Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (984 page)

   HFE gene sequence analysis: analysis of the entire coding region—testing to identify rare mutant alleles

   Limitations

   The results of a genetic test may be affected by DNA rearrangements, blood transfusion, bone marrow transplantation, or rare sequence variations.

HIGH MOLECULAR WEIGHT KININOGEN AND PREKALLIKREIN (FLETCHER FACTOR)
*

   Definition

   These clotting proteins activate the early phase of the intrinsic pathway and the complement system. When decreased, they may prolong PTT but not PT. They do not depend on vitamin K carboxylation.

   
Normal ranges:

   High molecular weight kininogen: 59–135%

   Prekallikrein: 55–207%

   Interpretation

Decreased In

   Extremely rare congenital deficiencies

   No bleeding diathesis associated with deficiencies; reflected in prolonged PTT

HOMOCYSTEINE (Hcy)
^†

   Definition

   Total Hcy is a thiol-containing amino acid, produced by the intracellular demethylation of methionine to cysteine. Elevated tHcy has primary atherogenic and prothrombotic properties. Elevations in plasma homocysteine may be the result of genetic defects; nutritional deficiencies of vitamin B
₆
(pyridoxine), vitamin B
₁₂
, and folic acid; some chronic medical conditions such as chronic renal insufficiency; and certain drugs. The most common form of genetic hyperhomocysteinemia results from the production of a thermolabile variant of methylene tetrahydrofolate reductase (MTHFR). Homozygosity for this form of MTHFR is a relatively common cause of elevated total Hcy (tHcy) in the general population (5–14%). Highly elevated levels of tHcy are found in patients with homocystinuria (hyperhomocysteinemia), a rare genetic disorder of enzymes involved in homocysteine metabolism. These patients exhibit arterial and venous thromboembolism, severe early arteriosclerosis, mental retardation, osteoporosis, and ocular abnormalities. Moderately elevated levels of tHcy are associated with less severe genetic defects. Moderate hyperhomocysteinemia is an independent risk factor for venous and arterial thromboembolism but less profound than other well-established risk factors. Because of that, population screening for total Hcy level is not recommended.