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General Reference ⬇

Nejm 2004;350:2383; 1999;341:1986; Jama 1998;280:172

Pathophys and Cause ⬆ ⬇

Cause:

Genetic (Ann IM 1999;130:953), most are autosomal recessive HFE gene mutation C282Y on chromosome 6 (Nejm 1999;341:718, 755); but a small % are H63D mutations of the same gene (Jama 2001;285:2216)

Iron overload, eg, in thalassemia major patients (Ann IM 1983;99:450), or dietary overload in African genetically predisposed (Nejm 1992;326:95). Heterozygous state may have some reproductive advantage to women by preventing iron deficiency (Nejm 1996;335:1799)

Pathophys:A chronic hepatitis; hemosiderin deposition especially in pancreas, skin, liver, testes, heart, kidneys

Epidemiology ⬆ ⬇

Usually in patients age >40 yr; women usually older than men since menstruation protects (Ann IM 1997;127:105)

C282Y gene frequency ~1/15, M:F = 4:1; 1/250 whites are homozygotes (Nejm 2005;352:1769). Lower rates inother ethnic groups down to <1/million in Asians.

H63D homozygote prevalence higher, 2/5% of whites, 0.2% of Asians; but iron levels in homozygotes only equal to C282Y heterozygotes

Signs and Symptoms ⬆ ⬇

Sx:Increased skin pigmentation (iron stimulation of melanin production); weakness/fatigue (70%); abdominal pain (60%); arthritis (often 1st sx in 40-60%); diabetic sx's

Si:Skin pigmentation (75%), diabetic si's (60%); cardiac failure

Course ⬆ ⬇

Normal life expectancy with phlebotomies if no cirrhosis (Nejm 1985;313:1256); heterozygotes have mildly elevated iron levels but no iron overload cmplc's (Nejm 1996;335:1799)

Complications ⬆ ⬇

Hepatic cirrhosis (60%), hepatoma (10%); pituitary impotence (30%), reversible with rx (Ann IM 1984;101:629); CHF from myocardiopathy with a rapidly downhill course; diabetes, usually insulin dependent

Lab and Xray ⬆ ⬇

Lab:

Chem: alpha.gif-Fetoprotein elevated (r/o hepatoma); hepatitis LFTs;

  • Ferritin >250 µgm/L (women), >350 µgm/L (men) (99.5% sens, 94% specif) (Ann IM 1998;128:338) or less (Ann IM 2000;133:329); cirrhosis very unlikely unless ferritin >1000 (7% false neg—Ann IM 2003;138:627)
  • Iron/TIBC % saturations >60% (Nejm 1982;307:1702) in men, >50% in women (98% sens, 94% specif) (Ann IM 1998;128:338) or less (Ann IM 2000;133:329)
  • Genetic analysis for C282Y mutation of HFE gene (Ann IM 2000;132:261)

Path:Bx of liver, synovium, marrow, rectal mucosa all show increased iron deposition and, in liver, cirrhosis with periportal concentrations

Treatment ⬆

Rx:

Prevent: screening all adults with Fe and TIBC for homozygous state by above iron level criteria is not indicated (USPSTF—Ann IM 2006;145;204, 209) but may be for pt's family members for C282Y mutation of HFE gene useful and cheap ($95) (Ann IM 2000;132:261)

of disease:

  • 1st: Phlebotomy of 1 U q3-7d to keep ferritin <50 µgm/L, may take 1+ yr, then 3-4 ×/yr to keep there; rapid, effective, and safer than deferoxamine (Clem Finch, 1972)
  • 2nd: Deferoxamine iv or sc (Nejm 1977;297:418); 12-h sc pump best, esp for Fe overload patients, eg, thalassemia major (Ann IM 1983;99:450); adverse effects: deafness and blindness (Nejm 1986;314:869). Or L1, an iron chelator, oral as effective as parenteral (Clin Pharmacol Ther 1991;50:294)