Amebiasis: Causes, Symptoms, and Life Cycle

• Amebiasis results from infection by the intestinal protozoan Entamoeba histolytica.
• Clinical syndromes range from asymptomatic colonization to invasive amebiasis.
• Invasive amebiasis manifests as intestinal colitis or extraintestinal amebiasis, with liver abscesses more common than lung or brain involvement.

Life Cycle and Transmission

• E. histolytica spreads through ingesting viable cysts from contaminated water, food, or hands.
• Food-borne transmission is the most common, occurring via shedding cysts by food handlers or growing food with contaminated soil.
• Less common methods include oral-anal sex and direct rectal inoculation.
• Trophozoites are released from cysts in the small intestine, remaining harmlessly in the large bowel in most cases.
• Encystation occurs, and infectious cysts are shed in stool which can survive for weeks in moist environments.
• Trophozoites invade bowel mucosa, causing colitis, or enter the bloodstream.
• Trophozoites do not encyst in active dysentery patients, and hematophagous trophozoites are often in fresh stools.
• Trophozoites are rapidly killed by air or stomach acid and cannot transmit infection.

Epidemiology

• E. histolytica disproportionately impacts underdeveloped tropical regions due to inadequate sanitation and hygiene, often affecting children under 5.
• Regions with high prevalence include the Indian subcontinent, Africa, parts of East Asia (Thailand), and Central and South America (Mexico & Colombia).
• In 2016, amebiasis caused 26,748 deaths of all ages, including 4,567 children under 5 globally.
• In contrast, developed countries primarily see amebiasis in returning travelers, recent immigrants, MSM, military personnel, and institutional inmates.
• GeoSentinel Surveillance Network data (1997-2011) indicates E. histolytica is a common cause of diarrhea in long-term travelers exceeding six months.
• Amebiasis is emerging in developed countries like Japan, especially among HIV-positive patients and MSM.
• Globally, E. histolytica ranks as the second leading parasitic cause of death after malaria.
• Invasive colitis and liver abscesses are more frequent in men, linked to differences in complement-mediated killing and testosterone's effect on interferon y secretion.
• The clinical diversity of Entamoeba infections is due to differences between E. histolytica and E. dispar, with only E. histolytica being truly virulent.
• Most asymptomatic carriers, such as MSM and AIDS patients, harbor E. dispar, resulting in self-limited infections.
• New species of Entamoeba, E. moshkowskii and E. bangladeshi, have been identified and are microscopically identical to E. histolytica.

