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Case Details

An 18 –year- old female reported to the physician for consultation. She complained of generalized weakness, lethargy and inability to do the routine work from the previous few months. On further questioning she revealed that she was having excessive bleeding during menstruation from the previous six months. She complained of breathlessness and palpitations while climbing stairs for her house. She also had experienced periods of light-headedness, though not to the point of fainting. Other changes she had noticed were cramping in her legs, a desire to crunch on ice, There was no history of any fever, drug intake or abdominal discomfort. Her appetite had also decreased and she was taking meals only once a day.

Upon examining, her physician found that she had tachycardia, pale gums and nail beds, and her tongue was swollen. Given her history and the findings on her physical examination, the physician suspected that the patient was anemic and ordered a sample of her blood for examination. The results were as shown below:

Red Blood Cell Count -3.5 million/mm3

Hemoglobin (Hb) -7 g/dl

Haemtocrit (Hct)- 30%

Serum Iron – low

Mean Corpuscular Volume (MCV) – low

Mean Corpuscular Hb Concentration (MCHC)- low

Total Iron Binding Capacity in the Blood (TIBC)- high

What is the cause of anemia in this patient?

What are the possible complications in the untreated cases?


Case Discussion- The most likely diagnosis is iron deficiency anemia.

Generalized weakness, exercise intolerance, dyspnea, palpitations, history of blood loss during menstruation, tachycardia and low Hb, all are suggestive of iron deficiency anemia. Iron deficiency is the most prevalent single deficiency state on a worldwide basis. Iron deficiency, is related in part to abnormal iron metabolism

Overview of iron metabolism

The balance of iron in humans is tightly controlled and designed to conserve iron for reutilization. There is no regulated excretory pathway for iron, and the only mechanisms by which iron is lost from the body are blood loss (via gastrointestinal bleeding, menses, or other forms of bleeding) and the loss of epithelial cells from the skin, gut, and genitourinary tract. Normally, the only route by which iron comes into the body is via absorption from food or from medicinal iron taken orally. Iron may also enter the body through red-cell transfusions or injection of iron complexes. The margin between the amount of iron available for absorption and the requirement for iron in growing infants and the adult female is narrow; this accounts for the great prevalence of iron deficiency worldwide—currently estimated at one-half billion people.

 Iron requirement

The amount of iron required from the diet to replace losses averages about 10% of body iron content a year in men and 15% in women of childbearing age. Dietary iron content is closely related to total caloric intake (approximately 6 mg of elemental iron per 1000 calories). Iron bioavailability is affected by the nature of the foodstuff, with heme iron (e.g., red meat) being most readily absorbed. Certain foodstuffs that include phytates and phosphates reduce iron absorption by about 50%.

Infants, children, and adolescents may be unable to maintain normal iron balance because of the demands of body growth and lower dietary intake of iron. During the last two trimesters of pregnancy, daily iron requirements increase to 5–6 mg. That is the reason why iron supplements are strongly recommended for pregnant women in developed countries.

Iron absorption

Iron absorption takes place largely in the proximal small intestine and is a carefully regulated process. In general, there is no regulation of the amounts of nutrients absorbed from the gastro intestinal tract. A notable exception is iron, the reason that absorption must be carefully regulated is that the body does not possess a physiological mechanism to eliminate much iron from the body. The small amount of iron that is lost each day (about 1-2 mg) is matched by dietary absorption of iron.

Mechanism of iron absorption

Iron is found in the diet  is present as ionic (non-haem) iron and haem iron. Absorption of these two forms of iron occurs by different mechanisms. Absorption is a multistep process involving the uptake of iron from the intestinal lumen across the apical cell surface of the villus enterocytes and the transfer out of the enterocyte across the basolateral membrane to the plasma. Ionic iron is present in the reduced (ferrous) or oxidised (ferric) state in the diet and the first step in the uptake of ionic iron involves the reduction of iron. Recently, a reductase that is capable of reducing iron from its ferric to ferrous state has been identified. It is a membrane bound haem protein called Dcytb that is expressed in the brush border of the duodenum. Next, ferrous ion is transported across the lumen cell surface by a transporter called divalent metal transporter 1 (DMT1) that can transport a number of other metal ions including copper, cobalt, zinc, and lead.

Once inside the gut cell, iron may be stored as ferritin or transported through the cell to be released at the basolateral surface to plasma transferrin through the membrane-embedded iron exporter, ferroportin. The function of ferroportin is negatively regulated by hepcidin, the principal iron regulatory hormone. More the Hepcidin levels lesser is the iron absorption and vice versa. In the process of release, iron interacts with another ferroxidase, hephaestin, which oxidizes the iron to the ferric form for transferrin binding. Hephaestin is similar to ceruloplasmin, the copper-carrying protein.


