Hemochromatosis¶

Chapter 426 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 426

Key Clinical Points¶

Hemochromatosis is an inherited iron-storage disorder, primarily caused by HFE gene mutations (C282Y homozygosity).
Screening criteria: Transferrin saturation (TS) ≥ 45% and/or serum ferritin (SF) ≥ 300 μg/L.
First-line treatment is phlebotomy, with a target serum ferritin ≤ 100 μg/L.
Cirrhosis is the critical determinant of prognosis and risk of hepatocellular carcinoma (HCC).
Classic triad: skin bronzing, diabetes mellitus, and arthropathy.
Alcohol consumption increases risk of cirrhosis nearly tenfold and must be eliminated.
Secondary iron overload (e.g., thalassemia, sideroblastic anemia) requires chelation, not phlebotomy.
Liver biopsy is the gold standard for assessing fibrosis and iron concentration.
Early diagnosis allows for identification of asymptomatic patients before organ damage occurs.
Mandatory family screening of first-degree relatives for all diagnosed cases.

1. DEFINITION & OVERVIEW¶

• Definition (Harrison's 22e): Hemochromatosis is a relatively common inherited disorder of iron metabolism more prevalent in European populations. It is now known to be an iron-storage disorder with underlying genetic heterogeneity that, in nearly all cases, causes inappropriately high cellular release of iron from iron exporting cells such as enterocytes and macrophages.

• Pathophysiology: Increased intestinal absorption → deposition of excess iron in parenchymal cells → tissue fibrosis and organ failure.

• Clinical Consequences: Cirrhosis of the liver, diabetes mellitus, arthritis, cardiomyopathy, and hypogonadotropic hypogonadism.

• Specific Characteristics: ◦ High serum transferrin saturation. ◦ Iron overload in the liver but not the spleen. ◦ Involvement of periportal hepatocytes with iron sparing of Kupffer cells.

• Genetic Basis: ◦ Primarily caused by mutations in the HFE gene (linked to HLA-A locus on chromosome 6p). ◦ C282Y homozygosity accounts for 80–90% of cases in northern European populations.

1.1 Classification of Iron Overload States¶

• Hereditary Hemochromatosis: ◦ HFE-related (type 1): C282Y homozygosity or C282Y/H63D compound heterozygosity. ◦ Non-HFE-related: → Juvenile hemochromatosis (type 2A) (hemojuvelin mutations) → Juvenile hemochromatosis (type 2B) (hepcidin mutation) → Mutated transferrin receptor 2, TFR2 (type 3) → Mutated ferroportin 1 gene, SLC40A1 (type 4)

• Acquired Iron Overload: ◦ Iron-loading anemias: Thalassemia major, Sideroblastic anemia, Chronic hemolytic anemias. ◦ Transfusional and parenteral iron overload. ◦ Chronic liver disease: Hepatitis C, Alcoholic cirrhosis (especially when advanced), Nonalcoholic steatohepatitis (NASH), Porphyria cutanea tarda (PCT). ◦ Dietary iron overload. ◦ Dysmetabolic iron overload syndrome. ◦ Post-portacaval shunting. ◦ Miscellaneous: Iron overload in sub-Saharan Africa, Neonatal iron overload, Aceruloplasminemia, Congenital atransferrinemia.

2. EPIDEMIOLOGY¶

• Prevalence: ◦ Most common in northern European populations. ◦ ~1 in 10 are heterozygous carriers; 0.3–0.5% are homozygotes. ◦ Higher prevalence in Celtic populations (Ireland, Brittany).

• Modifying Factors: Alcohol consumption, dietary iron intake, blood loss (menstruation/pregnancy), and blood donation.

• Clinical Progression Statistics: ◦ ~40% of homozygous men develop iron overload–related complications. ◦ ~6% of homozygous men develop hepatic cirrhosis. ◦ ~10% of women develop iron overload–related complications.

• Age of Presentation: ◦ ~70% of untreated patients show symptoms between ages 40 and 60. ◦ Rarely evident before age 20; early detection possible via screening.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

• Genetic Basis: ◦ HFE-related: C282Y (homozygous G to A transition) is the most common. ◦ H63D variant: Not associated with significant iron overload alone; acts as a cofactor for other conditions like PCT or MASH. ◦ Non-HFE forms: Result from mutations in hepcidin pathway genes (HJV, TFR2, SLC40A1).

