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Answers to the Exam Questions

First Question (above the visible portion - Iron Deficiency Anemia with Pica)

a) Probable Diagnosis (1M)

Iron Deficiency Anemia (IDA)

The clinical picture is classic: microcytic hypochromic anemia (MCV 56 fL, MCH 15.5 pg/cell, MCHC 27.5 g/dL), brittle nails, pallor, and most tellingly - pica (consuming crayons for 9+ years). Pica is highly specific for iron deficiency and rarely occurs in other clinical settings.

The Washington Manual of Medical Therapeutics: "Pica (consumption of substances of no nutritional value such as ice, starch, or clay) occurs in about 25% of patients with chronic iron deficiency anemia and rarely occurs in other clinical settings."

b) Metabolism and Regulation of Iron (6M)

Total Body Iron Distribution

Total iron: ~4-5 grams
65% as hemoglobin, 4% as myoglobin, 1% in heme enzymes (cytochromes, catalase, peroxidase), 0.1% as plasma transferrin-bound iron, 15-30% stored as ferritin/hemosiderin
(Guyton and Hall Textbook of Medical Physiology)

Intestinal Absorption

Dietary iron: ~15 mg/day in Western diet; only 1-2 mg absorbed (limited by enterocyte capacity)
Non-heme iron (Fe3+): Converted to Fe2+ by duodenal cytochrome B (DCYTB, a ferrireductase) via the low local pH in the duodenum, then imported into enterocytes by DMT1 (divalent metal transporter-1)
Heme iron: (from red meat) absorbed via a separate undefined mechanism - more bioavailable
Inside the enterocyte: iron can be stored as ferritin or exported across the basolateral membrane by ferroportin into the plasma
Ascorbic acid (Vitamin C) enhances non-heme iron absorption; phytates and tannins inhibit it

Transport in Blood

Absorbed iron binds to apotransferrin (a beta-globulin made in the liver) to form transferrin (plasma transferrin)
Transferrin carries 3-4 mg iron but has rapid turnover (20-25 mg/day delivered to bone marrow)
Transferrin binds transferrin receptors (TfR1) on erythroblasts; the complex is internalized by endocytosis; iron is delivered to mitochondria for heme synthesis

Cellular Storage

Ferritin: Iron combines with apoferritin (MW ~460,000) in the cytoplasm - main storage form, small particles (EM visible); iron is easily mobilizable
Hemosiderin: Insoluble aggregate when ferritin capacity is exceeded; seen as large aggregates on light microscopy; not easily mobilized
Storage occurs mainly in liver hepatocytes, reticuloendothelial cells of bone marrow, and spleen macrophages

Recycling

Macrophages (Kupffer cells in liver, splenic/bone marrow macrophages) phagocytose senescent RBCs (after 120-day lifespan) and recover iron from hemoglobin
Recovered iron re-enters the cycle via ferroportin export and transferrin transport back to bone marrow
The porphyrin ring becomes bilirubin

Regulation - The Hepcidin-Ferroportin Axis (key regulatory mechanism)

Hepcidin (liver-derived peptide hormone) is the master regulator of systemic iron homeostasis
Hepcidin binds ferroportin on enterocytes, macrophages, and hepatocytes → causes its internalization and degradation → blocks iron export → decreases plasma iron
High iron stores / inflammation → high hepcidin → blocks ferroportin → iron sequestered in stores
Low iron / hypoxia / increased erythropoiesis → low hepcidin → ferroportin active → increased iron absorption and mobilization
Erythroferrone (from erythroblasts stimulated by erythropoietin) suppresses hepcidin, boosting iron supply to the bone marrow
Iron Regulatory Proteins (IRPs): At the cellular level, IRPs sense intracellular iron and regulate translation of ferritin (storage), transferrin receptor (uptake), and ferroportin via iron-responsive elements (IREs) in their mRNAs
Daily iron loss: ~0.6 mg/day in men (mainly feces); ~1.3 mg/day in women (adding menstrual loss)

(Harrison's Principles of Internal Medicine 22E, Guyton and Hall)

c) Disorders Related to Iron Metabolism (3M)