Pathogenesis and Pathology

• Trophozoites attach to colonic mucus and epithelial cells using Gal/GalNAc adherence lectin, releasing glycosidases and proteases, causing degradation of mucous polymers.
• Cysteine proteinases degrade collagen, elastin, IgA, IgG, and anaphylatoxins C3a and C5a.
• Mucosa damage occurs through contact-dependent (apoptosis, trogocytosis) and contact-independent cytotoxicity.
• Contact-independent cytotoxicity results from production of inflammatory mediators like prostaglandin E2, leading to increased ion permeability of intercellular tight junctions.
• E. histolytica resists reactive oxygen and nitrogen species via hydrogen peroxide-regulatory motif-binding protein overexpression.
• The thioredoxin-thioredoxin reductase system is essential due to the lack of glutathione and glutathione reductase.
• Metronidazole's antiparasitic effect is likely tied to inhibition of this antioxidant system.
• Auranofin, an approved rheumatoid arthritis drug, inhibits thioredoxin reductase and is effective in vitro and in vivo.
• Phagocytosis is a virulence factor, where trophozoites phagocytose intestinal bacteria for nutrients.
• Commensal bacteria like E. coli can reduce E. histolytica's virulence by decreasing Gal/GalNAc lectin expression.
• Enteropathogenic bacteria like E. coli and Shigella dysenteriae increase Gal/GalNAc lectin expression and E. histolytica cysteine protease activity.
• E. histolytica can alter gut microbiota, decreasing Bacteroides, Clostridium coccoides and leptum subgroups, Lactobacillus and Eubacterium, while increasing Bifidobacterium.
• High parasite burden early in life correlates with expansion of Prevotella copri in gut microbiota and presence of diarrhea.
• Cathelicidins, innate immunity peptides, are induced by intestinal invasion in mice.
• IgA is critical in acquired immunity, reducing new E. histolytica infection risk by 64% via intestinal response to Gal/GalNAc.
• Serum IgG antibody is not protective; higher titres are associated with longer duration of illness rather than decreased disease severity.
• Maternal parasite-specific IgA via breastfeeding results in 39% reduced infection risk and 64% reduced diarrheal disease risk from E. histolytica.
• MHC class II allele DQB1*0601 heterozygosity protects against amebic intestinal disease.
• Adipocyte leptin receptors (LEPRs) on intestinal epithelial cells prevent apoptosis, promote tissue repair, and may decrease neutrophil infiltration.
• Micro-ulcerations initially form on mucosa of the cecum, sigmoid colon, or rectum, releasing erythrocytes, inflammatory cells, and epithelial cells.
• Colonoscopies show small ulcers with raised edges and normal intervening mucosa.
• Submucosal extension under viable-appearing surface mucosa prompts classic flask-shaped ulcers containing trophozoites.
• Human intestinal infection has few inflammatory cells because trophozoites kill neutrophils.
• Treated ulcers typically heal with little or no scarring.
• Rarely, amebomas, or mass lesions, form in the bowel lumen, characterized by exuberant granulation tissue.
• Amebic liver abscesses are more common by ~10-12 times in men aged 30-60, a rate demonstrated by studies to modulate interferon y secretion by natural killer T cells.
• Liver abscesses are preceded by intestinal colonization, where blood vessels may be compromised by lysis and thrombus formation.
• Trophozoites resist complement-mediated lysis, and inoculation into the hamster portal system results in acute cellular infiltrate consisting predominantly of neutrophils before toxins released by neutrophils induce hepatocytes.
• The liver parenchyma is replaced by sterile granular necrotic material adjacent to thin capsulated congested tissues.

Clinical Syndromes

• Even in highly endemic regions, most patients pass asymptomatic cysts, usually harboring E. dispar.
• Symptomatic amebic colitis develops 2-6 weeks following cyst ingestion, progressing from mild lower abdominal distress and diarrhea to malaise, weight loss, and lower back pain.
• Patients with full-blown dysentery may pass 10-12 stools per day, consisting mainly of blood and mucus with little fecal material.
• Fewer than 40% of dysentery patients have fever, whereas heme-positive stools are present in the majority.
• Rare fulminant intestinal infection with severe abdominal suffering, elevated temperature, and diarrhea may occur in children or those having glucocorticoids, with a risk for toxic megacolon.
• An occasional patient may have an ameboma, which is easily confused with cancer during barium studies.
• Tropical environmental enteropathy is observed in tropical developing areas with endemic enteric infections, leading to gastrointestinal impairment causing malnutrition and stunted growth in children <2 years old.
• Symptomatic E. histolytica infections associated with significantly higher rates of malnourishment.
• Extraintestinal infection most often involves the liver, where most travelers having abscesses after leaving endemic areas do so within 5 months.
• Young patients with amebic liver abscesses are more likely vs. older patients to present in an acute phase (<10 days' duration) along with fever and right-upper-quadrant pain.
• Older patients from endemic areas are more likely to have a subacute course lasting >6 months, with weight loss and hepatomegaly.
• About a third of chronic presentation patients are febrile, such that the diagnosis may depend on suspected "fever of unknown origin".

Complications of Amebic Liver Abscess

• Pleuropulmonary involvement, reported in 20-30% of patients, is the most frequent complication of amebic liver abscess.
• A hepatobronchial fistula may cause cough productive of large amounts of necrotic material that may contain amebae.
• Abscesses might also rupture into the peritoneum or pericardium.
• Genitourinary tract may become involved by direct extension of amebiasis from the colon or by hematogenous spread of the infection.
• Cerebral involvement has been reported in fewer than 0.1% of patients.

