General Considerations

Wilson disease is a hereditary condition in which defective cellular copper transport leads to excessive deposition of copper in several organs—most commonly the liver, brain, and cornea.

-It is an autosomal recessive disorder caused by mutations in the ATP7B gene on chromosome 13.  

-It usually presents in childhood or young adult life with mean age of onset is between 12 and 23 years of age

Symptoms & Signs

-Wilson disease tends to present as liver disease in adolescents and neuropsychiatric disease in young adults

Hepatic features: acute or chronic liver failure, jaundice, hepatomegaly, cirrhosis, portal hypertension

Neurologic features: basal ganglia dysfunction, tremor, ataxia, incoordination, spasticity, ataxia, migraines, seizures, dysarthria, dysphagia

Psychiatric features: behavioral, personality changes, depression

Miscellaneous: Sunflower cataracts, KF rings, splenomegaly may cause hemolytic anemia and thrombocytopenia.

Kayser-Fleischer ring: Pathognomonic sign of Wilson’s disease; Brownish or gray-green pigmented granular deposits in Descemet membrane in the cornea

Diagnsois

-Decreased serum copper concentration despite the presence of copper overload

-Elevated hepatic copper concentration

-Low serum ceruloplasmin (the plasma copper-carrying protein) level

-Elevated urinary copper excretion

-Testing for mutations in ATP7B can be done and is recommended for a definitive diagnosis.

-Liver biopsy with quantitative copper assays: gold standard for diagnosis

-MRI Brain:  “face of the giant panda” sign in the midbrain and a “face of the miniature panda” in the pontine tegmentum.

Treatment

-Treatment of choice: Copper chelation with D-penicillamine or trientine hydrochloride

Drug of choice: Oral Penicillamine; always add pyridoxine to penicillamine

-Oral zinc acetate (interferes with intestinal absorption of copper)

-Administration of trientine and zinc should be separated by at least 1 hr because trientine chalates zic and forms ineffective complexes

-Tetrathiomolybdate for neurologic therapy

-Patients with Wilson disease require lifelong therapy.

-Liver transplantation for advanced liver disease

Prognosis

-The prognosis of untreated Wilson disease is poor, but it is good if effective treatment occurs before liver or brain damage

1. What is the most common presentation of Wilson disease? Chronic liver disease
2. What is the most common ocular finding of Wilson disease? Kayser–Fleischer rings

General Considerations

Hemochromatosis refers to a group of genetic diseases that predispose to iron overload, potentially leading to fibrosis and organ failure

-Increased accumulation of iron as hemosiderin in the liver, pancreas, heart, testes,adreanls, pituitary, and kidneys

-Major clinical manifestations: Cirrhosis of the liver, diabetes mellitus, arthritis, cardiomyopathy, and hypogonadotropic hypogonadism

-The quantity of total iron is 3 g in women and 5 g in men. Most iron resides in red blood cells.

-Almost all iron absorption occurs in the duodenum.

-Hepcidin normally functions as a regulatory protein which controls iron absorption

-In hemochromatosis, mucosal absorption is greater than body requirements and amounts to ≥4 mg/d.

-Most common autosomal recessive disease in Caucasians

–HFE gene mutation (usually C282Y/C282Y) is found in most cases

-C282Y is the major mutation and H63D the minor mutation of the HFE gene

-The onset is usually after age 50

-The disease is more common in men than in women

Symptoms & Signs

-Most patients are aymptomatic

-Lethargy, arthralgia, skin pigmentation, loss of libido, loss of body hair, jaundice, hepatomegaly, cirrhosis, diabetes mellitus, increased pigmentation, spider angiomas, splenomegaly, arthropathy, ascites, cardiac arrhythmias, congestive heart failure, testicular atrophy

Diagnosis

-Measure serum iron, tranferrin saturation, ferritin concentration, liver biopsy, MRI liver

-Hepatic iron index generally > 1.9

-An elevated plasma iron with > 45% transferrin saturation

-An elevated serum ferritin

-A TSAT ≥45 percent and/or a serum ferritin >200 ng/mL (>200 mcg/L) in men or >150 ng/mL (>150 mcg/L) in women is consistent with iron overload

-Test for HFE mutations when serum iron/total iron-binding capacity and/or serum ferritin are elevated

-Genetic testing is not recommended for the general population.

 

Treatment

-therapy involves removal of the excess body iron and supportive treatment of damaged organs

Iron removal: therapeutic Phlebotomy (mainstay of treatment), Chelating agents (Deferoxamine, Dererasirox)

-counsel and screen other family members

-Stop alcohol consumption

-Liver transplantation for advanced cirrhosis

Prognosis

-Survival appears normal in those with a serum ferritin <2000 ng/mL at the time of diagnosis.

-The principal cause of death are cardiac failure, portal hypertension, liver cancer

 

Q.What is the most common autosomal-recessive disorder in Caucasians? HFE-related hemochromatosis

1. What is the single best screening test for hereditary hemochromatosis? Transferrin saturation
2. What is the key regulatory hormone that controls iron metabolism? Hepcidin
3. What is the first organ to be affected by hemochromatosis? Liver
4. What is the most common cardiac manifestation of hemochromatosis? Congestive heart failure
5. What are the most common endocrine manifestaions of hemochromatosis? Diabetes mellitus and hypogonadism
6. What is the classic presentation of arthropathy in hemochromatosis? the second and third metacarpophalangeal and proximal interphalangeal joints of the hands