Currently, which one of the following is the best screening test for hereditary hemochromatosis?
Correct Answer B:
The best screening test for hereditary hemochromatosis is serum transferrin saturation, which is the calculated ratio of serum iron to total serum iron-binding capacity. An elevated serum transferring saturation is usually the earliest phenotypic expression of the disease, with a sensitivity for iron overload of 94%-98%, and a specificity of 70%-98%. In the Caucasian population these values translate into a positive predictive value of approximately 20% and a negative predictive value of 99.9%. Elevated serum ferritin generally occurs later in the course of iron overload than does elevated transferrin saturation and liver enzymes become elevated only after liver toxicity has occurred. HFE gene testing is now available, but its higher cost currently precludes using it as a screening tool, and not all cases of hereditary hemochromatosis result from the same mutation.
A 42-year-old male presents with complaints of painful wrist joints and knee joints. He says that he began to feel discomfort 2 months ago but it has gotten progressively worse in the past week. He also says that he noticed he looks like someone who has been “sun tanning” although he is an office worker and spends most of the time indoors. His past medical history is only significant for glucose intolerance found 1 year ago that he has been managing with lifestyle modifications; however as he puts it "the joint pains are making it hard for him to exercise." Family history reveals a father who died of heart disease at the age of 57 and had a long history of diabetes. The patient has a 65-year-old mother who is healthy.
Physical examination reveals hyperpigmentation of skin and pain on palpation of the proximal interphalangeal joints, wrist joints and knee joints. Imaging studies and laboratory studies are ordered.
Which of the following is the most important step in management of this patient?
Correct Answer D:
Based on the patient’s history of glucose intolerance, hyperpigmentation of skin, arthropathy, and family history of heart disease, hereditary hemochromatosis which is known to cause “bronze diabetes” should be considered as the likely diagnosis. Hemochromatosis is an autosomal recessive genetic disorder characterized by iron overload and accumulation in parenchymal organs. While as many as 75% of patients are asymptomatic, those with symptoms often present with skin bronzing, diabetes mellitus, cardiomyopathy, liver disease, and infertility. Transferrin saturation which is the ratio of serum iron and total iron-binding capacity suggests the diagnosis. It may be confirmed by liver biopsy and genotypic investigation for HFE mutations on chromosome 6. Management of this condition consists of removal of accumulated iron via phlebotomy (choice D) or, rarely, iron chelation and reducing iron absorption by dietary limitations. Phlebotomy continues for life based on ferritin levels.
→ Ibuprofen (choice A) is a NSAID that may be used to treat osteoarthritis and other arthropathies. It is important to acknowledge that arthropathy in this patient is due to iron overload and management should focus on the cause.
→ ACTH inhibitors such as pasireotide (choice B) are approved for treating Cushing’s syndrome. While Cushing syndrome increases the risks of insulin resistance and developing diabetes and is associated with hyperpigmentation, this patient’s family history and arthropathy suggest hereditary hemochromatosis.
→ Colchicine (choice C) may be used in hemochromatosis patients who have had recurrent acute episodes of joint involvement; however, this is not the initial treatment once hemochromatosis is confirmed. Phlebotomy should be done first to decrease iron stores.
→ Metyrapone (choice E) blocks 11-beta-hydroxylase activity, the final step in cortisol synthesis and is used in the treatment of Cushing’s syndrome, it is not appropriate as initial management of this patient.
Key point:
Hereditary hemochromatosis is characterized by iron overload and deposition of iron in different organs of the body. This may result in diabetes due to pancreatic islet cell failure, liver disease, dilated cardiomyopathy, and arthropathy. The initial treatment is phlebotomy.
A 40-year-old white male presents to your department with concerns of darkening of the skin recently. He denies pain anywhere in his body but reports of being unusually thirsty and urinating more often, including waking up a couple of times at night to urinate. His father died of cirrhosis at the age of 50 and his mother died of lung cancer. On physical examination you note skin hyperpigmentation and an enlarged liver.
