Fascioliasis

Etiology

Adult Fasciola hepatica flukes grow to become spiny-appearing, brown leaf-shaped, flatworms, typically around 30 mm by 15 mm in size and easily seen with the naked eye. Anteriorly, they have 2 suckers, a large one on the ventral side referred to as the acetabulum that allows the fluke to suction itself to the wall of the bile duct and remain in place so the smaller more anterior sucker may feed on the bile.[2] As their name implies, Fasciola gigantica flatworms can grow up to 75 mm in length but are otherwise similar in appearance to their smaller counterparts.[3][4]

Regardless of whether the host is bovine or human, the life cycle remains the same. Adult liver flukes release un-embryonated eggs into their host’s bile ducts which then pass into their stools. The host defecates in the environment near or within a pond or stream. Eggs become embryonated when they reach a water source and hatch into free-swimming miracidia that seek out an intermediate host, one of several species of amphibious snail. The miracidium will bore itself directly into the tissues of the snail. Once inside, miracidia go through several metamorphoses first becoming sporocysts that give rise to mother rediae which in turn produce daughter rediae. Germ balls develop inside the daughter rediae that become cercariae which will grow and bore back out of the snail to again become free-swimming in the environment. They go on to encyst as metacercariae on aquatic vegetation and are eaten by their definitive host.[5]

The flatworms most commonly cause infection in humans when they eat vegetation contaminated with metacercariae, for example, watercress. Metacercariae excyst in the duodenum, as they do in the snail, and penetrate through the intestinal wall into the peritoneum. From there, they migrate cephalad, boring through the parenchyma of the liver before finally settling in the biliary ducts. In 3 to 4 months they develop into adults, occupying the large biliary ducts primarily and laying more than 20,000 eggs per day. Adults can live up to 13 years in a human host if untreated.[2]

The migrating metacercariae cause parenchymal liver damage, setting off a cascade of inflammatory and immune responses leading to a constellation of acute symptoms. Adult flukes may partially or completely obstruct the bile ducts, over time causing fibrosis, hypertrophy, and later dilation of the proximal biliary tree. Parasite load is typically positively correlated with the degree of liver damage.[1]

Epidemiology

The global prevalence of Fasciola infection is estimated between 2.4 and 17 million and is typically under-reported and under-diagnosed. In the United States, sporadic cases are seen mainly in travelers and immigrants. Disease in cattle and livestock is more prevalent in the United States and varies in geographical location.[6][7] Fasciola hepatica is endemic to Europe and Asia, occasionally seen in Northern Africa, Central and South America, and the Middle East, and sporadic cases rarely pop in the United States and the Caribbean.[8] Fasciola gigantica infects domestic livestock across Asia, the Pacific Islands, and some parts of Northern Africa.[3] In parts of Africa and Asia, the 2 species overlap, and their clinical presentations are indistinguishable. Cattle and sheep are the most common definitive hosts, but the flatworms often infect several other grazing animals in the wild. Humans who live in regions where cattle and sheep industries are prominent and who consume raw aquatic vegetation, watercress, in particular, are at the highest risk of contracting the parasite.[1]

History and Physical

There are 2 distinct phases of the fascioliasis infection.

The acute (hepatic) phase usually begins 6 to 12 weeks after ingestion of metacercariae from a contaminated water source. The first sign is usually very high fever, followed by right upper quadrant pain, hepatomegaly, and occasionally jaundice. A complete blood count (CBC) differential will show a marked peripheral eosinophilia. Patients often present with associated myalgias, urticarial rash, nausea, anorexia, and diarrhea. These symptoms are attributed to the Fasciola flatworms migrating through the liver parenchyma and setting off the inflammatory and immune responses along the way. Additional laboratory diagnostic clues include transaminitis, anemia, elevated erythrocyte sedimentation rate (ESR), and hypergammaglobulinemia. Early complications are rare but may be seen with high parasite load and include ascites, hemobilia, subcapsular hematomas, and rarely severe parenchymal liver necrosis. However, in most cases, acute symptoms generally resolve within 6 weeks, and the infection settles into the chronic phase.[1]

Early extrahepatic manifestations are typically type III (immune complex deposition) or type IV (IgE) hypersensitivity-mediated. A reactive eosinophilic pneumonitis is nonspecific for helminth infections and is well described in the literature.[9] Overwhelming activation of the host’s immune system and inflammatory response can cause vasculitis. In the heart, this can lead to myocarditis which in turn can cause cardiac conduction abnormalities. In the brain, cerebral vasculitis may lead to focal neurologic deficits or seizures but these are all highly uncommon. Generalized lymphadenopathy is often present.[1]

The chronic (biliary) phase usually begins about 6 months after acute infection once the flukes have settled into the bile ducts and may last up to a decade or more. This phase is usually asymptomatic but occasionally can present as chronic epigastric and right upper quadrant pain, nausea, vomiting, diarrhea, hepatomegaly, jaundice, and failure to thrive. Peripheral eosinophilia will not likely be present. Chronic common bile duct obstructions may develop and lead to recurrent jaundice, cholelithiasis, pancreatitis, and more seriously, ascending cholangitis. Prolonged infection and/or high parasite load leads to chronic hepatobiliary damage and can result in chronic biliary cirrhosis, sclerosing cholangitis, and even cholangiocarcinoma.[1][10][11]

