Hemochromatosis Clinical Presentation
- Author: Andrea Duchini, MD; Chief Editor: Julian Katz, MD more...
History and Physical Examination
Patients with hereditary hemochromatosis may be asymptomatic or may present with general and organ-related signs and symptoms.
Symptoms from hemochromatosis usually begin between age 30 years and age 50 years, but they may occur much earlier in life. Most patients are asymptomatic (75%) and are diagnosed when elevated serum iron levels are noted on a routine chemistry screening panel or when screening is performed because a relative is diagnosed with hemochromatosis.
Early symptoms include severe fatigue (74%), impotence (45%), and arthralgia (44%); fatigue and arthralgia are the most common symptoms prompting a visit to a physician. The most common signs at the time of presentation are hepatomegaly (13%), skin pigmentation, and arthritis.
Clinical manifestations include the following:
Liver disease (hepatomegaly, 13%; cirrhosis, 13%, usually late in the disease)
Skin bronzing or hyperpigmentation (70%)
Diabetes mellitus (48%)
Amenorrhea, impotence, hypogonadism
Liver function abnormalities occur in 35-75% of patients. Among organ-related symptoms, hepatomegaly is seen in more than 95% of patients and can be accompanied by signs of chronic liver disease, such as abdominal pain and cutaneous stigmata of liver disease (palmar erythema, spider angioma, or jaundice), and liver failure (ascites or encephalopathy). Right upper quadrant tenderness with hepatomegaly or splenomegaly may be present.
Cirrhosis is due to progressive iron deposition in the liver parenchyma, and it is one of the most common disease manifestations of the tissue damage caused by hemochromatosis. Cirrhosis may be complicated by liver cancer years later (risk > 200-fold). This condition is also the most common cause of death in patients with hereditary hemochromatosis.
Cirrhosis reversibility after iron removal has been reported, usually early in the course of liver disease, although reversal of advanced liver disease with varices has also been reported.
Some studies show that HFE mutations in patients with hepatitis C infection are associated with higher frequencies of fibrosis and cirrhosis.[59, 60] Increased fibrosis was also found in patients with nonalcoholic steatohepatitis (NASH) who had the C282Y mutation.[61, 62]
Skin bronzing or hyperpigmentation
A combination of iron deposition and melanin causes the skin bronzing or hyperpigmentation that is typical of the disease. The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation occurs late in the disease, when total iron body content is 20 g (ie, > 5-times normal).
Diabetes, often requiring insulin therapy, occurs due to progressive iron accumulation in the pancreas. The damage appears to be relatively selective for the pancreatic beta cells. Most patients with hemochromatotic diabetes have other signs of hemochromatosis, such as liver disease or skin pigmentation.
Diabetes mellitus can be seen in 30-60% of patients with hereditary hemochromatosis; therefore, polyuria, polydipsia, and high blood and urine glucose levels may be found. In one study, the prevalence of diabetes mellitus was 21.9% in patients with hereditary hemochromatosis. The type of mutations for hereditary hemochromatosis, ferritin level, or the presence of cirrhosis were not predictive for diabetes mellitus development. In the majority patients, the insulin requirements or glucose level was not influenced by iron depletion.
Arthropathy is due to iron accumulation in joint tissues. It is associated with characteristic radiologic findings, that is, squared-off bone ends and hooklike osteophytes in the metacarpophalangeal (MCP) joints, particularly in the second and third MCP joints. Symptoms usually do not respond to iron removal.
Chondrocalcinosis, which involves the knees and the wrists, may occur and may be asymptomatic.
The most commonly affected joints include the following:
Proximal interphalangeal joints
Amenorrhea, impotence, hypogonadism
Amenorrhea, loss of libido, impotence, and symptoms of hypothyroidism can be seen in patients with hereditary hemochromatosis. Although amenorrhea can occur in women, it is less frequent than hypogonadism in men.
Hypogonadism is the most common endocrine abnormality causing decreased libido and impotence in men. It usually is due to pituitary iron deposition. Primary hypogonadism, presumably due to testicular iron deposition, also can occur but is much less common.
Cardiac enlargement, with or without heart failure or conduction defects, is another mode of presentation, particularly in younger patients. Hereditary hemochromatosis C282Y/C282Y, C282Y/H63D, and C282Y/wild-type genotypes have not been associated with ischemic heart disease or myocardial infarction.
Dilated cardiomyopathy is characterized by the development of heart failure and conduction disturbances, such as sick sinus syndrome. In the past, cardiac disease was the presenting manifestation in as many as 15% of patients; therefore, the absence of other manifestations of hemochromatosis should not preclude the diagnosis. Signs of fluid overload are seen with congestive heart failure.
Osteopenia and osteoporosis as well as hair loss and koilonychia (spoon nails) may occur in patients with hemochromatosis.
