CLINICAL FEATURES

• Symptoms usually begin between age 30 years and age 50 years, but they may occur much earlier.
• On average females present 10 years later than males [198].
• The classic triad of skin bronzing, cirrhosis, and diabetes is found in only a small percentage of patients at the time of diagnosis [198].
• Early symptoms include the following:
o Severe fatigue (74%)
o Impotence (45%)
o Arthralgia (44%)
• Later, patients may experience the following symptoms:
o Skin bronzing or hyperpigmentation (70%): This reflects a combination of iron deposition and melanin. The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation occurs late in the disease, when total iron body content is 20 grams (ie, >5-times normal).
o Diabetes mellitus (48%): This is due to progressive iron accumulation in the pancreas. The defect 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.
o Hepatic involvement manifested by elevated liver enzymes occurs in up to 65% of affected patients at the time of diagnosis [199]
o The expression and severity of hepatic disease is dependent on concurrent toxins, such as alcohol, viruses, and medications. Hepatic fibrosis eventually leads to cirrhosis in many untreated patients [200]
o The hepatic fibrosis resulting from hereditary hemochromatosis is a causative factor in approximately 3% of cases of hepatic cirrhosis [201, 202] and 10% to 30% of cases of hepatocellular carcinoma (risk >200-fold). It also is the most common cause of death in patients with hereditary hemochromatosis.
• Other symptoms may include the following:
o Fatigue and arthralgia are the most common symptoms prompting a visit to a physician.
o Most patients are asymptomatic (75%) and are diagnosed when elevated serum iron levels are noted on a routine a chemistry screening panel or when screening is performed because a relative is diagnosed with hemochromatosis.
• Cardiac involvement occurs in 5% to 50% of the cases. Diastolic dysfunction, dilated cardiomyopathy, ST-T segment changes, atrial and ventricular arrhythmias, and conduction abnormalities can occur [199]

o Hypogonadism is the most common endocrine abnormality causing decreased libido and impotence in men. It usually is due to pituitary involvement by iron deposition. Primary hypogonadism, presumably due to testicular iron deposition, also can occur but is much less common.
o Amenorrhea can occur in women but is less frequent than hypogonadism in men.
o Arthropathy is due to iron accumulation in joint tissues. It is associated with characteristic radiologic findings, ie, 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.
o Thyroid gland involvement is manifest by thyroid tissue inflammation and fibrosis, with initial hyperthyroid function followed by low thyroid output [199]

• Patients may have susceptibility to certain bacterial infections such as Yersinia enterocolitica liver abscess, Yersinia pseudotuberculosis sepsis, Vibrio vulnificus sepsis, and Listeria monocytogenes meningitis
Physical:
• The most common signs at the time of presentation are hepatomegaly (13%), skin pigmentation, and arthritis.
• Liver function abnormalities occur in 35-75% of patients.
• Cirrhosis occurs in 13%, usually late in the disease.
• Other findings upon examination include the following:
o Right upper quadrant tenderness with hepatomegaly or splenomegaly if cirrhosis present
o Signs of fluid overload with congestive heart failure
o Sick sinus syndrome with conduction abnormalities
• The most commonly affected joints include the following:
o MCP joints
o Proximal interphalangeal joints
o Knees
o Feet
o Wrists
o Back
o Neck
• Chondrocalcinosis, which involves the knees and wrists, may occur and may be asymptomatic.
DIFFRENTIAL DIAGNOSIS
• Hemolytic Anemia
Thalassemia, Beta
• Biliary cirrhosis
• Alcoholic liver disease
• Ineffective erythropoiesis with marrow hyperplasiaExamples include the hereditary sideroblastic anemias, severe alpha and beta thalassemia, and the myelodysplastic syndrome variants such as refractory anemia with ringed sideroblasts (RARS).
• Iron overload associated with chronic anemia
• Multiple transfusions
• Porphyria cutanea tarda (PCT)