Diagnostic Tests

• Stool examination, serologic tests, and noninvasive imaging are the most key in diagnostics. Positive fecal findings include heme, absent neutrophils, cysts, or trophozoites.
• The definite diagnosis of amebic colitis hinges on identifying hematophagous E. histolytica trophozoites in at least three fresh specimens examined via wet mount, iodine-stained concentrate, and trichrome-stained preparations.
• Cultures can be more sensitive but aren't readily available.
• If stool exams are unrevealing, sigmoidoscopy with ulcer edge biopsy might assist, albeit with fulminant colitis perforation risks.
• Diagnostic accuracy mandates experience since trophozoites might be confused with neutrophils, and E. hartmanni, E. coli, and Endolimax nana cysts require distinction vs E. histolytica.
• The microscopic diagnosis mandates detecting Entamoeba trophozoites that ingested erythrocytes to rule out E. dispar, E. moshkovskii, or E. bangladeshi.
• Enzyme immunoassay stool tests for E. histolytica Gal/GalNAc lectin and multiplex PCR panels are more sensitive and specific.
• Serology is an important addition for invasive amebiasis.
• Positive enzyme-linked immunosorbent and agar gel diffusion assays in >90% of colitis, ameboma, or liver abscess cases suggest active disease because serologic findings usually revert to negative within 6-12 months.
• Repeat negative serologic testing after 1 week in cases of suspected acute amebic liver abscess if initial results are negative.

Radiographic Studies

• Amebomas are usually identified first by barium enema, but biopsy is necessary for differentiation from carcinoma.
• Ultrasonography, CT, and MRI techniques can assess location due to round/oval hypoechoic cyst observation.
• More than 80% of patients having symptoms for >10 days have solitary abscesses of the right liver lobe.

Treatment

• Drugs used to treat intestinal disorders are classified according to the site of action.
• Luminal amebicides are nonabsorbed and reach high bowel concentrations, limiting to cysts as well as those near mucosal surface, including iodoquinol and paromomycin; tissue amebicides such as Metronidazole/Tinidazole for treating Colitis.
• Tinidazole has a greater potency and is versatile for long-term periods.
• Full therapy required, since Matronidazole does not eradicate cysts.
• Shorter Nitroimidazole also proven efficacy (tinidazole/ornidazole).
• A reduction of appropriate doses or durations of therapy promotes tolerance to infection from lower antibiotic properties and failure to heal.
• Metronidazole is the drug of choice for treating amebic liver disorders.
• Studies have demonstrated how nearly 72% individuals that do not have intestinal problems are exposed to E. Histolytica, which is essential to include in all treatment regimens.
• Longer treatments decrease severity rapidly.
• Indications for liver tapping due to Pyogenic reasons, those with multiple lesions, lack of swift healing times, and threat of rupturing lobe.
• Aspiration does not accelerate healing times.
• Surgery must handle bowel ruptures.
• Prevention focuses on ingestion of fecally introduced food and/or water.
• Avoid unpeeled fruits/vegetables.
• No effective prophylaxis exists.

Infection with Free-Living Amebae

• Involves multiple genera, but major human pathogens are Acanthamoeba, Naegleria, and Balamuthia.
• Acanthamoeba is also resistant to protozoa protections from heat shock proteins.
• Multiple studies also suggest water is the origin, but Naegleria's is soil.
• Naegleria contains fulminant CNS infections and Balamuthia contains granulomatous amebic.
• These pathogens include pseudomonas aeruginosa, non-tuberculosis mycobacterium, chlelona, and viruses.

Naegleria Infections

• In the US alone, 138+ cases were reported since 1962, spanning through 2015.
• Reported cases annually have remained roughly stable (0-8).
• Northernmost state cases came from Minnesota, Indiana, and Kansas during 2011-2012.
• 63%+ of samples have shown female presence, with a median age near 11.
• Occurrences happen when aspirations of water become contaminated with trophozites and cysts, plus olfactory neuroepithelium intrusion.
• Incubation spans from 2-15 days.
• A diagnostic PCR test is available through CDC.
• Number of antimicrobial agents, such as azoles, azithromycin, and rifampin, are given throughout samples.
• Miltefosine had been shown success, along with neurologic compilations.

Acanthamoeba infections

• Comes from immunosuppressed or debilitated patients.
• Typically can reach CNS through the primary focus in the skin, sinuses, and lungs.
• Biopsy specimens can test positive regarding protoplasm through non-nutrient agar.
• Includes Balamuthia Madillaris first found in California in 1986.
• Patients are often treated with macrocodes and sulfa-diazine.