monitor ECG, treat per standard protocols

— Splenic sequestration — rare; more common in coexistent sickle cell trait

— Kernicterus / acute bilirubin encephalopathy — devastating, often permanent neurologic injury

— Long-term sequelae: choreoathetoid cerebral palsy, sensorineural hearing loss, gaze palsy, dental enamel dysplasia

— Prevention is everything: timely phototherapy and exchange transfusion

— Iron overload from repeated transfusions and chronic hemolysis — monitor ferritin; chelation if indicated

— Pigment gallstones (calcium bilirubinate) — chronic indirect hyperbilirubinemia; consider cholecystectomy if symptomatic

— Aplastic crisis with parvovirus B19 infection (as with any chronic hemolytic anemia)

— Splenomegaly with hypersplenism (uncommon in episodic disease)

— Growth delay in children with chronic hemolysis

— Rasburicase-induced methemoglobinemia + massive hemolysis in a patient with unscreened G6PD status — black box warning

— Tafenoquine without prior screening → severe hemolysis

— These are major patient safety events with significant liability

— Lifelong vigilance about drug and food triggers can cause anxiety; counsel and provide written materials

— Family screening can reveal unexpected diagnoses, requiring genetic counseling

Acute complications:

Neonatal complications:

Chronic complications (in class I variants with CNSHA):

Drug-related catastrophic events:

Psychosocial:

Key distinction: G6PD hemolysis causes indirect hyperbilirubinemia and hemoglobinuria — if you see direct hyperbilirubinemia or true hematuria with RBCs on micro, look elsewhere (cholestasis, glomerulonephritis, urologic source).

Step 3 management: Document rasburicase as a contraindication in the EMR for every G6PD-deficient patient; verify G6PD status before initiating tumor lysis prophylaxis in oncology — this is a top patient-safety pearl.

When to Escalate Care

— Hemodynamic instability (SBP <90 despite fluids, HR >120, lactate >2)

— Hb <6 g/dL or symptomatic anemia with end-organ ischemia (chest pain, ECG changes, AMS)

— Severe AKI with oliguria or rising Cr requiring possible RRT

— Hyperkalemia >6.5 mEq/L with ECG changes

— Massive intravascular hemolysis with DIC features

— Respiratory compromise from severe anemia (need transfusion + monitoring)

— Any first episode of hemolysis to confirm diagnosis and counsel on triggers

— Recurrent unexplained hemolysis despite trigger avoidance — consider class I variant or coexisting disorder (PNH, AIHA)

— Need for radical cure of P. vivax malaria (primaquine decision)

— Chronic non-spherocytic hemolytic anemia management

— Pregnant patients with significant hemolysis

— AKI with rising Cr despite hydration

— Need for RRT

— Suspected pigment nephropathy not resolving

— Massive transfusion (>4 units in 24 hours)

— Difficulty crossmatching due to recent transfusions

— Exchange transfusion in neonates

— Bilirubin approaching exchange transfusion threshold on Bhutani nomogram

— Signs of acute bilirubin encephalopathy (hypotonia, high-pitched cry, opisthotonus)

— Need for IV access for exchange transfusion

— Family screening of at-risk relatives

— Prenatal counseling for known carriers

— Distinguishing variant subtypes for prognostic counseling

— Outpatient: stable, mild, trigger removed, reliable follow-up

— General ward: moderate hemolysis, need IV fluids and serial labs, transfusion possibly

— Stepdown/ICU: severe hemolysis, organ dysfunction, hemodynamic instability

ICU admission criteria:

Hematology consultation:

Nephrology consultation:

Transfusion medicine consultation:

NICU escalation for neonates:

Genetics referral:

Inpatient triage logic:

CCS pearl: When the simulator shows a G6PD patient with Hb 5.5, Cr rising from 1.0 to 2.2, and oliguria, transfer to ICU, transfuse 2 units PRBC, continue aggressive IV fluids, call nephrology and hematology, and stop all oxidant drugs — don't wait for the Cr to peak.