INVESTIGATIONS

• Considering how commonly the above signs and symptoms occur in typical primary care practice, a low-cost method to evaluate for hereditary hemochromatosis is essential.
• Screening for hemochromatosis has resulted in earlier diagnosis. In some studies 75% of new cases are diagnosed during the clinically asymptomatic stage of the disease
WHO SHOULD BE EVALUATED [203]
Symptomatic patients
• Unexplained manifestations of liver disease or a presumably known cause of liver disease with abnormality of one or more indirect serum iron markers
• Type 2 diabetes mellitus, particularly with hepatomegaly, elevated liver enzymes, atypical cardiac disease or early-onset sexual dysfunction
• Early-onset atypical arthropathy, cardiac disease, and male sexual dysfunction
Asymptomatic patients
• Priority groups
• First-degree relatives of a confirmed case of hemochromatosis
• Individuals with abnormal serum iron markers discovered during routine testing
• Individuals with unexplained elevation of liver enzymes or the serendipitous finding of asymptomatic hepatomegaly or radiologic detection of enhanced computed tomography attenuation of the liver
• General population
LAB EVALUATION
• When clinical findings warrant evaluation, the best phenotypic screening tool is the serum transferrin saturation [200, 205].
• Elevated transferrin saturation is usually the earliest phenotypic expression of the disease [200]; its sensitivity for iron overload is 94% to 98%, with a specificity of 70% to 98% [200]. In the white population, the sensitivity and specificity yield a positive predictive value of approximately 20%, and a negative predictive value of 99.9%.
• Transferrin saturation is a calculated value (serum iron divided by total iron-binding capacity) that can be affected by other factors.
• If a screening transferrin saturation is high, the test should be obtained after an overnight fast, as serum iron levels can vary considerably after an oral dose [205]
• The iron-binding capacity is affected by acute and chronic disease states, oral contraceptives, and acute hepatitis [204]
• Normal transferrin saturation is less than 45%, and elevations above this level warrant further evaluation.
• In men and postmenopausal women, transferrin saturations of 45% to 54% should be monitored at 1- to 2-year intervals [200]
• If the transferrin saturation exceeds 45% in premenopausal women or 55% in men and postmenopausal women, the workup should proceed with determination of serum ferritin and hepatic enzyme levels.
• Serum ferritin concentration is linearly related to total body iron stores [200]
• Serum ferritin levels are normally less than 300 µmg/L in men and postmenopausal women, and less than 200 µmg/L in premenopausal women.[1]
• In patients with an elevated transferrin saturation but normal serum ferritin levels and normal liver enzyme levels, it is prudent to monitor these values yearly [200]
• An elevated serum ferritin level defines the point at which treatment should be initiated in patients with a confirmed diagnosis [200]. Serum ferritin is an acute phase reactant and can be elevated in the absence of iron overload. Elevated levels of the serum ferritin generally occur later in the course of iron overload than elevated transferrin saturation. For these reasons, serum ferritin is less useful as an initial screening test for hereditary hemochromatosis.
• Hepatic enzymes are useful to gauge the likelihood of hepatic iron toxicity, but they are not useful as a screening tool. Studies have shown, however, that up to 3.4% of patients with elevated hepatic enzymes might have hereditary hemochromatosis.
• Also, because concurrent hepatic toxins accelerate the hepatic toxicity of iron overload, it is recommended to screen for iron overload in patients with evidence of liver disease.
• Elevated serum ferritin or elevated hepatic enzyme levels in patients with elevated fasting transferrin saturation indicate the need for further evaluation with HFE gene testing or liver biopsy.
• The test is performed on a whole blood specimen. A much less costly method for identifying both mutations has recently been described. This lower cost test might eventually affect the role of genetic testing in both suspected persons and for general population screening.
• Currently, the appropriate use of HFE gene testing is being debated and refined [200] HFE gene testing will not distinguish the 10% to 40% (depending on the population) of whites with non-HFE iron overload, nor will it determine the cause of iron overload in most African-Americans or Asians. Thus, the HFE gene test is not recommended as a screening test for iron overload.
• At present, one well-defined use of HFE gene testing is to diagnose hereditary hemochromatosis in relatives of patients who have a confirmed diagnosis. First-degree relatives should be screened with HFE gene testing to determine risk and need for further evaluation and treatment.
• In the pre-HFE testing era, liver biopsy was considered the reference standard for diagnosis of hereditary hemochromatosis, but this concept has recently been challenged.
• Liver biopsy has a low complication rate in properly selected patients. Mortality ranges from 0.01% to 0.1%, and the risk of hemorrhage is 0.3%.
• Periportal iron deposition is usually seen in hereditary hemochromatosis as opposed to other patterns of iron deposition in other disease states [200]
• Liver biopsy establishes the presence and severity of iron overload as well as the presence or absence of hepatic fibrosis, which has important implications for future evaluation. Some authorities state that liver biopsy is not necessary in selected patients aged 30 to 40 years or younger with homozygous C282Y defect and no laboratory or physical evidence of liver disease. A serum ferritin level of less than 1,000 µmg/L has also been shown to predict the absence of liver fibrosis and is included in the decision process by some authorities.
• Because liver disease itself can cause elevated serum transferrin saturation and ferritin levels, biopsy combined with HFE gene testing is often necessary in patients with evidence of iron overload and suspected coexistent liver disease (such as viral hepatitis or ethanol-induced disease) to establish a definitive diagnosis. In these cases HFE gene testing can confirm hereditary hemochromatosis as the cause of the iron overload and can help in the risk stratification of family members.
• For patients who cannot or will not receive liver biopsy, HFE gene testing should definitely be performed. In these patients, serum markers of iron overload, in combination with homozygous C282Y mutation, are sufficient for the diagnosis and to initiate treatment. For patients 30 to 40 years or younger with no evidence of liver involvement and serum ferritin levels of less than 1,000 µmg/L, a similar strategy is recommended.
• For patients showing evidence of iron overload with heterozygous C282Y results, isolated H63D homozygous mutations, or concurrent liver disease, liver biopsy and consultation with an expert can be helpful in defining the cause of the problem.

TREATMENT

NON PHARMACOLOGICAL TREATMENT
• Patients should maintain a diet with only moderate amounts of high-iron-content foods [206]
• Iron supplementation in any form should be strictly avoided.
• There is no reason to discourage vitamin C intake, with the exception of limiting those patients who choose to take supplements to 500 mg/d [206, 207]
• Ethanol should be avoided completely in patients with liver disease [208]
• Patients should be advised to avoid uncooked seafood, because they have a unique susceptibility to Vibrio vulnificus infection.
• Similarly, these patients are at increased risk of infection with this organism if they expose open wounds to warm coastal seawater. Therapeutic phlebotomy treatment does not reduce susceptibility to V vulnificus infection