Figure- 1-Showing the mechanism of iron absorption

Factors affecting iron absorption

Iron absorption is influenced by a number of physiologic states.

1)      Erythroid hyperplasia stimulates iron absorption, even in the face of normal or increased iron stores, and  in this state hepcidin levels are inappropriately low. The molecular mechanism underlying this relationship is not known. Thus, patients with anemias associated with high levels of ineffective erythropoiesis absorb excess amounts of dietary iron. Over time, this may lead to iron overload and tissue damage. In iron deficiency, hepcidin levels are low and iron is much more efficiently absorbed from a given diet; the contrary is true in states of secondary iron overload.

2)      Hypoxia-Both the rate of erythropoiesis and hypoxia regulate iron absorption. Expression of ferroportin and Dcytb are increased in hypoxia, resulting in more iron absorption.

3)      Body Stores– Iron absorption is stimulated if the level in body stores is low.

Hepcidin is produced by hepatocytes when iron stores are full, hepcidin makes a complex with ferroportin resulting in  its degradation and thus iron is not  transported to the blood and remains in the enterocyte in the form of ferritin.

4)      Interfering substances- Iron absorption is decreased by phytic acid (in cereals) and oxalic acid(in leafy vegetables) due to the formation of insoluble salts.

5)      Other Minerals- Calcium, copper, zinc, lead and phosphates also inhibit iron absorption

6)     Inflammation can also stimulate hepcidin production resulting in lower iron absorption.

Free Iron toxicity

Iron is a critical element in the function of all cells, although the amount of iron required by individual tissues varies during development. At the same time, the body must protect itself from free iron, which is highly toxic in that it participates in chemical reactions that generate free radicals such as singlet O2 or OH. Consequently, elaborate mechanisms have evolved that allow iron to be made available for physiologic functions while at the same time conserving this element and handling it in such a way that toxicity is avoided.

Iron Transport

Iron absorbed from the diet or released from stores circulates in the plasma bound to transferrin, the iron transport protein. Transferrin (Tf) is a bilobed glycoprotein with two iron binding sites. Tf is normally about one-third saturated with iron Transferrin that carries iron exists in two forms—monoferric (one iron atom) or diferric (two iron atoms).  

The turnover (half-clearance time) of transferrin-bound iron is very rapid—typically 60–90 min. The half-clearance time of iron in the presence of iron deficiency is as short as 10–15 min. With suppression of erythropoiesis, the plasma iron level typically increases and the half-clearance time may be prolonged to several hours.

The iron-transferrin complex circulates in the plasma until it interacts with specific transferrin receptors on the surface of marrow erythroid cells. Diferric transferrin has the highest affinity for transferrin receptors; apo transferrin (transferrin not carrying iron) has very little affinity. While transferrin receptors are found on cells in many tissues within the body—and all cells at some time during development will display transferrin receptors—the cell having the greatest number of receptors (300,000 to 400,000/cell) is the developing erythroblast.

Utilization of iron

Once the iron-bearing transferrin interacts with its receptor, the complex is internalized via clathrin-coated pits and transported to an acidic endosome, where the iron is released at the low pH. The iron is then made available for heme synthesis while the transferrin-receptor complex is recycled to the surface of the cell, where the bulk of the transferrin is released back into circulation and the transferrin receptor re anchors into the cell membrane. At this point a certain amount of the transferrin receptor protein may be released into circulation and can be measured as soluble transferrin receptor protein. Within the erythroid cell, iron in excess of the amount needed for hemoglobin synthesis binds to a storage protein, apoferritin, forming ferritin. This mechanism of iron exchange also takes place in other cells of the body expressing transferrin receptors, especially liver parenchymal cells where the iron can be incorporated into heme-containing enzymes or stored. The iron incorporated into hemoglobin subsequently enters the circulation as new red cells are released from the bone marrow. The iron is then part of the red cell mass and will not become available for reutilization until the red cell dies.

