A routine check-up 
reveals a significant 
genetic abnormality

A routine check-up 
reveals a significant 
genetic abnormality
A routine check-up 
reveals a significant 
genetic abnormality

As a part of his employer's incentive pay program, Mr. B came in for a routine physical. He was a seemingly healthy 37-year-old white man with no medical complaints to report.

Mr. B worked as a correctional officer and, as such, was encouraged to keep his health records current. His annual exam was supposed to be pro forma, but it revealed silent traits that even he was astonished to find.


1. History


Mr. B appeared in robust health and had an unremarkable medic­al history. His family history was positive for diabetes (a paternal grandfather), and hypertension (his father). Mr. B had stable, though stressful, employment, with no evident signs of depression.

Married with two children, Mr. B mentioned that he exercised regularly — often daily. He engaged in both aerobic activity and weight training and reported no nicotine habits and minimal alcohol intake (three beers per week). Mr. B also noted that approximately once a month he used ibuprofen for muscle aches. 


His immunizations, including hepatitis B vaccine series, were up to date. His tuberculin skin test, done within the past year, was negative. Except for occasional mild muscle aches or pains, which he associated with his physical activity, Mr. B showed no symptoms of disease. 


2. Examination and Laboratory Tests


Mr. B's vital signs on physical examination were good: BP 134/80 mm Hg; pulse rate 98 beats per minute; temperature 98.4° F; and oxygen saturation 98%. Mr. B was 5 ft 8 in tall and weighed 
162 lbs, with a BMI of 24.63. His complete physical was essentially normal.


Mr. B had not had laboratory work done in more than three years. At this visit, routine lab work was ordered, including a fasting lipid panel, fasting blood sugar, alanine transaminase (ALT) test, creatinine and a complete blood count. All results were within normal range except for a mildly elevated ALT at 
45 U/L (normal <36 U/L). 


Additional tests were done to further evaluate the elevated ALT. Hepatitis screening for A, B and C, and antinuclear antibody (ANA) test results were negative. Ceruloplasmin, albumin, alkaline phosphatase, aspartate aminotransferase (AST), alpha-1 antitrypsin and hemoglobin electrophoresis tests were all within normal range. 


Iron study results, however, were abnormal, with results as follows: 205 iron mg/dL (normal range: 41-96 mg/dL), total iron-binding capacity (TIBC) 295 mg/dL (baseline range: 236-
404 mg/dL), transferrin saturation 69% (normal:15%-60%) and ferritin 363 ng/mL (normal is 22-322 ng/mL). (Table 1 lists tests and disorders associated with elevated ALT.) 


3. Diagnosis and Discussion


Mr. B acknowledged that his father did indeed have "an iron disease," which he forgot to mention. DNA testing was done and Mr. B was found to have a C282Y/H63D compound heterozygous mutation, indicative of hemochromatosis. Mr. B was referred to a hematologist, who confirmed the diagnosis of hereditary hemochromatosis (HH).


Hereditary hemochromatosis is a recessively inherited disorder of iron metabolism, leading to abnormal increase in body iron stores. It is considered the most common genetic disorder in populations of Northern European ancestry1,2 with a genetic incidence in white populations in the United States of approximately 0.4% for homozygotes and 9.6% for heterozygotes.1

Approximately 10% of patients with clinical manifestations of HH are heterozygous, carrying a single copy each of the C282Y and H63D mutations, and 70%-100% of patients with a clinical diagnosis of HH are homozygous for the C282Y mutation.1 However, not all patients with genetic markers for HH develop iron overload. In fact, recent studies have shown rates of development of clinical iron overload even in those homozygous for the C282Y mutation as low as 50%.1,3 The genetic and environmental factors for the differences are not well defined, but they may be linked to modifying genes.1,4,5

Most dietary iron absorption and regulation occurs in the duodenum. In patients with HH, duodenal absorption is increased, which leads to iron overload, especially in the liver, heart and endocrine tissues. Humans have no mechanism for the excretion of excess absorbed iron, and chronic accumulation progresses to end organ dysfunction and damage. 


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