Amoebic liver abscess, undiagnosed and untreated, has a very high mortality rate, of almost 100%.' With early diagnosis and prompt institution of specific therapy, the prognosis is excellent and the mortality is extremely low ²
As early as 1935 (based on the analysis of 4,484 cases, which included their own series) Ochsner and DeBakey³ advocated the following three principles of treatment:-

1. every case of suspected amoebic liver abscess should be given a course of amoebicidal drug therapy before any other procedure is used, unless rupture of the abscess appears imminent.
2. if evacuation of pus is necessary, aspiration and preliminary administration of amoebicidal drugs is the procedure of choice.
3. open drainage of the abscess should be reserved for the relatively few cases of secondarily infected abscesses.

Today after more than forty years, there has been no change in these principles of management even after the availability of modern amoebicidal drugs.

General management
Every patient of amoebic liver abscess should ideally be hospitalised as continuous observation is required for early recognition of complications.
The patient is advised complete bed rest, only if rupture seems imminent or complications like pericarditis and acute abdomen supervene. The patients are usually more comfortable sitting propped up in bed although the decubitus depends on the site of the abscess-the patient assuming a position, which alleviates the pain by relieving the tension on the capsule of the liver. Analgesics may be administered initially.^1,2 Antipyretics may be required if the fever is high.
Although the diet is not specific, it should be of a high caloric value and should include a substantial amount of fluids. Alcohol should be forbidden. If nausea and vomiting are present, the total calories and fluid intake must be administered parenterally.
Anaemia, when present, usually responds to antiamoebic therapy. If severe, it must be corrected by a transfusion of packed cells or whole blood.⁴

Amoebicidal drugs
The treatment of invasive amoebiasis should be directed to all sites where E. Histolytica may be present. Hence the ideal amoebicide should be able to act within the intestinal lumen, in the intestinal wall as well as systemically, particularly in the liver.
Systemic amoebicidal drugs include emetine, dehydroemetine, chloroquine diphosphate, metronidazole and tinidazole.

Emetine
Ipecac or ipecacuanha consists of the dried rhizome and roots of Cephaelis ipecacuanha.
The medical virtues of ipecac are almost entirely due to the action of its alkaloids-emetine and cephaline. Till today, emetine remains one of the best drugs for treating amoebic liver abscess. It has a direct action on the trophozoites.^5,6,7
Its greater concentration and duration of action in the liver as compared to that in the intestinal wall explains its high efficacy in amoebic liver abscess and also its low parasitic cure rate for intestinal amoebiasis.
The drug is detoxicated and eliminated slowly.⁷ It may, therefore, produce cumulative effects. In man, emetine poisoning is characterized by muscular tremors, weakness and pain in the extremities which tend to persist until drug administration is stopped.⁷ Gastro-intestinal symptoms include nausea, vomiting and bloody diarrhoea. The latter may be mistaken for a recurrence of amoebic dysentery. ⁸
Many clinicians fear the occurrence of cardiac toxicity due to this drug and hence avoid using it. Serious cardiac toxicity, however, is rare. In more than twenty years' experience, I have seen only two patients who developed an enlarged heart with congestive cardiac failure. Both recovered with the treatment for heart failure and withdrawal of emetine. One patient who was given fifteen injections of emetine in a dose of 60 mgm. per day, died.
Overdosage of emetine produces focal necrosis of cardiac muscle resulting in cardiac failure and sudden death.⁷
Emetine, like digitalis may produce mild ST and T wave changes in the electrocardiogram which does not necessarily mean serious toxicity. In fact, they are encountered, though less commonly, after the use of chloroquine and metronidazole as well.
Toxic effects on the myocardium have been described even in doses generally considered safe. These are rise in pulse rate, fall in systolic blood pressure and ST-T changes in the electrocardiogram.²
The other rare E.C.G. changes include deformity of QRS complexes, prolongation of PR interval, atrial premature beats and atrial tachycardia.² In adults, fatal cases have been reported with a total dose of 0.6 G. or less. The incidence of toxic heart damage greatly increases in patients with anaemia.⁹
In patients having myocardial disease or marked hypertension, emetine can be used for amoebic liver abscess, as the benefits from it may outweigh possible hazards.⁷ This situation is unlikely to arise these days, as equally good alternative drugs like metronidazole are available. Patients receiving emetine should be monitored for changes in pulse, blood pressure and electrocardiography. Absolute bed rest during and several days after emetine therapy has been recommended⁷ although we have often seen patients in whom no untoward reactions have occurred in spite of neglecting the above precaution.
Theoretically the use of emetine in children is not advised.⁷ However, in practice it has been used as discussed elsewhere. It should not be administered during pregnancy unless absolutely necessary.^7,8
Although emetine is undeniably moderately toxic, the risk of using it would be worth accepting in such a serious illness were it not for the fact that less toxic drugs like chloroquine and metronidazole are now available.
In practice, emetine still produces a more dramatic clinical response thanchloroquine or metronidazole. This point would score in favour of emetine in places where facilities for a proper diagnosis are not available and a therapeutic test remains as the only weapon with a practitioner.
Emetine should always be given deep intramuscularly or deep subcutaneously but never intravenously.^2,7 The total dose in amoebic liver abscess should not exceed 650 mg. or 10 mg/kg. This should be given over a period of 10 days in a dose of 6G65 mg. daily. A relapse rate of 7% follows one such course.⁴ Therefore, the treatment could be repeated after a period of 2-6 weeks.⁴ Of late such a need does not arise, as drug combinations are commonly used. When parenteral emetine is combined with oral chloroquine or two courses of emetine are given, the relapse rate can be brought down to 1 percent. 4