Figure-2 showing the internalization of Iron- Transferrin complex, utilization of iron and transport to other cells via Transferrin  from the hepatocyte

Conservation of iron

In a normal individual, the average red cell life span is 120 days. Thus, 0.8–1.0% of red cells turn over each day. At the end of its life span, the red cell is recognized as senescent by the cells of the reticuloendothelial (RE) system, and the cell undergoes phagocytosis. Once within the RE cell, the hemoglobin from the ingested red cell is broken down, the globin and other proteins are returned to the amino acid pool, and the iron is shuttled back to the surface of the RE cell, where it is presented to circulating transferrin. It is the efficient and highly conserved recycling of iron from senescent red cells that supports steady state (and even mildly accelerated) erythropoiesis. Persistent errors in iron balance lead to either iron deficiency anemia or hemosiderosis. Both are disorders with potential adverse consequences.

Storage of iron

Ferritin and Haemosiderin are iron-containing compound meant for storage of iron. Ferritin is a protein bound, water-soluble, mobilizable storage compound and is the major source of storage iron. Haemosiderin is a water-insoluble form that is less readily available for use. When the amount of total body iron is relatively low, storage iron consists predominately of ferritin. When iron stores are high, Haemosiderin predominates. Unlike ferritin, Haemosiderin stains with the Prussian blue stain (Pens reaction) and may be observed in tissues. Storage forms normally comprise approximately 30% of total body iron. Iron stores provide a source of iron when physiologic demand is high, e.g., blood loss, pregnancy, and periods of rapid growth.

Metabolic role of iron

Iron is vital for all living organisms because it is essential for multiple metabolic processes, including oxygen transport, DNA synthesis, and electron transport.

The major role of iron in mammals is to carry O2 as part of hemoglobin. O2 is also bound by myoglobin in muscle. Iron is a critical element in iron-containing enzymes, including the cytochrome system in mitochondria. Without iron, cells lose their capacity for electron transport and energy metabolism. In erythroid cells, hemoglobin synthesis is impaired, resulting in anemia and reduced O2 delivery to tissue.

Iron containing Proteins

a) Haem containing proteins

Hemoglobin, Myoglobin, Cytochromes, Catalase, Peroxidase, Lactperoxidase and tryptophan pyrrolase

b) Non haem containing proteins

Aconitase, Phenyl alanine hydroxylase, Transferrin, Ferritin and hemosiderin

c) Iron sulfur complexes

Adrenodoxin, Complex-III of Electron transport chain, Succinate dehydrogenase and Xanthine oxidase

Demand and supply imbalance

Since each milliliter of red cells contains 1 mg of elemental iron, the amount of iron needed to replace those red cells lost through senescence amounts to 16–20 mg/d (assuming an adult with a red cell mass of 2 L). Any additional iron required for daily red cell production comes from the diet. Normally, an adult male will need to absorb at least 1 mg of elemental iron daily to meet needs, while females in the childbearing years will need to absorb an average of 1.4 mg/d. However, to achieve a maximum proliferative erythroid marrow response to anemia, additional iron must be available. With markedly stimulated erythropoiesis, demands for iron are increased by as much as six- to eightfold. With extravascular hemolytic anemia, the rate of red cell destruction is increased, but the iron recovered from the red cells is efficiently reutilized for hemoglobin synthesis. In contrast, with intravascular hemolysis or blood loss anemia, the rate of red cell production is limited by the amount of iron that can be mobilized from stores. Typically, the rate of mobilization under these circumstances will not support red cell production more than 2.5 times normal. If the delivery of iron to the stimulated marrow is suboptimal, the marrow’s proliferative response is blunted, and hemoglobin synthesis is impaired. The result is a hypoproliferative marrow accompanied by microcytic, hypochromic anemia.

Menstrual blood loss in women plays a major role in iron metabolism. The average monthly menstrual blood loss is approximately 50 mL, or about 0.7 mg/d. However, menstrual blood loss may be five times the average. To maintain adequate iron stores, women with heavy menstrual losses must absorb 3–4 mg of iron from the diet each day. This strains the upper limit of what may reasonably be absorbed, and women with menorrhagia of this degree will almost always become iron deficient without iron supplementation.

Pregnancy may also upset the iron balance, since requirements increase to 2–5 mg of iron per day during pregnancy and lactation. Normal dietary iron cannot supply these requirements, and medicinal iron is needed during pregnancy and lactation. Repeated pregnancy (especially with breast-feeding) may cause iron deficiency if increased requirements are not met with supplemental medicinal iron.

Decreased iron absorption can on very rare occasions cause iron deficiency and usually occurs after gastric surgery, though concomitant bleeding is frequent.

By far the most important cause of iron deficiency anemia is blood loss, especially gastrointestinal blood loss. Chronic aspirin use may cause it even without a documented structural lesion. Iron deficiency demands a search for a source of gastrointestinal bleeding if other sites of blood loss (menorrhagia, other uterine bleeding, and repeated blood donations) are excluded.