Which of the following is the most likely diagnosis?
This patient is presenting with skin hyperpigmentation, polyuria, polydipsia, and hepatomegaly on physical examination. By combining this patient’s history of present illness and his family history of a father who died of liver cirrhosis, the most likely diagnosis is bronze diabetes from hemochromatosis (choice D). This is an autosomal recessive genetic disorder characterized by accumulation of iron in parenchymal organs. Other common symptoms are fatigue, impotence, arthralgia, and symptoms related to cardiomyopathy. Definitive diagnosis is made when laboratory studies of transferrin saturation, serum ferritin, and the HFE gene mutation for hemochromatosis are done. Skin and liver biopsy can also be done for diagnosis but currently, genetic testing is considered enough to reach the final diagnosis.
→ Cushing’s syndrome (choice A) is caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids. It may cause skin hyperpigmentation, diabetes, infertility, and impotence, which are also seen in hemochromatosis; however, it is not known to cause hepatomegaly and is not a hereditary disease.
→ Porphyria cutanea tarda (choice B) is a familial disorder characterized by uroporphyrinogen decarboxylase deficiency. Patients with this disease present with cutaneous fragility and blistering, sunlight exposure often plays a role in the appearance of skin lesions.
→ Primary biliary cirrhosis (choice C) is an autoimmune disease that leads to progressive cholestasis and often end-stage liver disease. While it may present with hyperpigmentation in 25% of patients or hepatomegaly in 25% of patients, the most common symptom is pruritus in 60% of patients due to hyperbilirubinemia. Sicca symptoms (dry mucosa) are also found in 50% to 75% of patients.
→ Wilson’s disease (choice E) is an autosomal recessive inherited disorder of copper metabolism that is characterized by excessive deposition of copper in the liver. Kayser-Fleischer rings are seen in at least 98% of symptomatic patients who have not received chelation therapy. Frequent early symptoms include difficulty speaking, excessive salivation, ataxia, mask-like facies, clumsiness with the hands, and personality changes.
Hemochromatosis is an autosomal recessive genetic disorder characterized by accumulation of iron in parenchymal organs. It may present with hyperpigmentation, arthralgia, impotence, and diabetes.
A 50-year-old-man develops hematuria. He is found to have a mass in the kidney which has an increased blood supply.
What is the most likely cause?
Renal cell carcinoma is the most common renal cancer. Symptoms appear late and include hematuria, flank pain, a palpable mass, and fever. Diagnosis is by CT or MRI and occasionally by biopsy. Treatment is with surgery. Infection, stones and drugs are all causes of hematuria, but are unlikely to show a mass with increased blood supply.
An elderly woman develops a stasis ulcer on her lower extremity that causes pigmentary changes. See picture:
The most appropriate intervention in the prevention and treatment of this condition is:
Correct Answer A:
Venous ulcers form when blood flow through the legs is reduced, causing blood to pool in the leg veins. Then, pressure increases in the veins and capillaries (tiny blood vessels that connect arteries and veins). The increased pressure causes fluid to leak from the blood vessels into surrounding tissue, and swelling develops.
If venous ulcers result from chronic venous insufficiency, the legs are swollen, and the skin is dark reddish brown and very firm (a condition called stasis dermatitis). The skin may itch, and the ulcers are usually very painful.
The goals of prevention and treatment are to reduce leg swelling and reduce the pressure in veins. If swelling is reduced enough, a venous ulcer may never form or may heal on its own. Often, specially designed bandages and pneumatic (compression) stockings help reduce swelling.
If cellulitis or signs of an infection of deeper tissues (such as pus) are present, antibiotics are taken by mouth or given intravenously. Drugs, such as nonprescription antibiotics, should not be applied directly to the skin of the leg. These drugs can cause allergic reactions that worsen the problem, particularly when the skin is cracked or there is an open sore.
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