Dehydroemetine
It is a synthetic compound developed by Osbond et al and Brossi et al in 1959.¹⁰ It is as effective as emetine in its amoebicidal properties. Given parenterally dehydroemetine is surprisingly painless.¹¹ Oral tablets have been introduced.¹² But for some reason, these tablets have not become popular. A high cure rate can be obtained with this drug.¹³ Compared to emetine, its concentration in the heart is less. Electrocardiographic changes are not seen so often. When present, they are more transient than with emetine.⁷
Dehydroemetine is excreted by the kidneys, heart and the other organs more rapidly than emetine. Therefore, a daily dose of 1.25 mg. or 1.5 mg/kg. body weight is necessary. The total dai Iy dose should not exceed 90 mgs. The course should not be repeated in less than 14 days.⁷

Chloroquine
The introduction of cinchona into therapeutics was due to the discovery of its efficacy in malaria. In 1921, John¹⁴ used Quinine hydrochloride, an alkaloid of cinchona in the treatment of amoebic liver abscess.
Later when synthetic derivatives of quinine were introduced, chloroquine phosphate, a 4 aminoquinoline was found to be less toxic than the parent drug. The drug was first quoted in the treatment of this condition in very early reports by Conan (1948)¹⁵, Murgatroyd and Kent (1948)¹⁶.
It is absorbed rapidly and completely from the gastrointestinal tract. It is found to be very effective in invasive amoebiasis although the drug is a weaker amoebicide when compared to emetine. It is only feebly amoebicidal in the intestinal lumen.⁷
The high concentration in the liver parenchyma and the lung allows the drug to act upon E. Histolytica in cases of amoebic liver abscess and pleuropulmonary amoebiasis.¹⁷
It is usually well tolerated, but in some individuals it may cause mild headache, itching, nausea, vomiting or blurred vision. Rarely incoordination, convulsions, peripheral neuritis and bleaching of hair can occur.⁷ Diminution of T waves has been noticed on routine electrocardiographic recordings. Retinopathy does not occur with the usual dosage for amoebic liver abscess.² Psychic disturbances though rare may interfere with the safe operation of machines and vehicles.⁸ The drug may be toxic to children in large doses¹⁸ and causes deafness in the foetus.
Each 0.5 G. tablet contains chloroquine diphosphate equivalent to 0.3 G. of the base. For the treatment of amoebic liver abscess, it is administered in doses of 0.6 G. base per day in 2 to 3 divided doses orally for 2 days followed by 0.15 G. base twice daily for 2 to 3 weeks. However, Plorde recommends that it be given as 0.6 G. base initially, 0.3 G. base six hours later and then 0.3 G. base twice daily for fourteen to twenty eight days.¹⁹ Chloroquine is also available in an injectable form. Since it is quite toxic by this route, it should not be used for more than 24-48 hours after which oral therapy should be continued. Rarely, when patients of amoebic liver abscess are vomiting, injection chloroquine can be used in a dose of 0.3-0.6 G. base in 24 hours not exceeding 0.9 G.).
Chloroquine given alone is a safer drug than emetine in amoebic liver abscess, but unfortunately the relapse rate is almost 25%.⁹ Rarely repetition of the course may induce a dramatic response.^20,21

