Outline – Hereditary Hemochromatosis/Wilsons
HEREDITARY HEMOCHROMATOSIS
4 types: 3 are AD and 1 is AR
Iron Homeostasis
o Normal = 5-6grams in body; no method of iron excretion esists.
Bulk = erythrocytes (75%), bone marrow, marcophages, hepatocytes (20%), myoglobin,
catalase, perixidase, cytochromes (5%)
Travels in blood bound to transferrin – saturation range 20-50%
Stored bound to Ferritin – 12-300ng/mL men, 10-150 ng/mL women.
o Absorption/Handling
Dietary FeDuodenal enterocytes DMT1 (divalent metal transporter) used, stored in ferritin,
or exported by ferroportin Fe bound to transferring in blood Transferrin receptor (Tfr1)
enters erythroblasts
o Iron regulation
IRP (iron reg prot) – inhibit translation of ferritin/ferroportin when \/ [Fe] but are inactive
when /\ [Fe]
Hepcidin – made by hepatocytes when /\ [Fe] or inflammation. Expression via BMP-SMAD Fe
sensing pathway
Bind ferroprtin degraded \/ Fe exporting from inside cell.
Hemojuvelin – regulates Hepcidin expression (interacts w/ BMP as co-receptor)
HFE protein – duodenal crypt associated w/ Tfr1 \/’d affinity for transferrin.
HFE Hemochromatosis
Etiology
o Genes = HFE gene: homozygous HFE C282Y or H63D, low penetrance, M>F. Both mutations prevent
HFE protein binding can’t bind Tfr1 can’t tell has enough Fe so keeps absorbing all dietary Fe.
Epidemiology = Northern European, M>F, age 40 for men, age 50 for women.
Present = shows up in 30-50yo because kids use a lot of Fe,
o Early signs = most have no Sx or fatigue, arthralgia, impotence.
o Late signs
Liver dz – hepatomegaly w/ chronic liver dz signs, cutaneous stigmata of liver dz (palm
erythema, spider angioma, jaundice) cirrhosis liver cancer (most common C.O.D)
Skin hyperpigmentation – Fe deposits + melanin = bronze skin. Classic triad = cirrhosis,
diabetes, skin pigmentation (when body Fe = 20g)
Diabetes Mellitus – (30-60%) Fe accumulation in pancreas Beta cells.
Arthropathy – Xray show squared off bone ends, hook like osteophytes in 2nd/3rd MCP.
MCP > PIP > knees
Hypogonadism – ameorrhea, \/ libido, impotence from pituitary/testicular Fe deposits
Cardiomyopathy – enlarged heart, heart failure, arrythmia, conduction defects
Gross Morpho – deposition of hemosiderin in liver > pancreas> heart >pituitary > adrenal > thyroid >
parathyroid > joints> skin. Cirrhosis and pancreatic fibrosis also seen.
o Liver – golden-yellow hemosiderin granules in cytoplasm (Prussian blue) progressing to whole lobule,
duct epi, and Kupffer cells. ROS damage to cells (no inflam).
o Pancreas – intense pigment, diffuse interstitial fibrosis, hemosiderin in acinus, islets, and stroma.
Outline – Hereditary Hemochromatosis/Wilsons
o Heart – large, hemosiderin granules in myocardium (brown), delicate interstitial fibrosis
o Skin – some hemosiderin in dermal macros + fibroblasts, but most from /\’d melanin production. Skin
has slate grey color.
o Synovial linings – deposition of Ca pyrophosphate damages cartilage pseudogout.
o Testes – small atrophic secondary to pituitary-hypothalamic axis derangement
Hepatic [Fe] – have over 10,000mg Fe/gram dry weight. > 22,000mg/gram dry weight = cirrhosis +fibrosis
Labs values
o Transferrin sat – more sensitive and specific; 90% have > 60% saturation of Transferrin.
o Serum Ferritin – elevated but is acute phase reactant too.
Diagnosis – gene testing or liver biopsy
Non-HFE Hemochromatosis
Juvenile – rare, AR, mutation of HJV coding Hemojuvelin (90%) or HAMP coding Hepcidin (10%). Before 30 yo, M=F
o Hypogonadotropic hypogonadis, cardiomyopathy (COD), arthropathy, liver fibrosis/cirrhosis
TrfR2 – rare, AR, TfR2 gene on Ch 7q22, severity between HFE and juvenile flavors
o Arthralgia, hyogonadism, skin pig, diabetes, heart failure, cirrhosis. Fe is not as high, not as progressive. 30-40s.