Chronic hemoglobinuria may lead to iron deficiency since iron is lost in the urine; traumatic hemolysis due to a prosthetic cardiac valve and other causes of intravascular hemolysis (eg, paroxysmal nocturnal hemoglobinuria) should also be considered. Frequent blood donors may also be at risk for iron deficiency.

While blood loss or hemolysis places a demand on the iron supply, conditions associated with inflammation interfere with iron release from stores and can result in a rapid decrease in the serum iron level.

Summary of Causes of Iron Deficiency

Conditions that increase demand for iron, increase iron loss, or decrease iron intake or absorption can produce iron deficiency;

  • Increased demand for iron and/or hematopoiesis
    • rapid growth in infancy or adolescence
    •  pregnancy
    • erythropoietin therapy
  • Increased iron loss
    • chronic blood loss
    • menses
    • acute blood loss
    • blood donation
    • Phlebotomy as treatment for polycythemia vera.
    • Decreased iron intake or absorption
      • inadequate diet  
      • malabsorption from disease (sprue, Crohn’s disease)
      • malabsorption from surgery (post-gastrectomy)  
      • acute or chronic inflammation

 Iron deficiency anemia

Iron deficiency is defined as decreased total iron body content. Iron deficiency anemia occurs when iron deficiency is sufficiently severe to diminish erythropoiesis and cause the development of anemia. Iron deficiency is the most prevalent single deficiency state on a worldwide basis. It is important economically because it diminishes the capability of individuals who are affected to perform physical labor, and it diminishes both growth and learning in children.


In countries where little meat is in the diet, iron deficiency anemia is 6-8 times more prevalent . This occurs despite consumption of a diet that contains an equivalent amount of total dietary iron because heme iron is absorbed better from the diet than nonheme iron. In certain geographic areas, intestinal parasites, particularly hookworm, worsen the iron deficiency because of blood loss from the gastrointestinal tract. Anemia is more profound among children and premenopausal women in these environs.


Chronic iron deficiency anemia is seldom a direct cause of death; however, moderate or severe iron deficiency anemia can produce sufficient hypoxia to aggravate underlying pulmonary and cardiovascular disorders. In children, the growth rate may be slowed, and a decreased capability to learn is reported.

Clinical Manifestations

As a rule, the only symptoms of iron deficiency anemia are those of the anemia itself (easy fatigability, tachycardia, palpitations and tachypnea on exertion). Severe deficiency causes skin and mucosal changes, including a smooth tongue, brittle nails, and cheilosis. Dysphagia because of the formation of esophageal webs (Plummer–Vinson syndrome) also occurs. Many iron-deficient patients develop pica, craving for specific foods (ice chips, etc) often not rich in iron.

Laboratory Findings

  • CBC count
    • This documents the severity of the anemia. In chronic iron deficiency anemia, the cellular indices show a microcytic and hypochromic erythropoiesis, ie, both the mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) have values below the normal range for the laboratory performing the test. Reference range values for the MCV and MCHC are 83-97 fL and 32-36 g/dL, respectively.
    • Often, the platelet count is elevated (>450,000/µL). This normalizes following iron therapy.
    • The WBC count is usually within reference ranges (4500-11,000/µL).
    • If the CBC count is obtained after blood loss, the cellular indices do not enter the abnormal range until most of the erythrocytes produced before the bleed are destroyed at the end of their normal lifespan (120 d).
  • Peripheral smear
  • In the early stages, the MCV remains normal. Subsequently, the MCV falls and the blood smear shows hypochromic microcytic cells (see blood smear). With further progression, anisocytosis (variations in red blood cell size) and poikilocytosis (variation in shape of red cells) develop. Severe iron deficiency will produce a bizarre peripheral blood smear, with severely hypochromic cells, target cells, hypochromic pencil-shaped cells, and occasionally small numbers of nucleated red blood cells. The platelet count is commonly increased.(Figure-3)
  • Combined folate deficiency and iron deficiency are commonplace in areas of the world with little fresh produce and meat. The peripheral smear reveals a population of macrocytes mixed among the microcytic hypochromic cells. This combination can normalize the MCV.