Ambilhar
Until 1964, all available amoebicides were selective in their sites of action. The development of newer nitro-imidazole derivatives led to Niridazole. It was given in a daily dose of 25-30 mgm. per kg. to 50 patients for seven days. The cure rate was found to be 84% with serious side effects in one patient.^{22 23} An Indian study of 30 patients on this drug revealed that it acted as a contact amoebicide and also against the invasive forms.²³ The therapeutic action of Ambilhar was found to be significantly better than that produced by a combination of dehydroemetine and chloroquine.²⁴

Metronidazole
This is another derivative of the parent drug and its results are better than niridazole. This amoebicide acts directly on the trophozoites of E. Histolytica. Studies showed that because of very high concentration in the liver extremely small amounts of the drug were effective in amoebic liver abscess, but with such low doses, ²⁵ eradication of amoebae in the bowel was uncertain. The drug is quickly absorbed, partly metabolized and rapidly excreted without any cumulative effect. It is more active in the tissues than in the gut lumen. It follows that a higher dosage is needed in the cure of luminal than systemic infection.
The side effects of metronidazole are infrequent.²⁶ Gastro-intestinal symptoms and headache occur occasionally.⁷ Heavy coating of tongue, brownish urine, metallic taste, dry mouth and nausea occur more often. Vertigo, incoordinate ataxia and paraesthesias have been reported on rare occasions. Tsai et al²⁷ observed psychosis which usually disappeared within a day or two after metronidazole was withdrawn but tremors and muscle spasm lasted for several days. It has an antabuse like action and alcohol should be avoided during its use.¹³ A transitory leucopenia may occur. Cardiovascular symptoms are rare. Treatment should be discontinued promptly if ataxia or any other symptoms of C.N.S. involvement occur.⁷
Only a few years ago when metronidazole was introduced it was considered to be the last word in the therapy of amoebiasis. However, the recent evidence that this drug is carcinogenic¹⁹ and possibly mutagenic²⁸ in animals is disturbing. Due to such reports the use of the drug remains controversial. The potential risk in human beings must be weighed against the severity of the disease.¹⁹
The oral dose of 400 mg. thrice daily for 5 days suffices for the treatment of amoebic liver abscess.⁷ Adams29 in his analysis of 2,074 cases of liver abscess preferred metronidazole to other amoebicidal agents. A single oral dose of 2.5 G. metronidazole combined with closed aspiration has also produced dramatic response and cure in patients with amoebic liver abscess.⁹ Recently the use of intravenous preparation of metronidazole has been reported.³⁰ Studies by Lazarachick et al³¹ revealed presence of anaerobic bacteroides in as many as 26% cases of amoebic liver abscess with so called 'sterile' pus. Intravenous metronidazole is a drug of choice for anaerobic infections ³² Therefeore it may be of extra advantage, if used in amoebic liver abscess.
Metronidazole should not be used as a single agent for the eradication of bowel infection.³³ When used alone, a few cases are known to have developed amoebic liver abscess, months after apparently successful cure of dysentery. Cases refractory to metronidazole have been occasionally described.

Tinidazole
This nitroimidazole compound, like metronidazole has shown a marked therapeutic response in amoebic liver abscess.³⁴ Occasional side effects include nausea and dizziness. Tinidazole is not widely available though it is more effective than metronidazole.³⁵ Zuberi and Ibrahim found tinidazole to be effective in 86.7% cases of intestinal amoebiasis and in 100% cases of amoebic liver abscess.³⁶
Luminal amoebicides like halogenated oxyquinolines, e.g. di-idohydroxyquinoline in a dose of 0.6 G. thrice daily for 3 weeks, diloxanide furoate 0.5 G. three times a day for 10 days and sometimes tetracyclines 1-2 G./day for 5 days should be used concurrently with any of the above drugs as adjuncts to eliminate intestinal infection.