Disorder	Defect/Mechanism
Iron Deficiency Anemia	Inadequate iron (poor intake, chronic blood loss, malabsorption, increased demand) → microcytic hypochromic anemia, pica, koilonychia, angular stomatitis
Hereditary Hemochromatosis	Mutation in HFE gene → inadequate hepcidin → unregulated ferroportin activity → excess iron absorption (0.5-1 g/year) → accumulates in liver (cirrhosis), pancreas (diabetes), heart (cardiomyopathy), joints, skin (bronzing) - "bronze diabetes"
Anemia of Chronic Disease (ACD)	Inflammation → high hepcidin → ferroportin degradation → iron trapped in macrophages → functional iron deficiency despite adequate stores; normocytic or mildly microcytic
Sideroblastic Anemia	Defect in heme synthesis (X-linked: ALA synthase-2 mutation) → iron accumulates in mitochondria of erythroblasts → ring sideroblasts on Prussian blue stain; iron overload despite anemia
Iron Overload (Transfusion-related)	Multiple transfusions (e.g., thalassemia) → no physiological pathway for iron excretion → tissue damage
IRIDA (Iron-Refractory IDA)	TMPRSS6 mutation → hepcidin cannot be suppressed → reduced iron absorption refractory to oral iron
Plummer-Vinson Syndrome	Chronic IDA → esophageal webs + glossitis; associated with upper GI cancers

Second Question (Reasoning Out)

Clinical Scenario:

4-day-old neonate: poor feeding, vomiting, lethargy, hypotonia, no hepatosplenomegaly

Plasma ammonia: extremely elevated
BUN: very low
Plasma glutamine: elevated
Urine orotic acid: normal

a) Most Likely Diagnosis (1M)

Carbamoyl Phosphate Synthetase I (CPS-1) Deficiency

or alternatively N-Acetylglutamate Synthase (NAGS) Deficiency

Both are proximal urea cycle defects that present with severe neonatal hyperammonemia with normal urine orotic acid - which is the key distinguishing feature.

b) Cause of Elevated Ammonia Levels (2M)

The urea cycle converts toxic ammonia (NH3) to urea for excretion. The cycle proceeds:

NH3 + CO2 + ATP → CPS-1 → Carbamoyl phosphate → OTC → Citrulline → ... → Urea

CPS-1 is the first and rate-limiting enzyme of the urea cycle, located in the mitochondrial matrix. It requires N-acetylglutamate (NAG) as an obligate allosteric activator (NAGS synthesizes NAG).

When CPS-1 is deficient:

The urea cycle is blocked at the first step
Ammonia cannot be incorporated into carbamoyl phosphate
Ammonia accumulates in blood (hyperammonemia)
Excess NH3 is instead detoxified by glutamine synthetase: Glutamate + NH3 → Glutamine - which explains the elevated plasma glutamine
BUN is very low because urea cannot be synthesized
The ammonia that does not enter the urea cycle accumulates, causing the neurological features (lethargy, hypotonia, coma) - brain damage occurs at NH4+ >200 μmol/L

(Harrison's 22E, Thompson & Thompson Genetics and Genomics in Medicine 9th ed.)

c) Why is Urine Orotic Acid Normal? (2M)

This is the key distinguishing feature between CPS-1 deficiency and OTC deficiency.

Understanding orotic acid production:

Urine orotic acid is a byproduct of the pyrimidine synthesis pathway. Carbamoyl phosphate (made by CPS-1 in the mitochondria) that flows through the urea cycle normally stays in the mitochondria. However, if carbamoyl phosphate overflows into the cytosol (as happens in OTC deficiency), it is channeled into pyrimidine synthesis via cytosolic CPS-2, eventually producing orotic acid in excess.

In CPS-1 deficiency:

CPS-1 cannot produce carbamoyl phosphate at all
There is NO excess carbamoyl phosphate to overflow into the cytosol
Therefore, pyrimidine synthesis via the cytosolic pathway is not overloaded
Orotic acid is normal (or low)

In OTC deficiency (contrast):

CPS-1 works normally and makes carbamoyl phosphate
OTC is deficient, so carbamoyl phosphate cannot condense with ornithine
Carbamoyl phosphate accumulates and spills into the cytosol
It enters the pyrimidine synthesis pathway → elevated urine orotic acid

This is why urine orotic acid measurement is a diagnostic tool to distinguish CPS-1/NAGS deficiency (orotic acid normal) from OTC deficiency (orotic acid elevated) - both present with severe neonatal hyperammonemia.

(Harrison's Principles of Internal Medicine 22E: "Citrulline is low or undetectable in proximal defects of the urea cycle (N-acetylglutamate synthase, carbamylphosphate synthase 1, and ornithine transcarbamylase deficiency), with urine orotic acid being increased only in ornithine transcarbamylase deficiency.")

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