 Figure –3- showing microcytic hypochromic cells in peripheral smear

  • Serum iron, total iron-binding capacity (TIBC), and serum ferritin: Iron deficiency develops in stages. The first is depletion of iron stores. At this point, there is anemia and no change in red blood cell size. The serum ferritin will become abnormally low. A ferritin value less than 30 mcg/L is a highly reliable indicator of iron deficiency. The serum total iron-binding capacity (TIBC) rises. After iron stores have been depleted, red blood cell formation will continue with deficient supplies of iron. Serum iron values decline to less than 30 mcg/dL and transferrin saturation to less than 15%. A low serum iron and ferritin with an elevated TIBC are diagnostic of iron deficiency. While a low serum ferritin is virtually diagnostic of iron deficiency, a normal serum ferritin can be seen in patients who are deficient in iron and have coexistent diseases (hepatitis, anemia of chronic disorders). These test findings are useful in distinguishing iron deficiency anemia from other microcytic anemias
  • A bone marrow aspirate can be diagnostic of iron deficiency. Bone marrow biopsy for evaluation of iron stores is now rarely performed because of variation in its interpretation.
  • Other laboratory tests are useful to establish the etiology of iron deficiency anemia and to exclude or establish a diagnosis of 1 of the other microcytic anemias.
    • Testing stool for the presence of hemoglobin is useful in establishing gastrointestinal bleeding as the etiology of iron deficiency anemia. Severe iron deficiency anemia can occur in patients with a persistent loss of less than 20 mL/d.
    • Hemoglobinuria and hemosiderinuria can be detected by laboratory testing . This documents iron deficiency to be due to renal loss of iron and incriminates intravascular hemolysis as the etiology.
    • Hemoglobin electrophoresis and measurement of hemoglobin A2 and fetal hemoglobin are useful in establishing either beta-thalassemia or hemoglobin C or D as the etiology of the microcytic anemia. 
    • Serum Levels of Transferrin Receptor Protein-Because erythroid cells have the highest numbers of transferrin receptors on their surface of any cell in the body, and because transferrin receptor protein (TRP) is released by cells into the circulation, serum levels of TRP reflect the total erythroid marrow mass. Another condition in which TRP levels are elevated is absolute iron deficiency. Normal values are 4–9 μg/L determined by immunoassay. This laboratory test is becoming increasingly available and, along with the serum ferritin, has been proposed to distinguish between iron deficiency and the anemia of chronic inflammation

Differential Diagnosis

Other causes of microcytic anemia include anemia of chronic disease, thalassemia, and sideroblastic anemia. Anemia of chronic disease is characterized by normal or increased iron stores in the bone marrow and a normal or elevated ferritin level; the serum iron is low, often drastically so, and the TIBC is either normal or low. Thalassemia produces a greater degree of microcytosis for any given level of anemia than does iron deficiency. Red blood cell morphology on the peripheral smear is abnormal earlier in the course of thalassemia.


The diagnosis of iron deficiency anemia can be made either by the laboratory demonstration an iron-deficient state or evaluating the response to a therapeutic trial of iron replacement.

Since the anemia itself is rarely life-threatening, the most important part of treatment is identification of the cause—especially a source of occult blood loss.

Oral Iron

Ferrous sulfate, 325 mg three times daily, which provides 180 mg of iron daily of which up to 10 mg is absorbed (though absorption may exceed this amount in cases of severe deficiency), is the preferred therapy.

Parenteral Iron

The indications are intolerance to oral iron, refractoriness to oral iron, gastrointestinal disease (usually inflammatory bowel disease) precluding the use of oral iron, and continued blood loss that cannot be corrected. Because of the possibility of anaphylactic reactions, parenteral iron therapy should be used only in cases of persistent anemia after a reasonable course of oral therapy. 

Red Cell Transfusion

Transfusion therapy is reserved for individuals who have symptoms of anemia, cardiovascular instability, continued and excessive blood loss from whatever source, and require immediate intervention. The management of these patients is less related to the iron deficiency than it is to the consequences of the severe anemia. Not only do transfusions correct the anemia acutely, but the transfused red cells provide a source of iron for reutilization, assuming they are not lost through continued bleeding. Transfusion therapy will stabilize the patient while other options are reviewed.


Iron deficiency anemia is an easily treated disorder with an excellent outcome; however, it may be caused by an underlying condition with a poor prognosis, such as neoplasia. Similarly, the prognosis may be altered by a comorbid condition such as coronary artery disease.


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Case Details

A 15 –year-old girl presented with abdominal pain and diarrhoea for 3 days. She became jaundiced and a presumptive diagnosis of infective hepatitis was made, but serological tests were negative. She subsequently died of fulminant liver failure. At post-mortem her liver copper concentration was found to be grossly increased.