Response to drugs
The response to amoebicidal drugs in amoebic liver abscess is often dramatic. The temperature usually subsides by Iysis, returning to normal within an average of 46 days. Liver tenderness diminishes or disappears and the patient's general condition improves appreciably. This is normally accompanied by a definite improvement in the radiological appearance of the chest. The full course of therapy must be completed even if the patient shows positive signs of improvement.
Persistence or recurrence of hepatic pain, tenderness or fever should be an indication for needle aspiration of the liver.
Having described in detail the drugs used in amoebic liver abscess I will now briefly discuss the line of treatment, I commonly follow.
I prefer a combination of at least two drugs, one of which is always injection emetine, unless it is strongly contra-indicated. But, if the patient is apprehensive about the toxicity of this drug, (of which he has heard from his family practitioner) or if he wishes to remain ambulatory, I omit emetine and administer metronidazole and chloroquine. In an adult, I usually advise dehydroemetine in a dose of 90 mg. per day for a period of eight to ten days. This drug has also been frequently administered to patients in the fifth and sixth decades. Although patients receiving these drugs are advised rest at home, complete bed rest is rarely enforced.
This therapy is usually preceded by taking an E.C.G. which would serve as a basal record for future reference. In the past, ST-T changes in E. C. Gs., taken repeatedly, had often misguided me into withdrawing emetine prematurely. Therefore, now-adays, only if the pulse and blood pressure (which are closely monitored) show abnormalities, out of proportion to the height of fever or the severity of pain do I ask for a repeat E.C.G. Moreover looking out for features of congestive cardiac failure has helped me as much as monitoring the pulse and blood pressure.
I choose metronidazole or chloroquine as the second drug. The former is always preferred in patients having an associated diarrhoea or dysentery. Instead of the 'theoretical' dose of 200400 mg. thrice daily, I prefer a dose of 600 to 800 mg. three times a day for ten days with the intention of simultaneously eradicating a co-existing intestinal infection. The patient is forewarned that nausea might occur and he is advised that since effective drugs for this serious disease are very few, he should tolerate it. I hardly remember having had to omit metronidazole because of nausea alone.
I n patients without associated diarrhoea or dysentery, chloroquine is often substituted for metronidazole, in the dose of 300 mgm. (base) twice a day for 2 days followed by 150 mgm. twice a day for three weeks.
Ten days after the institution of the above therapy, (by the time metronidazole course is over) either di-iodohydroxyquinoline, 600 mg. three times daily for three weeks or diloxanide furoate-500 mg. thrice daily for ten days is invariably prescribed. If, the patient complains of flatulence, the latter drug is avoided as it increases the severity of such symptoms.

The evaluation of response
Every morning I enquire about the degree of relief from pain experienced during the past 24 hours in terms of "percentage". This, in my opinion, is the single most important parameter in the evaluation of response to the therapy. I would be satisfied if the pain is alleviated by 20-25% every day. In an average patient having an uncomplicated, moderate sized, deep seated amoebic liver abscess the relief obtained is around 90% within four to five days. It should be a matter of concern if improvement ceases at 50-60% and thereafter the condition remains steady.
Apart from this subjective evaluation, the less important objective criteria which may indicate the response to therapy are as follows:-

1. A decrease in intercostal or point tenderness. (I would avoid hasty aspiration in patients where, although pain responds according to my expectation, intercostal or point tenderness does not diminish proportionately).
2. A fall in temperature.
3. A good night's sleep and a better appetite.
4. If elevated initially, a fall in the white cell count or erythrocyte sedimentation rate and an improvement in the liver functions (if originally abnormal).

The evaluation of progress may be inaccurate if any of the following factors are taken into consideration:

1. Complaints of weakness-Often it increases and especially if the patient is receiving emetine.
2. Relief from diarrhoea or constipation-Diarrhoea may even increase.
3. Regression of liver enlargement-Much importance should not be given to this sign as dramatic reduction in size usually does not occur.
4. The size of the cold area on liver scan and the titre of a serological test (IHA) would very often misguide evaluation, since no dramatic changes occur immediately after therapy in these investigations.
5. The fall in the erythrocyte sedimentation rate, unless markedly elevated initially, may also cause confusion in the estimation of the progress.
6. Finally, as a slight fall in the blood pressure is quite common after a patient is confined to bed, this parameter should not cause undue concern to the physician in relation to emetine toxicity.

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