Of patients with hereditary hemochromatosis, 25% have osteoporosis, while 41% are diagnosed with osteopenia. The osteoporosis is independent of genetic background and is associated with hypogonadism, increase in alkaline phosphatase, increase in body weight, and the severity of iron overload.
Partial loss of body hair is evident in 62% of patients. The pubic area is affected most commonly, although total loss of body hair is seen in about 12% of patients. Hair loss and thinning may be reversed by therapy in some patients.
Koilonychia, usually of the thumb and index and middle fingers, is seen in almost half of patients. Overall, one fourth of patients with hemochromatosis have prominent spoon nails.
As the most common autosomal recessive disorder in populations of northern European descent, hereditary hemochromatosis may be an almost ideal disease for which to perform population screening. The advent of genetic testing for hereditary hemochromatosis focuses concern on informed consent and the ethical, legal, and social implications of screening, particularly in relation to medical and general discrimination.
The American Association for the Study of Liver Diseases (AASLD) guidelines recommend screening of high-risk groups such as those with suggestive organ involvement, a familial history of hereditary hemochromatosis, and those with biochemical or radiologic abnormalities suggestive of the possibility of iron overload, as detailed below.
CDC-suggested screening guidelines
The Centers for Disease Control and Prevention (CDC) does not recommend universal screening for hemochromatosis but rather suggests evaluating iron overload in individuals with a family history and in individuals who are symptomatic.
Overall, the clinical expressivity of C282Y homozygosity appears to be much lower than previously thought, and the cost effectiveness of screening has been challenged, because many people must be screened in order to prevent severe disease in only a few. During a screening program conducted in a health appraisal clinic, classic multiorgan disease was detected in only 1 of 152 homozygotes.[67, 68, 69]
Screening for hemochromatosis should be considered in the following individuals :
All first-degree relatives of subjects known to have hemochromatosis: Human leukocyte antigen (HLA) typing is no longer necessary; family members identified as having C282Y homozygosity should be tested for transferrin saturation, serum ferritin, and liver enzymes; screening of young children of patients with hemochromatosis does not need to be performed if the spouse is tested and does not have the C282Y mutation
Individuals presenting for a standard medical check: Transferrin saturation should be measured; if levels are higher than 45%, the estimation should be repeated after fasting—if the fasting level still is higher than 45%, further investigation is warranted 
The general population: This group possibly should be screened, although screening is more difficult and debatable in these individuals,  and cost is a major consideration; a consensus stated that population screening is best performed by phenotype (using iron-binding capacity), but using genotype screening (using C282Y mutation) is considered premature until all unanswered questions are clarified
If a proband is negative for C282Y mutation, family members must be screened by other means, such as serum iron studies or HLA typing; HLA typing or tissue typing has been used to detect homozygous hemochromatosis in a sibling of a proband who has hemochromatosis by other means, such as liver biopsy or quantitative phlebotomy—in this setting, a sibling who is HLA-A identical and HLA-B identical to the proband is considered homozygous; if only 1 haplotype is shared with the proband, the sibling is considered heterozygous
AMA-suggested screening guidelines
As a result of the high frequency of hereditary hemochromatosis–associated mutations, the American Medical Association recommended the establishment of guidelines for population screening, as follows:
Screening tests for the general population comprise measurement of serum transferrin saturation or serum iron concentration; when transferrin saturation is greater than 60% or greater than 50% in women who are premenopausal, or when serum iron concentration is greater than 150 mcg/dL, other measurements are recommended
Screening and diagnosis cannot be based on single-measurement transferrin saturation or serum iron concentrations, because they can be falsely increased as the result of diet, alcohol consumption, or other liver diseases
Adams and coworkers suggested the introduction of the unbound iron-binding capacity measurement to preselect patients for genotyping 
Detection of homozygosity for the C282Y mutation or compound heterozygosity for the C282Y/H63D mutations is believed to be diagnostic; however, negative results on DNA tests do not exclude hereditary hemochromatosis, which can also be the result of other mutations 
Liver biopsy is not required for the diagnosis of hereditary hemochromatosis; however, liver biopsy may be useful in C282Y homozygotes with suspected liver disease, in C282Y homozygotes or heterozygotes with serum ferritin levels greater than 1000 mcg/L, in patients without C282Y mutations with unexplained iron overload, and in patients with additional risk factors for liver disease 
Relatives of patients with hereditary hemochromatosis should undergo DNA testing to detect subclinical cases of hereditary hemochromatosis so that early treatment for the disease can be begun 
AASLD-suggested screening guidelines
Measurement of transferrin saturation after an overnight fast should be considered the initial screening of individuals with suspected iron overload and first-degree relatives of patients with hereditary hemochromatosis older than 20 years. Measurement of serum ferritin at the same time increases the predictive accuracy for diagnosis of iron overload.
HFE gene mutation analysis should be performed for all individuals with abnormal iron study results and on those who are first-degree relatives of identified homozygotes. Patients younger than 40 years may be treated by therapeutic phlebotomy without the need for liver biopsy.
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