What is the probable diagnosis?

What kind of investigations should be carried out for her sister?

Case details

High liver copper concentration, indicates that the patient died of Wilson’ disease, which is an autosomal recessive disorder caused by mutations in the ATP7B gene, a membrane-bound copper transporting ATPase. Clinical manifestations are caused by copper toxicity and primarily involve the liver and the brain. Because effective treatment is available, it is important to make this diagnosis early. The patient’s sister should be screened for Wilson’s disease. Serum copper, Caeruloplasmin and urinary copper excretion may indicate if she also has the disease. A liver biopsy may be indicated. DNA analysis can assist in the confirmation of diagnosis.

Basic concept

Overview of copper metabolism

Copper is an essential trace element which is a component of many intracellular metalloenzymes, including Cytochrome oxidase, Tyrosinase, Superoxide dismutase, Lysyl oxidase and Dopamine β oxidase. Most of the copper in plasma is bound to Caeruloplasmin.

About 50% of the average daily dietary copper of around 25μmol (1.5 mg) is absorbed from the stomach and the small intestine. Absorbed copper is transported to the liver in portal blood bound to albumin and is exported to peripheral tissues mainly bound to caeruloplasmin and to a lesser extent to albumin.

Copper is present in all metabolically active tissues. The highest concentrations are found in liver and in kidney, with significant amount in cardiac and skeletal muscles and in bones. The liver contains 10% of the total body content of 1200 μmol(80mg). Excess copper is excreted in bile and then in to gut, and the fecal copper output(12.5 μmol/24 hours), is the sum of the unabsorbed dietary copper and that re-excreted in to the gut.

Copper deficiency

Both children and adults can develop symptomatic copper deficiency. Premature infants are the most susceptible since copper stores in liver are laid down in the third trimester of pregnancy. In adults copper deficiency is found in intestinal bypass surgeries or in patients who are on parenteral nutrition Symptoms range from bone disease to iron resistant microcytic hypochromic anemia.

Copper toxicity

Copper toxicity is uncommon and is mostly due to administration of copper Sulphate solutions. Oral copper Sulphate may lead to gastric perforation. Serum copper may be greatly elevated. Copper is toxic to many organs, but renal tubular damage is more common and is of major concern. Treatment is by chelation with Penicillamine.

 Wilson’s disease

The condition is characterized by excessive deposition of copper in the liver, brain, and other tissues. The major physiologic aberration is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver. Patients with Wilson disease usually present with liver disease during the first decade of life or with neuropsychiatric illness during the third decade. The diagnosis is confirmed by measurement of serum caeruloplasmin, urinary copper excretion, and hepatic copper content, as well as the detection of Kayser-Fleischer rings.

 Biochemical defect

The genetic defect has been shown to affect the copper-transporting adenosine triphosphatase (ATPase) gene (ATP7B) in the liver. Many of the gene defects for ATP7B are small deletions, insertions, or missense mutations. Most patients carry different mutations on each of their 2 chromosomes. More than 200 different mutations have been identified, the most common of which is a change from a Histidine to a glutamine (H1069Q).


In Wilson disease, the processes of incorporation of copper into ceruloplasmin and excretion of excess copper into bile are impaired.The transport of copper by the copper-transporting P-type ATPase is defective secondary to one of several mutations in the ATP7B gene. The excess copper acts as a promoter of free radical formation and causes oxidation of lipids and proteins. Initially, the excess copper is stored in the liver and causes damage to the hepatocytes.

Defective copper incorporation into apo Ceruloplasmin leads to excess catabolism and low blood levels of Ceruloplasmin. Serum copper levels are usually lower than normal because of low blood Ceruloplasmin, which normally binds >90% of serum copper. As the disease progresses, non-Ceruloplasmin serum copper (“free” copper) levels increase, resulting in copper buildup in other parts of the body, such as the brain, leading to neurologic and psychiatric disease.


The frequency of Wilson disease in most populations is about 1 in 30,000–40,000.

Clinical Manifestations


Wilson disease may present as hepatitis, cirrhosis, or as hepatic decompensation. An episode of hepatitis may occur, with elevated blood transaminase enzymes, with or without jaundice, and then spontaneously regresses. Hepatitis often reoccurs, and most of these patients eventually develop cirrhosis.

Hepatic decompensation is associated with elevated serum bilirubin, reduced serum albumin and coagulation factors, ascites, peripheral edema, and hepatic encephalopathy. In severe hepatic failure, hemolytic anemia may occur because large amounts of copper derived from hepatocellular necrosis are released into the bloodstream. The association of hemolysis and liver disease makes Wilson disease a likely diagnosis.