Board pearl: Persistent hemoglobinuria >48 hours after trigger removal suggests ongoing exposure (missed drug, occult infection) or a non-G6PD diagnosis — re-evaluate.

Key Differentials — Other Hemolytic Anemias

— Positive direct Coombs (DAT) — the key differentiator

— Warm AIHA: IgG, often idiopathic or secondary to lupus/CLL/lymphoma/drugs (methyldopa)

— Cold AIHA: IgM, associated with Mycoplasma and EBV infections, lymphoma

— Smear: spherocytes, not bite cells

— Treatment: steroids ± rituximab (warm); avoid cold for cold AIHA

— Chronic hemolysis, family history, splenomegaly, pigment gallstones

— Spherocytes on smear, increased MCHC, abnormal osmotic fragility or EMA flow cytometry

— Negative Coombs (like G6PD) — don't be fooled

— Treatment: folate, splenectomy in moderate-severe disease

— Autosomal recessive, chronic non-spherocytic hemolytic anemia

— No trigger relationship; constant hemolysis

— Smear: echinocytes (burr cells), no bite cells

— Enzyme assay confirms

— Chronic intravascular hemolysis, morning dark urine, thrombosis (esp. hepatic vein), pancytopenia

— Flow cytometry: absent CD55 and CD59 on RBCs/WBCs

— Treatment: eculizumab/ravulizumab

— Schistocytes + thrombocytopenia

— TTP: ADAMTS13 <10%, pentad (fever, neuro, renal, thrombocytopenia, MAHA)

— HUS: post-diarrheal (STEC) or atypical (complement)

— DIC: prolonged PT/PTT, low fibrinogen, elevated D-dimer

— Hb electrophoresis with HbS

— Sickle cells on smear, vaso-occlusive crises

— Can coexist with G6PD deficiency

— Microcytic, target cells, basophilic stippling

— Hb electrophoresis abnormal

Autoimmune hemolytic anemia (AIHA):

Hereditary spherocytosis:

Pyruvate kinase (PK) deficiency:

Paroxysmal nocturnal hemoglobinuria (PNH):

Microangiopathic hemolytic anemia (MAHA) — TTP, HUS, DIC, HELLP:

Sickle cell disease:

Thalassemia:

Key distinction: G6PD = bite cells + Heinz bodies + negative Coombs + recent trigger + episodic. This 5-point combination separates it from every other hemolytic anemia in 90% of question stems.

Board pearl: A positive DAT immediately rules out G6PD as the primary diagnosis — pivot to AIHA workup.

Differentials Beyond Hemolytic Anemia

— Acute viral hepatitis (A, B, E): ALT/AST in thousands, direct + indirect hyperbilirubinemia, hepatomegaly, RUQ tenderness — but hepatitis can also trigger G6PD hemolysis in deficient patients, so the two can coexist

— Choledocholithiasis / cholangitis: direct hyperbilirubinemia, dilated CBD on imaging, RUQ pain, Charcot triad if cholangitis

— Gilbert syndrome: mild indirect hyperbilirubinemia precipitated by fasting, stress, infection — but no anemia, no hemolysis markers, completely benign

— Crigler-Najjar syndrome: indirect hyperbilirubinemia, severe (type I) or moderate (type II), no hemolysis

— Rhabdomyolysis: myoglobinuria (UA blood positive, no RBCs, like hemolysis) but with elevated CK >5×ULN, often after trauma or statin use; potassium and phosphate elevated

— Porphyria: acute attacks with abdominal pain, neuropathy, dark urine that darkens on standing; elevated urine porphobilinogen

— Beeturia, rifampin, phenazopyridine: harmless drug/food discoloration

— Glomerulonephritis: UA shows RBC casts and dysmorphic RBCs — true hematuria, not hemoglobinuria

— GI bleed: melena, hematemesis, elevated BUN/Cr ratio, ferric stools — not jaundice

— Splenic rupture: trauma history, hemodynamic instability, abdominal pain, free fluid on FAST

