Secondary Diabetes

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Diagnosis and reasoning

At first glance, this seems to be an open and shut case: this patient with type 2 diabetes has persistently poor glycemic control, and probably needs to be started on insulin therapy. However, his examination reveals an unexpected finding - generalized hyperpigmentation. Could this be due to an underlying pathology ? Might this be related to his diabetes ? The differential diagnosis of generalized hyperpigmentation and diabetes includes Cushing's syndrome; polyglandular autoimmune syndromes (where Addison's disease and diabetes may occur in conjunction); chronic kidney disease (CKD) in association with diabetes; and primary and secondary hemochromatosis. Cushing's syndrome is clinically less likely, as these patients are usually overweight, with upper body obesity, a rounded face, and relatively slender arms and legs. In addition purplish striae and hypertension are also frequently present. The normal serum electrolytes are against Addison's disease (as both hyponatremia and hyperkalemia are very common in these patients). In addition, the normal morning cortisol and 24 hour urinary cortisol provide further evidence against an endocrinopathy. Hyperpigmentation due to CKD occurs in severe to end-stage disease. Thus, the normal renal functions rule out this possibility. Hemochromatosis can be easily screened via iron studies. In this patient, the elevated serum iron and ferritin but normal total iron binding capacity are strongly suggestive of iron overload, hinting that this is the likely diagnosis. Note also the high transferrin saturation - in this clinical context, a saturation of over 60% is highly specific for hemochromatosis. Hemochromatosis may be primary (i.e. genetic) in origin, or secondary to another underlying etiology. Of these, two of the most common are hemolysis, and chronic liver disease (especially that due to hepatitis C infection). The normal full blood count and unremarkable blood picture make hemolysis unlikely. In addition, there are no clinical features suggestive of chronic liver disease. However, hepatitis C infection itself is an independent risk factor for iron overload, and an estimated 3% of baby boomers in the United States are believed to carry the disease. Thus screening for the disease is justifiable here (but turns out to be negative). In summary, this is almost certainly primary hemochromatosis - but genetic testing should be performed for definitive confirmation. The patient in this case was found to be homozygous for the HFE C282Y gene. Phlebotomy is key to the management of patients with hemochromatosis (regardless of etiology), and will control the iron overload. Unfortunately, the impact this will have on his glycemic control is hard to predict. It is probably wise to start him on insulin anyway, and adjust the dosage down the line as required. Ketoconazole is not indicated the management, while dexamethasone therapy is unnecessary and will very likely worsen his glycemic status. Discussion : Secondary Diabetes Diabetes mellitus (DM) secondary to another etiology is termed secondary diabetes. It is rare, accounting for < 2% of all cases diagnosed. While there are many causes of secondary DM, these can be broadly categorized into diseases of the pancreas; endocrinopathies; drugs; and genetic disorders. Diseases of the pancreas cause diabetes by destroying islet cell tissue. These include chronic pancreatitis, cystic fibrosis and hemochromatosis. In addition, surgical resection of the pancreas may result in iatrogenic diabetes. Endocrinopathies giving rise to diabetes include Cushing's syndrome, acromegaly, pheochromocytomas and glucagonomas. The hormones secreted in these conditions are counterregulatory to insulin, and may also promote inhibition of insulin secretion and insulin resistance. Drugs capable of inducing diabetes include glucocorticoids, alpha and beta blockers, thiazides and furosemide. Genetic disorders causing secondary diabetes include primary hemochromatosis, stiff-person syndrome, Wolfram syndrome and Rabson-Mendenhall syndrome.


The patient discussed in this case was diagnosed with primary hemochromatosis. This is an autosomal recessive genetic disorder in which there is excessive intestinal absorption of iron and abnormal deposition in parenchymal organs. In the United States, the incidence is 1 case per 200 to 500 individuals, with caucasians more frequently affected than other racial groups. The gene responsible is named HFE and is located on the short arm of chromosome 6. The most common genotype is homozygosity for HFE C282Y. In hemochromatosis, the main organs affected by the iron overload are the liver, heart, pancreas, pituitary, joints, and skin. Symptoms usually begin between 30 to 50 years of age, but many patients remain asymptomatic and are diagnosed incidentally when elevated serum iron levels are noted or when screening is performed. The most common initial symptoms are fatigue, impotence and arthralgia; hepatomegaly, hyperpigmentation and joint swelling are early signs. Other important clinical manifestations include diabetes mellitus, amenorrhea/hypogonadism and cardiomyopathy. Progressive iron deposition in the liver can lead to cirrhosis, hepatocellular carcinoma and liver failure. Note that cardiac involvement is completely reversible, but liver involvement is not. Diabetes in hemochromatosis is a result of several factors, including selective beta cell damage due to the uptake of iron, liver fibrosis leading to insulin resistance and underlying genetic tendencies to develop diabetes. The diagnosis depends on clinical features, laboratory tests showing deranged iron metabolism and positive genetic tests. Direct DNA testing for the two HFE gene mutations (C282Y and H63D) associated with hemochromatosis is available and helps in confirming the diagnosis and detecting asymptomatic patients. A liver biopsy is indicated in patients who are homozygotes with clinical evidence of liver disease, and a serum ferritin greater than 1,000 ug/L - especially if they are greater than 40 years of age, and have other risk factors for liver disease. In the management, the first step is to rid the body of excess iron by performing phlebotomy. In the induction phase, depending on how severe the iron overload is, a pint of blood is taken once or twice a week for several months to a year, or occasionally longer. Serum ferritin levels are tested after every four phlebotomies to monitor iron levels. The exact number of phlebotomies required to achieve a normal serum ferritin level depends on the degree of overload at diagnosis. Once iron levels return to normal, maintenance therapy (which involves removing a pint of blood every 1 to 4 months) should be continued for life, with the frequency guided by the ferritin level. Iron chelation therapy should be considered in patients who cannot undergo phlebotomies due to heart disease, anemia, or poor venous access. Other supportive measures include avoidance of iron rich foods in the diet (such as red meats and organ meats), avoidance of iron supplements, and refraining from alcohol (especially if liver disease is present). As many of the complications of primary hemochromatosis are irreversible, early detection and treatment is essential for a good outcome. Screening of close relatives should not be neglected.

Take home messages

  1. Secondary diabetes is rare - but unlike other forms of diabetes, offers the hope of cure if the underlying condition is reversible.
  2. The possibility of secondary diabetes should be considered in diabetic patients with pancreatic disease, endocrinopathies, or diabetogenic drug use.
  3. Iron studies are a useful screening test for suspected hemochromatosis.

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  1. How I treat hemochromatosis - Journal of the American Society of Hematology (2010)
  2. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c) - Diabetes/Metabolism Research and Reviews (May 2012)
  3. Secondary diabetes associated with principal endocrinopathies: the impact of new treatment modalities - Acta Diabetologica (2009)