The neurologic manifestations of Wilson disease typically occur in patients in their early twenties, although the age of onset extends into the sixth decade of life. The three main movement disorders include: dystonia, incoordination, and tremor. In some patients, the clinical picture closely resembles that of Parkinson disease. Sensory abnormalities and muscular weakness are not features of the disease.


A history of behavioral disturbances, with onset in the five years before diagnosis, is present in half of patients with neurologic disease. The features are diverse and may include loss of emotional control (temper tantrums, crying bouts), depression, hyperactivity, or loss of sexual inhibition.

Other Manifestations

Sunflower cataracts and Kayser-Fleischer rings (copper deposits in the outer rim of the cornea) may be seen. Electrocardiographic and other cardiac abnormalities have been reported but are not common.


Laboratory Studies

  • The presence of Kayser-Fleischer rings and caeruloplasmin levels of less than 20 mg/dL in a patient with neurologic signs or symptoms suggest the diagnosis of Wilson disease. If a patient is asymptomatic, exhibits isolated liver disease, and lacks corneal rings, the coexistence of a hepatic copper concentration of more than 250 mg/g of dry weight and a low serum ceruloplasmin level is sufficient to establish a diagnosis.
  • Serum ceruloplasmin
    • Serum Ceruloplasmin levels are low in newborns and gradually rise within the first 2 years of life. Approximately 90% of all patients with Wilson disease have ceruloplasmin levels of less than 20 mg/dL (reference range, 20-40 mg/dL).
    • Ceruloplasmin is an acute phase reactant and may be increased in response to hepatic inflammation, pregnancy, estrogen use, or infection.
    • Falsely low ceruloplasmin levels may be observed in any protein deficiency state, including nephrotic syndrome, malabsorption, protein-losing enteropathy, and malnutrition.
  • Urinary copper excretion

                           The urinary copper excretion rate is greater than 100 mg/d 

  • Hepatic copper concentration
    • This test is regarded as the criterion standard for diagnosis of Wilson disease.
    • A liver biopsy with sufficient tissue reveals levels of more than 250 mcg/g of dry weight even in asymptomatic patients. 
    • Imaging Studies– CT and MRI of brain and abdomen can be carried out to confirm the diagnosis.
  • Kayser-Fleischer rings– can only be diagnosed definitively by an ophthalmologist using a slit lamp. They are present in >99% of patients with neurologic/psychiatric forms of the disease and have been described very rarely in the absence of Wilson disease.

Figure- Showing Kayser –Fleischer ring in a patient suffering from Wilson’s disease



The mainstay of therapy for Wilson disease is pharmacologic treatment with chelating agents.

 Chelating agents bind excess copper.

Ammonium tetrathiomolybdate is being used. This drug works as both a chelating agent and an inhibitor of copper absorption from the GI tract.

Penicillamine was previously the primary anticopper treatment but now plays a minor role because of its toxicity and because it often worsens existing neurologic disease if used as initial therapy.

Trientine is a less toxic chelator and is supplanting penicillamine when a chelator is indicated.

For patients with hepatitis or cirrhosis, but without evidence of hepatic decompensation or neurologic/psychiatric symptoms, zinc is the therapy of choice.

B6 and Dimercaprol can also be used as a part of the treatment.

Anticopper therapy must be given for life long. With treatment, liver function usually recovers after about a year, although residual liver damage is usually present. Neurologic and psychiatric symptoms usually improve between 6 and 24 months of treatment.


The major complications in patients with untreated Wilson disease are those associated with liver failure and a chronic, relentless course to cirrhosis.


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Case Details

A 35 year -old female reported to emergency with severe pain in the left flank region, which was radiating towards lower leg and back. The patient was in acute distress and agony. History revealed that she frequently suffered from urinary tract infections and had several such episodes of pain. She further reported that she constantly felt weakness, fatigue and bone pains from the previous few months.

There was no history of fever and there was no personal or family history of medical problems.

Her physical examination was normal except for tenderness in the left renal region.The attending physician ordered for complete blood count, electrolytes and a complete urinalysis.

The laboratory investigation report revealed a normal complete blood count (CBC), and significantly elevated calcium level and low phosphorus level.Urine was cloudy and had plenty of pus cells. The patient was admitted and treated for renal colic.

What is the underlying cause for repeated episodes of renal colic?

What is the most likely diagnosis?

What is the relationship of bone pains and frequent urinary tract infections in this patient?