— Aplastic crisis (parvovirus B19): reticulocytopenia instead of reticulocytosis — key differentiator

— Chocolate-brown blood, cyanosis unresponsive to O₂, normal PaO₂ but low SaO₂

— Caused by oxidant drugs (benzocaine, dapsone, nitrites) — can coexist with G6PD-induced hemolysis

— Treat with ascorbic acid in G6PD patients (not methylene blue)

Causes of jaundice and dark urine that mimic G6PD presentation:

Causes of dark urine without hemolysis:

Causes of acute drop in hemoglobin:

Methemoglobinemia:

Wilson disease: can present with hemolytic anemia + acute liver failure + neuropsychiatric features; low ceruloplasmin, Kayser-Fleischer rings

Key distinction: Hemoglobinuria = UA blood-positive, microscopy with no RBCs, plus hemolysis labs (↑LDH, ↓haptoglobin). Hematuria = UA blood-positive with RBCs on microscopy → think GU/renal source, not hemolysis.

Step 3 management: When the smear shows bite cells but the trigger history is unclear, ask specifically about over-the-counter sulfa drugs, mothball storage, ethnic foods, and recent infections.

Secondary Prevention and Long-Term Plan

— Provide a written list of drugs to avoid (printed wallet card)

— Smartphone app: "G6PD Deficiency Drug Reference"

— Counsel on fava beans specifically — including derivatives in some Mediterranean dishes (foul, hummus made with broad beans)

— Counsel against naphthalene mothballs in the home, especially around infants

— Inform every new healthcare provider, including dentists, pharmacists, urgent care, of the diagnosis

— Document G6PD deficiency in the allergy/adverse reaction field, not just the problem list — this triggers hard-stop alerts when oxidant drugs are ordered

— Coordinate with the patient's primary pharmacy for cross-flag alerts

— Folic acid 1 mg PO daily for 4 weeks during erythropoietic recovery

— Discontinue the offending agent permanently; document in allergy list

— Substitute equivalent therapy as needed (e.g., switch TMP-SMX → cephalexin)

— No specific maintenance therapy required between episodes for class II/III variants

— Test mothers, sisters, daughters (carrier status); maternal brothers/uncles (affected status)

— Especially important if family planning is anticipated

— Refer for genetic counseling when class I variant or family planning concerns

— Hepatitis A and B vaccination — these infections are major triggers

— Standard influenza, pneumococcal, COVID-19 vaccines

— All routine childhood vaccines are safe

— No exercise restriction — exercise itself is not a trigger

— Caution with certain antimalarial prophylaxis when traveling to endemic regions — consult travel medicine for safe alternatives (atovaquone-proguanil generally safe)

— Stress reduction and infection prevention (hand hygiene, vaccinations) reduce episode frequency

— Iron monitoring with ferritin every 3–6 months

— Chelation therapy if iron overload develops

— Splenectomy considered in select severe cases

Patient education — the cornerstone of prevention:

EMR and pharmacy safeguards:

Discharge medications after an acute episode:

Family screening:

Vaccinations:

Lifestyle:

Chronic transfusion-dependent patients (class I variants):

Step 3 management: At every annual visit, review the trigger list with the patient and reconcile current medications against it — this is high-yield outpatient longitudinal care.

Board pearl: Hepatitis A vaccination is an underrecognized but high-yield secondary prevention measure for G6PD-deficient patients in the US.

Follow-Up, Monitoring, and Counseling

— Within 1 week of discharge: outpatient visit to confirm clinical recovery, review trigger

— 2–4 weeks post-episode: CBC to confirm Hb recovery (typically returns to baseline by 3–4 weeks)

— 3 months post-episode: quantitative G6PD enzyme assay (when reticulocyte effect has resolved) to confirm diagnosis and severity

— Annual: medication reconciliation, trigger list review, screen for new comorbidities and medications

— CBC and reticulocyte count q12h until trend stabilizes

— LDH, haptoglobin, bilirubin q24h

— BMP daily (track BUN/Cr and K+)

