Heinz Body Anaemia

Summary
Cause:	Oxidative injury to erythrocytes
Associated conditions:	Exposure to oxidative toxins
Differential diagnoses:	Other causes of anaemia
Diagnosis:	Examination of blood smears
Treatment:	Supportive

Introduction

Heinz bodies are inclusion bodies that form within erythrocytes as a result of oxidative injury to the cell. Named after Robert Heinz, the German physician who first described them, they consist of precipitated haemoglobin and their presence can result in premature phagocytosis of erythrocytes

Structure of haemoglobin

Haemoglobin is a conjugated protein consisting of four globin chains, each of which contains a heme group. Its structure allows it to combine reversibly with oxygen and is thus very important in the transportation of oxygen to tissues. Normally the iron within the heme group is in the ferrous (2+) form, the form able to combine with oxygen.

Pathophysiology of oxidative damage to haemoglobin

Oxygen can produce reactive free radicals such as hydrogen peroxide. These substances are generated under normal physiologic conditions and there are enzyme mechanisms to prevent damage to the cell. When these mechanisms are overwhelmed, oxidative damage occurs. As erythrocytes have no organelles they are unable to synthesise proteins and so have limited ability to repair themselves. The damaged cells have highly rigid membranes and so are more likely to be removed from circulation

Oxidation results in three major changes to the haemoglobin molecules:

• Heinz bodies are produced when the sylfhydral groups in the globin part of the haemoglobin molecule undergoes oxidation, causing the molecule to become unstable. Heinz bodies are formed when the damaged haemoglobin molecules coalesce. In most species, Heinz bodies can be removed from erythrocytes by the spleen.

• Methaemoglobinaemia formation occurs when the iron in the haemoglobin molecule is oxidised to the ferric (3+) state. In normal circumstances the methaemoglobin reductase enzyme reduces ferric (3+) back to ferrous (2+) but this system can become overwhelmed in some circumstances. This is the only form of oxidative damage which is reversible.

• Eccentrocytes have their haemoglobin concentrated on one side of the cell, causing the opposite side of the cell to appear clear. They are probably formed when there is damage to the erythrocyte membrane.

This article will cover only Heinz bodies in detail.

Substances causing Heinz body formation

Cats, dogs, horses and ruminants can all suffer from Heinz body anaemias but they are clinically significant mainly in the cat and dog.

Feline erythrocytes are particularly susceptible to oxidative damage as they have eight highly reactive sulfhydryl groups, as opposed to two less reactive ones in other species. In addition, the cat spleen is less efficient in the removal of Heinz bodies from erythrocytes. These two characteristics mean that cats may have 5-10% of erythrocytes containing Heinz bodies under normal circumstances and makes them very susceptible to developing clinical signs of toxicity on exposure to oxidative substances or secondary to other disease processes.

Cats

• Paracetamol (acetominophen) - cats have a low level of N-acetyltransferase enzymes, which prevents them from metabolising the drug to non-toxic substances as humans do. (ref name="ACVIM"> McConkey SE , Cribb A . The molecular mechanism of acetaminophen in dogs and cats. In: Proceedings of the 26th Annual American College of Veterinary Internal Medicine Meeting 2008, pp. 610 – 612 </ref>. They are also relatively deficient in methaemoglobin reductase and methaemoglobinaemia is also a feature of paracetamol toxicity in cats.

• Diabetes mellitus - there is increased production of radicals resulting from various disease-induced metabolic compromises. Ketoacidotic cats have significantly higher numbers of Heinz bodies than non-ketoacidotic patients. (

• Hyperthyroidism - one study found increased numbers of Heinz bodies in hyperthyroid cats but patients were not significantly anaemic. (

• Lymphoma - an increased percentage of Heinz bodies has been linked with lymphoma in cats.

Dogs

• Onions/garlic - contain oxidative agents which are active in raw, cooked and dehydrated forms. Heinz body anaemias are most common in small breeds, suggesting a dose relationship and in breeds with naturally high levels of potassium, such as Akitas and Shar-Peis.

• Paracetamol - dogs lack N-acetyltransferase enzymes, inhibiting their metabolism of the drug. They are less sensitive to the effects than cats due to the higher stablility of their sulfhydryl groups. 200 mg/kg is a toxic dose with the recommended dose being 15 mg/kg tid.

• Zinc - toxic doses are usually ingested from three major sources - skin products such as sunscreen, zinc-coated objects such as toy parts and American pennies. Indiscriminate eaters and small breeds whose narrow pylorus traps foreign objects in the stomach are most likely to develop clinical signs.

Horses

• Dried red maple leaves - contain gallic acid, which may be involved in Heinz body formation.

• Garlic - can be used as an antifungal agent in stock feed.

Clinical signs

Clinical signs depend on the oxidant and the time since intoxication. Mucous membranes can be pale if there is significant anaemia or cyanotic if there is methaemoglobinaemia. Anaemia and/or methaemoglobinaemia can result in tachycardia, increased respiratory rate, weakness, depression and haemoglobinuria. Vomiting, diarrhoea and anorexia may also be seen.

Laboratory findings

Heinz bodies are frequently missed on routine blood films as they tend not to stain well. However they are easily seen on slides stained with new methylene blue and with Wright-Giemsa stain.

Healthy cats may have up to 10% Heinz bodies Higher numbers of Heinz bodies may be seen in cats with underlying diseases such as diabetes mellitus, hyperthyroidism and lymphoma but anaemia is not severe in these cases. In contrast, cats suffering from oxidative ingestion will usually have severe anaemia accompanying the Heinz bodies. If a smear is examined more than about 2 days after the oxidative insult, allowing time for a regenerative response to be mounted, reticulocytosis and polychromasia will usually be evident.

Dogs do not normally have Heinz bodies present in their circulation and therefore if they are identified the patient history should be reviewed to try to pinpoint the oxidant exposure.

Treatment

If the source of the oxidant is still present (eg Zinc-containing foreign object, onions in stomach) it should be removed as soon as possible.

N-acetylcysteine (Mucomyst) should be given as soon as possible after drug exposure as it is only effective within the first few hours. It is thought to increase glutathione synthesis, which provides more substrate for the detoxification of the reactive metabolite.