• Hepcidin Pathway: ◦ Hepcidin: Liver-derived peptide; represses basolateral iron export from enterocytes and release from macrophages by binding to ferroportin (FPN). ◦ Regulation: Responds to signals via HFE, TFR2, and hemojuvelin (HJV). ◦ Pathway Dynamics: HJV-dependent BMP/SMAD pathway; modified by erythroferrone (inhibits BMP6); TMPRSS6 is a protease that modulates HJV activity.

• Iron Accumulation: ◦ Normal body-iron: 3–4 g. ◦ Hemochromatosis: ≥ 20 g (deposited in liver, pancreas, heart). ◦ Tissue Damage: Result of iron accumulation in parenchymal cells; progression to perilobular fibrosis and formation of fibrous septa due to activation of hepatic stellate cells.

• Secondary Iron Overload: ◦ Seen in sideroblastic anemia, thalassemia, and PCT. ◦ Note: In PCT, iron overload exacerbates enzyme deficiency; must avoid alcohol, estrogens, and halogenated compounds.

4. CLINICAL FEATURES¶

• Progression Stages: 1. Genetic predisposition (no symptoms). 2. Iron overload without symptoms. 3. Iron overload with symptoms (arthritis, fatigue). 4. Iron overload with organ damage (cirrhosis).

• General Symptoms: Lethargy, arthralgia, skin pigmentation, loss of libido, and diabetes mellitus.

• Advanced Disease Features: Hepatomegaly, spider angiomas, splenomegaly, ascites, cardiac arrhythmias, congestive heart failure, and jaundice.

Organ System Manifestations¶

• Skin: "Bronze" appearance (metallic/slate-gray) due to increased melanin and iron in the dermis.

• Pancreas: Diabetes mellitus in ~65% of advanced cases; likely due to direct islet damage.

• Joints: Arthropathy in 25–50% of symptomatic patients.

→ Often involves 2nd and 3rd metacarpophalangeal joints (distinguishes from idiopathic forms).

→ May include chondrocalcinosis (calcium pyrophosphate) in knees.

• Heart: Congestive heart failure in ~10% of young adults; can present as sudden, rapid progression to death.

• Reproductive: Hypogonadism (loss of libido, testicular atrophy, amenorrhea) due to pituitary/hypothalamic impairment.

5. DIFFERENTIAL DIAGNOSIS¶

• Hereditary vs. Acquired: ◦ Hereditary: Genetic mutations (HFE, HJV, TFR2, SLC40A1). ◦ Acquired: Thalassemia, Sideroblastic anemia, Hepatitis C, Alcoholism.

• Distinguishing Features: ◦ Hemochromatosis specifically involves iron in the liver but not the spleen; it features periportal hepatocyte involvement with sparing of Kupffer cells.

6. INVESTIGATIONS & DIAGNOSIS¶

Initial Screening: Identify high-risk individuals (first-degree relatives, symptomatic patients, or those with unexplained liver disease).
Biochemical Testing: Measure Transferrin Saturation (TS) and Serum Ferritin (SF).

Decision Pathway (Figure 426-3):

Step 1: Initial Screening

→ If TS < 45% AND SF < 300 μg/L → Reassess, possibly better later.

→ If TS ≥ 45% OR SF ≥ 300 μg/L → Proceed to Genotype Testing.

Step 2: Genotype Testing

→ If NO C282Y mutation → Counsel and consider non-HFE hemochromatosis.

→ If C282Y Homozygote or C282Y/H63D Compound Heterozygote → Proceed to Clinical Correlation.

Step 3: Clinical Correlation (for C282Y positive)

→ If SF 300–1000 μg/L and LFT normal: → If SF < 300 μg/L → Observe, retest in 1–2 years. → Otherwise → Proceed to Liver Biopsy.

→ If SF > 1000 μg/L and LFT abnormal → Liver biopsy.

Step 4: Post-Biopsy Action

→ If confirmed iron overload → Phlebotomy.

→ If no iron overload → Investigate and treat as appropriate.

Pathway of Normal Iron Homeostasis (Figure 426-1)¶

• Absorption: Dietary Iron → Duodenum (DMT1/DCYTB) → Plasma Transferrin.

• Regulation: Liver senses iron via HFE, TFR2, and HJV → regulates Hepcidin → inhibits Ferroportin (FPN).