— UA q12–24h until hemoglobinuria resolves

— Strict I/O; daily weights

— Vitals q4h on the floor, q1h in ICU

— No specific routine labs required between episodes for class II/III patients

— Class I (CNSHA): CBC every 3–6 months; ferritin annually; consider hepatic and cardiac iron MRI if transfusion-dependent

— Explain the condition in plain language: "Your red blood cells can break apart when exposed to certain triggers"

— Provide written list of drugs and foods to avoid

— Discuss what symptoms to watch for: jaundice, dark urine, fatigue, back pain

— Instruct: "Call or go to the ED if you notice dark urine or new jaundice"

— Emphasize: tell every new clinician, pharmacist, and dentist

— X-linked inheritance pattern explained

— Sons of affected fathers are unaffected (transmit only X to daughters)

— Daughters of affected fathers are obligate carriers

— Discuss reproductive risks if patient is a carrier mother

— Pre-travel consult for malaria-endemic regions; avoid primaquine/tafenoquine

— Carry medical alert documentation when traveling internationally

— Screen for health anxiety related to drug avoidance; reassure that between-episode life is normal

Post-acute episode follow-up timeline:

Monitoring during acute hospitalization:

Outpatient longitudinal monitoring:

Counseling priorities at the index diagnosis visit:

Genetic counseling:

Travel medicine counseling:

Mental health:

Step 3 management: The transition-of-care moment after an inpatient hemolytic episode is the single highest-risk time for re-exposure — ensure the discharge summary lists G6PD prominently and includes the trigger drug as a documented allergy that primary care can see at the next visit.

Board pearl: Reticulocyte count normalizing and Hb returning to baseline within 3–4 weeks is the expected course; failure to recover suggests ongoing trigger exposure or alternative diagnosis.

Ethical, Legal, and Patient Safety Considerations

— Rasburicase-induced hemolysis in an unscreened G6PD-deficient oncology patient is a sentinel event with FDA black box warning; institutions must have pre-rasburicase G6PD screening protocols

— Dapsone or primaquine without G6PD screening = preventable harm; some institutions mandate screening before prescription

— Pharmacy alert systems must flag G6PD as a documented adverse reaction, not buried in the problem list

— Patients moving between health systems may have G6PD status lost during EMR transitions — write it on discharge summaries, after-visit summaries, and ideally a wallet card

— Urgent care and ED visits are high-risk for inadvertent TMP-SMX prescription

— Verbal handoffs to covering physicians should include G6PD status when relevant medications are considered

— Before primaquine for P. vivax radical cure in mild G6PD deficiency, explicit informed consent about hemolysis risk vs. relapse risk is required; document the discussion

— Before rasburicase: document G6PD status confirmation in the chart

— In pediatric patients, parental consent for G6PD testing should include discussion of implications for family members and lifelong drug avoidance

— Newborn screening results have implications for parents and siblings — counsel sensitively

— In carriers (heterozygous females), interpretation can be ambiguous; explain limitations

— Genetic information may have insurance and employment implications (GINA protections in the US — non-discrimination in health insurance and employment, but not life/disability insurance)

— Counsel patients of Mediterranean, African, Middle Eastern, and Asian heritage with awareness of traditional foods (fava beans, broad beans, certain herbal remedies)

— Henna application in cultural ceremonies — counsel families before use in neonates

— Diagnosis in problem list AND allergy/adverse reaction field

— Specific drugs listed as contraindicated

— Variant type documented if known (severity counseling)

Patient safety — the dominant theme for G6PD on Step 3:

Transition-of-care risks:

Informed consent issues:

Genetic testing ethics:

Mandatory reporting: No specific mandatory reporting requirements for G6PD deficiency

Cultural competence:

Documentation best practices:

Step 3 management: When a covering night-shift physician is about to order TMP-SMX for a UTI in a patient with "no listed allergies," the EMR alert based on G6PD documentation in the adverse reaction field is what prevents the next morning's hemolytic crisis — this is exactly the kind of patient-safety system thinking Step 3 tests.