Ferropontin – AD, mutation in Ferroportin (expressedin macros and BM of enterocytes/hepatocytes)
o Hyperferritinemia, Fe overloaded macros in liver/spleen, normal Transferrin saturation.
General principles of Treatment – phlebotomy to remove Fe. Goal = anemia stimulates Fe utilization/erythopoeisis.
o If hypoproteinemia, anemia, cardiac dz = use chelating agents instead (not as good as phelb)
SECONDARY HEMOCHROMATOSIS
What = Fe overload disorders where excess Fe from /\ intestinal abs from dz or transfusional siderosis (repeat xfusion)
Etiology = ineffective erythropoeisis (B-thalassemia, sideroblastic anemia), chronic hemolytic anemi (pyruvate kinase def,
sickle cell), hypoplastic anemia (chronic renal fail, aplastic anemia).
Pathophys – extra RBC enter system from xfusion processed by macrophages Fe released builds in tissues bc
humans have no active secretion of Fe.
o Fe seen in macros seen in parenchyma eventually.
o Cardiac toxicity > hepatic/endocrine dysfunction
Special rare cases
o African Fe Overload (Bantu siderosis) – gene polymorphism for ferroportin predisposing Africans to Fe overload
+ drinking home made Fe laden beer =
o Neonatal Hemochromatosis = alloimmune dz where mom’s IgG sensitized to fetal hepatocyte cell surface antigen.
Cirrhosis in all cases, fetal loss in late 2nd-early 3rd trimester, siderosis of extrahepatic tissues (acinar epi
of pancreas, myocardium epi of thyroid follicles, minor salivary glands of mouth/resp tree).
Live babies get liver failure hours after birth, oligohydraminos, and intrauterine growth \/s
WILSON DISEASE – rare AR disorder of copper metabolism
Epidemiology = 1 in 90 are carriers, 1 in 30,000 affected. Age 10-13 yo (liver dz) and age 19-20 yo (psychosis)
Genetics = Ch 13q defect in ATP7B gene (Cu transporting ATPase gene). Most common = H1069Q in European pts (Glu for His)
Pathogenesis
Copper homeostasis = normal [Cu] is 50-100mg, average in take 1-2mg.
o Cu absorbed to blood enter liver Ctr1 transporter mediates uptake delivered to SOD by chaperones (Ccs2,
ATOX1, Cox17). ATP7B transports Cu from cytosol to Golgi secreted in bile/blood (ceruloplasmin or w/ enz).
Alteration of copper metabolism seen in Wilsons
o Cu can’t get from cytosol to Golgi stay in liver free radical damage liver [Cu] rises Cu released as free
copper (no ceruloplasmin) deposits in all tissues more free radical damage
Morphology
Hepatic lesions – moderate fatty infiltration (earliest) lipids inc in size/# chronic inflam
o Mononuclear cell infiltrate (lympho+plasma), piecemeal necrosis, parenchymal collapse, bridging hepatic
necrosis/fibrosis. Final stage = liver cirrhosis (macronodular cirrhosis w/ fibrous septa, bile duct proliferation,
variable septal lymphocytic infiltration)
Outline – Hereditary Hemochromatosis/Wilsons
o Stains for Cu = rhodamine, rubeanic stain for copper or Orcein stain for Cu-associated protein. In early dz, can’t
see it with rhodamine staining (Cu mainly cytoplasmic)
Hepatic [Cu] – standard for Dx of Wilson. Liver > 250mg/gram dry wt even in pts w/ no Sx.
EM studies – electron dense lysosomes, residual bodies in cells have Cu specific signals.
Neuro lesions – toxic injury, degeneration, atrophy of basal ganglia (caudate, putamen, GP, thalamus). Affected areas
DON’T have more Cu than unaffected parts, only more ROS injury.
Kayser-Fleischer rings – brownish-yellow or golden or reddish green rings around corneal limbu made of Cu deposits in
Descemet membrane = diagnostic!
Laboratory = ceruloplasmin level 100mg/day (N=<40mg/day)
Imaging
CT – BL cranial lesions are either slit like well defined low attenuating foci of BG (esp putamen) or large low attenuation of
BG, thalamus, or dentate. Frontal horns of lateral ventricles widen, diffuse brain atrophy neuronal loss.
MRI – sensitive; T1 weighted images show generalized brain atrophy w/ hypointensities in BG
Principels of Tx = pharmacological (chelating agents like penicillamine, trientine, and/or zinc)