• Recycling: Senescent RBCs → Macrophages → Release via FPN to plasma.

7. MANAGEMENT & TREATMENT¶

Initial Management: → Identify and treat co-factors (e.g., alcohol cessation).
Primary Treatment: Phlebotomy. → Goal: Reduce iron stores to target serum ferritin ≤ 100 μg/L.
Symptom Management: → Diabetes: Standard management for other forms of DM. → Hypogonadism: Testosterone replacement or gonadotropin therapy.
Monitoring: → Regular assessment of liver function and iron levels.
Referral/Escalation: → Refer to specialists if heart failure, advanced cirrhosis, or HCC is suspected.

8. PROGNOSIS & COMPLICATIONS¶

• Prognosis: Normal life expectancy if treated before cirrhosis develops.

• Mortality: Hepatocellular carcinoma (HCC) is the most common cause of death in patients with cirrhosis.

• Complications: → Heart failure (sudden onset possible). → Diabetes mellitus. → Joint destruction (arthropathy may progress despite phlebotomy).

Risk Factors for Poor Outcome¶

• Alcohol: Increases risk of cirrhosis nearly tenfold.

• Advanced Disease: Presence of cirrhosis or high iron concentration in liver is a primary determinant of fibrosis progression.

9. SPECIAL CONSIDERATIONS¶

• Young Patients: Often present with heart failure (10% of young adults) or hypogonadism.

• Women: Lower risk of cirrhosis than men due to menstrual blood loss, but still require screening.

• Patients with PCT: Must avoid alcohol and other exacerbating agents; iron overload must be managed carefully as it accentuates enzyme deficiency.

10. KEY PEARLS & CLINICAL TRAPS¶

• Screening Rule: TS ≥ 45% and/or SF ≥ 300 μg/L are the primary triggers for investigation.

• Treatment Goal: Target serum ferritin ≤ 100 μg/L via phlebotomy.

• Clinical Distinction: Hemochromatosis involves liver iron but not spleen iron; it affects periportal hepatocytes.

• Diagnostic Sequence: Screening → Genotype → (if needed) Biopsy → Phlebotomy.

• Key Difference: Secondary iron overload (e.g., Thalassemia) requires chelation, not phlebotomy.

Reference Tables¶

Harrison's 22e, p.3333

Hereditary Hemochromatosis
Hemochromatosis, HFE-related (type 1)
C282Y homozygosity
C282Y/H63D compound heterozygosity
Hemochromatosis, non-HFE-related
Juvenile hemochromatosis (type 2A) (hemojuvelin mutations)
Juvenile hemochromatosis (type 2B) (hepcidin mutation)
Mutated transferrin receptor 2, TFR2 (type 3)
Mutated ferroportin 1 gene, SLC40A1 (type 4)
Acquired Iron Overload
Iron-loading anemias Thalassemia major Sideroblastic anemia Chronic hemolytic anemias Transfusional and parenteral iron overload Dietary iron overload	Chronic liver disease Hepatitis C Alcoholic cirrhosis, especially when advanced Nonalcoholic steatohepatitis Porphyria cutanea tarda Dysmetabolic iron overload syndrome Post-portacaval shunting
Miscellaneous
Iron overload in sub-Saharan Africa
Neonatal iron overload
Aceruloplasminemia
Congenital atransferrinemia
426	Hemochromatosis Darrell H. G. Crawford, David M. Frazer

TABLE 426-2 Representative Iron Values in Normal Subjects, Patients with Hemochromatosis, and Patients with Alcoholic…¶

Harrison's 22e, p.3336

DETERMINATION	NORMAL	SYMPTOMATIC HEMOCHROMATOSIS	HOMOZYGOTES WITH EARLY, ASYMPTOMATIC HEMOCHROMATOSIS	HETEROZYGOTES	ALCOHOLIC LIVER DISEASE
Plasma iron, μmol/L (μg/dL)	9–27 (50–150)	32–54 (180–300)	Usually elevated	Elevated or normal	Often elevated
	45–66 (250–370)	36–54 (200–300)	36–54 (200–300)	Normal
Transferrin saturation, %	22–45	50–100	50–100	Normal or elevated	27–60
		1000–6000	200–500	Usually <500
	20–250
	15–150
Liver iron, μg/g dry wt	300–1400	6000–18,000	2000–4000	300–3000	300–2000
	<1.0	>2	1.5–2	<2