Board pearl: Always check G6PD status before rasburicase, dapsone, primaquine, and tafenoquine — failure to do so is a board-tested patient safety failure.

High-Yield Associations and Rapid-Fire Facts

— Class I: chronic hemolytic anemia (rare)

— Class II Mediterranean: severe episodic, fava bean sensitive

— Class III A−: mild-moderate, self-limited (older RBCs lyse, reticulocytes spared)

— Class IV: normal

— UTI: cephalexin, fosfomycin, amoxicillin-clavulanate

— PJP prophylaxis: atovaquone

— Tumor lysis prophylaxis: allopurinol + IV hydration

— Methemoglobinemia: ascorbic acid

Inheritance: X-linked recessive — males predominantly affected; heterozygous females variable

Most common enzymopathy worldwide: ~400 million people

Pathway: Pentose phosphate (HMP shunt) → NADPH → reduced glutathione → protects RBC from oxidative damage

Smear findings: Bite cells, blister cells, Heinz bodies (Heinz needs supravital stain)

Coombs: Negative — distinguishes from AIHA

Most tested drug trigger: TMP-SMX (Bactrim)

Most tested food trigger: Fava beans (favism) — Mediterranean variant

Most tested infection trigger: Any febrile illness; hepatitis A and B classic

Most tested neonatal trigger: Naphthalene mothballs

Most tested oncology pitfall: Rasburicase for tumor lysis prophylaxis

Most tested HIV pitfall: Dapsone or TMP-SMX for PJP prophylaxis → use atovaquone

Most tested malaria pitfall: Primaquine for P. vivax radical cure

Most tested methemoglobinemia pitfall: Methylene blue contraindicated → use ascorbic acid

Variants by severity:

Timing of hemolysis: 24–72 hours after trigger exposure

Self-limited episode duration: 7–10 days (A−); longer for Mediterranean

Diagnostic timing: Test enzyme ≥3 months after acute episode (avoids false negative from reticulocyte predominance)

Urine finding: Hemoglobinuria (dipstick blood +, microscopy no RBCs); urine hemosiderin positive several days later

Safe substitutes:

Vaccinations: All standard vaccines safe; hepatitis A and B especially important (infection-trigger prevention)

Coexistence: Can occur with sickle cell trait/disease, thalassemia — does not preclude diagnosis

Splenomegaly: Generally absent (helps distinguish from HS, thalassemia)

Aspirin: Low-dose cardioprotective is safe; high-dose anti-inflammatory may trigger

Step 3 management: Memorize the 5-drug "never" list — TMP-SMX, dapsone, primaquine/tafenoquine, rasburicase, nitrofurantoin — and the safe substitutes for each.

Board pearl: Reticulocyte count in early hemolysis (first 48–72 hours) may be falsely normal/low — don't let it dissuade you from the diagnosis when the smear shows bite cells.

Board Question Stem Patterns

— "A 22-year-old man of Greek descent presents with fatigue, jaundice, and dark urine. He was started on TMP-SMX for a UTI 3 days ago. Hb 7.2 (was 14), retic 3%, LDH 1450, haptoglobin <10, indirect bilirubin 4.2, direct Coombs negative."

— Answer: G6PD deficiency; next step → stop TMP-SMX, IV fluids, supportive care

— "A 5-year-old Italian boy presents with pallor and dark urine the day after a family reunion where he ate fresh fava beans for the first time."

— Answer: G6PD deficiency (Mediterranean variant); confirm with enzyme assay in 3 months

— "Peripheral smear shows red cells with a portion bitten out and supravital stain reveals dark intracellular inclusions."

— Answer: Bite cells + Heinz bodies → G6PD deficiency

— "A patient with newly diagnosed Burkitt lymphoma is started on rasburicase for tumor lysis prophylaxis. Several hours later, he develops cyanosis unresponsive to O₂, dark urine, and a drop in Hb."