Fasciola’s migration out of the intestine and up into the liver is not always perfect; sometimes they get lost. Ectopic fascioliasis is the term given to the infection occurring outside the hepatobiliary system. They may end up almost anywhere in the body. Their presence results in localized mononuclear, eosinophilic infiltration that causes secondary tissue damage from the host’s immune response. Frequently, when they get lost, they end up in the subcutaneous tissue of the abdominal wall, but they may also end up in the peritoneum, intestinal wall, lungs, heart, brain, muscles, or eyes. Traveling flatworms under the skin or fat tissue leave behind migrating, pruritic, erythematous, painful nodules 1 cm to 6 cm in diameter and may be seen or palpated. Occasionally nodules can become infected and turn into a local abscess.[1][12][13][14][15] Another rare form of ectopic fascioliasis is Halzoun syndrome or pharyngeal fascioliasis. It is sometimes seen in the Middle East in areas where people eat raw liver. In this case, the metacercariae or young adult flukes living in the ingested liver attach themselves to the mucosa of the upper respiratory or digestive tract causing pharyngitis or esophagitis. Rarely edema and swelling of the upper airway can be so severe that patients have asphyxiated.[16]

Evaluation

Fascioliasis is exceedingly rare in the United States, but should be on the differential for any patient with the combination of abdominal pain (especially right upper quadrant), transaminitis, and marked peripheral eosinophilia. Even more suspicion should arise if a patient has traveled to endemic areas of Europe, Asia, or the Pacific, and their dietary history includes watercress ingestion or consumption of raw vegetables washed in potentially contaminated water. Often there is a delay in the diagnosis of this disease even in endemics areas due to its rarity and nonspecific acute symptoms.[2][17]

Serology has become the fastest and most efficient way to test for fascioliasis in recent years. Titers against Fasciola antigens become positive during the early phase of parasite migration and are detectable for 2 to 4 weeks following initial exposure to the host’s immune system. Enzyme-linked immunosorbent assay (ELISA) techniques have largely replaced stool ova and parasite testing because of its fast turn-around, sensitivity, and quantification.[18][19] Serum Fasciola antigen levels often positively correlate with the degree of infection.[20] It also takes 5 to 7 weeks after the initial infection before adult worms are mature enough to produce eggs; thus, there are no eggs in stool during the acute phase of the infection. Antigen levels positively correlate with the infectious burden. Successful treatment and extermination of the parasites correlate with a decline in the ELISA titers to Fasciola antigens. Antibodies may still be detectable at low levels for years. The assay becomes undetectable in approximately 65% of patients one month following successful treatment. Some patients will have a low positive titer for life without any evidence of active infection.[21][22]

Microscopic examination of stool or duodenal bile aspirates for eggs is still useful for detecting chronic infections in rural or third-world settings where resources can be scarce. They are also sometimes found incidentally while working up biliary obstructions. Fasciola hepatica eggs are yellow-brown and ovoid measuring 130 to 150 micrometers long by 60 to 90 micrometers wide. A single adult fluke can release over 20,000 eggs per day, but that release is intermittent. Thus, an examination of multiple stool or duodenal aspirate specimens may be needed as one negative examination does not necessarily exclude the diagnosis.[23]

Rarely, one might also identify adult flukes in the biliary tree during endoscopic retrograde cholangiopancreatography (ERCP) during assessment in a patient with biliary obstruction. Occasionally capsular liver nodules can be seen by a surgeon during a diagnostic laparoscopy, but with no further clinical history are nonspecific. Liver biopsy is not routinely warranted as serology is much more specific, sensitive, and cost-effective.[24]

Computerized tomography (CT) scan may show multiple, nodular, small (approximately 25 mm in diameter), branching, subcapsular lesions in the parenchyma of the liver. These tortuous tracks are left behind by the migrating parasites. Necrotic areas may be seen on scans utilizing intravenous (IV) contrast.[24][25][26] Subcapsular hematoma, capsular thickening, or parenchymal calcifications can also be seen.[27]

Ultrasound, cholangiogram, and ERCP are helpful during the biliary stage and may show the mobile, leaf-like flukes in biliary ducts or gallbladder, and are often associated with stones. Irregular common bile duct wall thickening, hepatomegaly, splenomegaly, and/or periportal lymphadenopathy are often present, especially in the acute phase.[24]

Treatment / Management

The treatment of choice is oral triclabendazole 10 mg/kg daily taken after a meal for 2 days. Triclabendazole is an imidazole derivative and works by preventing the polymerization of tubulin into microtubules rendering cells incapable of producing their cytoskeletal structures. It is effective against all stages of fascioliasis with a cure rate of over 90%.[28][29] Fasciola species do not respond well to ivermectin, praziquantel, artesunate, mebendazole, or albendazole.[30] When a patient is diagnosed with fascioliasis, other family or house members should be tested for serum fasciola antigens. Treatment is warranted when a patient tests positive, regardless of if they are symptomatic or not to avoid the risk of future complications.(B3)

Differential Diagnosis

Acute hepatitis, autoimmune hepatitis, and shock liver will all have very significantly elevated transaminases, typically in the thousands. This is much high than the levels seen in fascioliasis which are usually in the hundreds. Toxocariasis, acute schistosomiasis, ascariasis, and strongyloidiasis, are all nearly indistinguishable from fascioliasis in the acute phase, especially in the presence of peripheral eosinophilia and pulmonary symptoms. Serologic testing is required to rule these out.

Prognosis

Once the diagnosis of fascioliasis is made, the prognosis is excellent. Triclabendazole is effective against all stages of fascioliasis with a cure rate of over 90%.[28][29]

Complications

Chronic infections can be complicated by ascending cholangitis which requires IV antibiotics and usually surgery. Biliary obstruction by parasites in the setting of ascending cholangitis requires emergency endoscopic retrograde cholangiopancreatography (ERCP) for the direct removal of the worms from the common bile duct if possible. Chronic infections lead to chronic biliary inflammation and destruction giving rise to sclerosing cholangitis, biliary cirrhosis, and cholangiocarcinoma.[5][10][11]