What is the cause for high serum calcium and low phosphorus level in this patient?


Case details Hypercalcemia, hypophosphatemia, recurrent urinary tract infections, renal stones and bone pains all signify underlying hyperparathyroidism. (Cloudy urine and pus cells are indicative of urinary tract infection).

Hyperparathyroidism is over activity of the parathyroid glands resulting in excess production of parathyroid hormone (PTH). The parathyroid hormone regulates calcium and phosphate levels.  

Hyperparathyroidism is classified in three categories-

1) Primary hyperparathyroidism-Primary hyperparathyroidism results from a hyper function of the parathyroid glands themselves. There is over secretion of PTH due to adenoma, hyperplasia or,rarely, carcinoma of the parathyroid glands.

2) Secondary hyperparathyroidism-Secondary hyperparathyroidism is the reaction of the parathyroid glands to a hypocalcaemia caused by something other than a parathyroid pathology, e.g.chronic renal failure or vitamin D deficiency.

3)Tertiary hyperparathyroidism- Tertiary hyperparathyroidism results from hyperplasia of the parathyroid glands and a loss of response to serum calcium levels. In cases of long-standing secondary hyperparathyroidism, the hypertrophied parathyroid glands can become autonomously functioning and continue to secrete PTH independent of whether the original stimuli to secrete PTH are still present.

In all cases, the raised PTH levels are harmful to bone, and treatment is often needed.

Serum calcium- In cases of primary hyperparathyroidism or tertiary hyperparathyroidism heightened PTH leads to increased serum calcium (Hypercalcemia) due to:

  1. increased bone resorption, allowing flow of calcium from bone to blood
  2. reduced renal clearance of calcium
  3. increased intestinal calcium absorption

By contrast, in secondary hyperparathyroidism effectiveness of PTH is reduced.

Serum phosphate

In primary hyperparathyroidism, serum phosphate levels are abnormally low as a result of decreased renal tubular phosphate reabsorption. However, this is only present in about 50% of cases.This contrasts with secondary hyperparathyroidism, in which serum phosphate levels are generally elevated because of renal disease.

Manifestations of hyperparathyroidism involve primarily the kidneys and the skeletal system. Kidney involvement is due to either deposition of calcium in the renal parenchyma or to recurrent nephrolithiasis. Renal stones are usually composed of either calcium oxalate or calcium phosphate. In occasional patients,repeated episodes of nephrolithiasis or the formation of large calculi may lead to urinary tract obstruction, infection, and loss of renal function. 

Nephrocalcinosis may also cause decreased renal function and phosphate retention.

There are great variations in the manifestations. Patients may present with multiple signs and symptoms, including recurrent nephrolithiasis, peptic ulcers,mental changes, and, less frequently, extensive bone resorption.

Treatment and monitoring Treatment depends upon the severity and cause of the condition. If there is mildly increased calcium levels due to primary hyperparathyroidism and no symptoms, just regular check ups are needed. If symptoms are present or calcium level is very high, surgery may be needed to remove the parathyroid gland that is overproducing the hormone. Treatment of secondary hyperparathyroidism depends on the underlying cause.Vitamin D and Phosphorus supplementation can also be done. 


A Calcimimetics (cinacalcet) is a new type of drug for people with primary and secondary hyperparathyroidism on dialysis. It mimics the effect of calcium in tissues. This reduces PTH release from parathyroid glands, leading to lower calcium and phosphorus levels in blood. 

Surgery for hyperparathyroidism may lead to low blood calcium levels, which causes tingling and muscle twitching. This requires immediate treatment.

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Case Details

A 35 year -oid female reported to emergency with severe pain in the left flank region, which was radiating towards lower leg and back. The patient was in acute distress and agony. History revealed that she frequently suffered from urinary tract infections and had several such episodes of pain.She further reported that she constantly felt weakness, fatigue and bone pains from the previous few months. There was no history of fever and there was no personal or family history of medical problems.

Her physical examination was normal except for tenderness in the left renal region.

The attending physician ordered for complete blood count, electrolytes and a complete urinalysis.

The laboratory investigation report revealed a normal complete blood count (CBC), and significantly elevated calcium level and low phosphorus level. Urine was cloudy and had plenty of pus cells. The patient was admitted and treated for renal colic.

What is the underlying cause for repeated episodes of renal colic?

What is the most likely diagnosis?

What is the relationship of bone pains and frequent urinary tract infections in this patient?

What is the cause for high serum calcium and low phosphorus level in this patient?

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