— Answer: Methemoglobinemia + hemolysis from rasburicase in undiagnosed G6PD deficiency; treat with ascorbic acid (NOT methylene blue)

— "An HIV-positive patient with CD4 of 150 and known G6PD deficiency needs PJP prophylaxis. Which agent is most appropriate?"

— Answer: Atovaquone

— "Patient with bite cells and recent TMP-SMX exposure has a normal G6PD enzyme assay during the acute episode."

— Answer: False negative due to reticulocyte predominance; repeat in 3 months

— "Patient with methemoglobinemia from benzocaine has known G6PD deficiency. What is the treatment?"

— Answer: Ascorbic acid IV (methylene blue contraindicated)

— "A 2-day-old Mediterranean newborn has total bilirubin 18 mg/dL. No ABO/Rh incompatibility. Mother used mothballs in stored baby clothes."

— Answer: G6PD deficiency triggered by naphthalene; phototherapy, possible exchange transfusion

— "Returning traveler with P. vivax and known G6PD deficiency. What is the radical cure plan?"

— Answer: Consult ID; primaquine contraindicated in severe deficiency; weekly primaquine × 8 weeks in mild deficiency with monitoring

— Bite cells + negative Coombs = G6PD; spherocytes + positive Coombs = warm AIHA; spherocytes + negative Coombs + family history = hereditary spherocytosis

Stem pattern 1 — Classic post-antibiotic hemolysis:

Stem pattern 2 — Favism in a child:

Stem pattern 3 — Smear identification:

Stem pattern 4 — Rasburicase trap:

Stem pattern 5 — HIV with PJP prophylaxis decision:

Stem pattern 6 — Negative enzyme assay trap:

Stem pattern 7 — Methylene blue trap:

Stem pattern 8 — Neonatal jaundice:

Stem pattern 9 — Vivax malaria radical cure:

Stem pattern 10 — Coombs differentiation:

Board pearl: The combination of at-risk ethnicity + recent oxidant drug + negative Coombs + bite cells = G6PD deficiency in nearly every Step 3 stem.

Step 3 management: When the question asks "what is the next best step," the answer is almost always stop the offending agent + supportive care, NOT immediate enzyme assay.

One-Line Recap

G6PD deficiency is an X-linked enzymopathy in which oxidant exposure (TMP-SMX, dapsone, primaquine, rasburicase, fava beans, naphthalene, infection) precipitates episodic intravascular hemolysis with bite cells, Heinz bodies, hemoglobinuria, and a negative Coombs test — managed by immediate trigger removal, supportive IV hydration, transfusion if severe, and lifelong avoidance counseling with EMR allergy flagging.

— Diagnosis: Bite cells + Heinz bodies (supravital stain) + negative Coombs + indirect hyperbilirubinemia + hemoglobinuria + recent trigger → quantitative enzyme assay ≥3 months post-episode to avoid false-negative reticulocyte effect

— Top triggers to memorize: TMP-SMX, dapsone, primaquine/tafenoquine, rasburicase, nitrofurantoin, methylene blue, fava beans, naphthalene mothballs, infections (especially hepatitis A/B)

— Critical substitutions: PJP prophylaxis → atovaquone; tumor lysis prophylaxis → allopurinol + hydration; methemoglobinemia → ascorbic acid (NOT methylene blue); UTI → cephalexin or fosfomycin

— Management: Remove trigger, IV fluids to protect kidneys (goal UOP >0.5 mL/kg/hr), transfuse if Hb <7 or symptomatic, folate during recovery, document as drug allergy in EMR with hard-stop alerts, hepatitis A/B vaccination, written wallet card, family genetic screening

High-yield recap bullets:

Board pearl: Reticulocyte count may be falsely low in the first 48–72 hours of hemolysis, and enzyme assay may be falsely normal during active hemolysis — both are classic Step 3 traps designed to push you off the correct diagnosis. Trust the bite cells, the smear, the trigger history, and the negative Coombs.

Step 3 management: The single most important longitudinal intervention is EMR documentation as an adverse reaction with an automated alert that prevents future oxidant drug prescription — a system-level patient safety win that defines outpatient G6PD care.