RECURRENT PYOGENIC CHOLANGITIS ARE WORMS THE CAUSE?

DR. LIM KEAN GHEE

Introduction
Recurrent Pyogenic Cholangitis, as its name suggests, is a chronic disease characterised by repeated suppurative infection of the biliary tract. It is also sometimes called Oriental cholangiohepatitis, Asiatic cholangiohepatitis, primary choledocholithiasis or just cholangiohepatitis. Patients characteristically have large friable brown calcium bilirubinate stones in both the extrahepatic and/or intrahepatitc bile ducts. The gallbladder usually does not have stones but the gallbladder may be distended and contain pus during an attack. E. coli cultures are obtainable from bile and portal venous blood in most instances. Recurrent cholangitis leads to biliary strictures and hepatic abscess formation, which has been said to be more common in the left lobe of the liver. In severe cases, multiple operations and even surgery to create percutaneous access to the biliary tree to clear intrahepatic stones may not succeed in removing all the stones packed in all the small ducts. Cirrhosis and hepatic abscesses may sometime necessitate liver transplant. There is also evidence that it may be linked to cholanglocarcinoma.

Questions about its aetiology
Many investigators expressed doubts about the aetiology of recurrent pyogenic cholangitis. The following are a sample:

"Although the exact pathology is unknown, infection of the biliary tract with enteric organisms in debilitated patients is regarded to be the primary event. Although parasitic infestation with Clonorchis sinensis and Ascaris lumbricoides is found in some patients, there is little evidence that these parasites play an important role in the development of recurrent pyogenic cholangitis although they may predispose to it." (1)

"The relation, if any, of the parasite to stone formation is the subject of dispute. Often, past or present helminthic infestation cannot be proven."(2)

"The precise etiology of Oriental cholangiohepatitis is uncertain. There is an association with parasitic infestation of the biliary tree; this however is not a uniform finding in Oriental cholangiohepatitis and such infestations are common in the endemic population." (3)

"Some investigators have described recurrent pyogenic cholangitis as being related to malnutrition, while others believe the cause is related to infestation with intrahepatic parasites." (4)

Reviewing the Evidence
Epidemiology
KH Digby who reported 8 cases from Hong Kong in the British Journal of Surgery in 1930(5) is generally recognised as the first to describe this disease in the medical literature. Cook(6) noted 30 cases a year in the Queen Mary Hospital, Hong Kong in a series from 1950 to 1952, and he coined the term 'recurrent pyogenic cholangitis' to describe this entity. Fung who used the term 'Oriental cholangiohepatitis' noted that it accounted for 58% of patients with biliary calculi in Hong Kong.(7) According to Stock and Fung(8) it was the third most common indication for emergency laparotomy, after appendicitis and perforated peptic ulcers, and the most frequent biliary disease in the 1960s in Hong Kong.

From China we have learned that this disease goes back in history to antiquity. Xiao Lu Jia reports that the examination of a female cadaver of the Western Han Dynasty excavated in 1972 in Changsha, Hunan, revealed the woman had suffered from primary intrahepatic stones before her death more than 2000 years ago(9). In a 44 year review of cases in the Sichuan Medical College Hospital from 1938 to 1981 Ran et. al. reported that they had 5,237 cases of inpatients with cholangitis and primary choledocholithiasis (119/year), compared to 2,945 cases of gallbladder stones and cholecystitis (10).

With modern day migration the condition has become known worldwide. Quite a number of cases have been reported from Western United States. Almost, but not all the patients, have been among South East Asian migrants. Stain et. al. noted 20 patients in a Los Angeles Hospital over 15 years from 1980 to 1994(4). Gott et. al. in Hawaii had 10 patients over an 8 year period from 1986 to 1994(8). Harris et al. had 45 patients over 12 years from 1984 to 1995 in San Francisco noting 28 were from China, 7 from the Philippines, 5 from Vietnam, 2 from Korea and one each from Burma, Cambodia and Laos(11). Case reports, for example, such as 3 patients in Leeds(12) and one in New Haven, Connecticut(13) among immigrants probably just reflect the smaller number of migrants from Southeast Asia in these areas.

Nevertheless, not all cases outside East Asia occur in migrant Orientals. Schulman reported a series of 40 patients over 8 years in South Africa(14). Khuroo et. al. In Srinagar, India who reported a total of 227 cases over 9 years up to 1991(15). Wilson et. al. in 1996 reported 4 cases
among Occidentals (Westerners) in Sydney Australia(16) showing that sporadic cases can probably occur anywhere.

In East Asia itself on the other hand, it has been reported that the incidence of Oriental cholangiohepatitis is declining in Taiwan and Hong Kong. (17,18)

Pathology
In Hong Kong, Fung(7) reported in 1961 that the histological findings found in Oriental cholangiohepatitis were similar to those found in clonorchiasis: namely ductal inflammation and fibrosis, and intraluminal conglomerations of desquamated ceils, worms, eggs and bile thrombi. He found evidence of Clonorchis infestation in 91% of his cases. These findings led to the parasite being implicated as the cause of the disease.

However, there was an epidemiologic fact that did not fit. The same disease was reported both in Taiwan and Japan where Clonorchis was not frequently found.

In 1962 Ong reported positive bacterial cultures from the portal vein in 39.5% of his patients with recurrent pyogenic cholangitis and suggested that it was an aetiologic factor. He also expressed doubts about Clonorchis being the cause as he found evidence of Clonorchis infestation in only 26% of 328 cases(19). He felt Clonorchis infestation may play a part in producing bile stasis but discounted their importance noting that Oriental cholangiohepatitis was not limited to areas with clonorchiasis.

But the strongest evidence Ong had to discount worms as the primary cause of the stones was that he could show experimentally in rabbits that stones in the bile ducts and gallbladder could be produced by merely constricting the common bile duct and then injecting E. coli into the portal vein.

With these findings it has been argued that chronic portal bacteremia, and portal phlebitis could antedate the biliary disease. In the presence of low glucaric, E. coli infection in the biliary system could cause the stones to form. With this seemingly complete chain of events, there did not seem to be any need to implicate any parasite in the genesis of such stones and some have argued the point.

Studying the pathogenesis of these calcium bilirubinate stones in 1966, Maki wrote that enteric bacteria such as E. coli, produce large amounts of the enzyme, beta glucuronidase which deconjugates bilirubin diglucuronide in the bile. The deconjugated bilirubin combines with calcium ions to form insoluble calcium bilirubinate(20).

Other Japanese investigators such as Matsushiro have suggested that a low protein diet could cause these stones(21). Their evidence was that in animal experiments, rats fed a low protein and low fat diet produced low levels of biliary glucaro 1:4 lactone (measured as its surrogate glucaric acid) a supposed inhibitor of beta glucuronidase as opposed to rats fed high protein high fat diets.

However, the year after Ong published his doubts on Clonorchis being the cause, Teoh(22) reported finding evidence of Ascaris as well in the large earthy stones. He found remnants or eggs of either A. lumbricoides or C. sinensis in stones of 24 out of 42 patients in Hong Kong with Oriental cholangiohepatitis and concluded that both were capable of initiating the disease.

From China we have a report that ascarid remains were found as the nuclei in 70-84% of the gallstones studied in Qingdao(23). Khuroo and Zargar in India also report Ascaris worm fragments as the nidus of the stones(13) and Schulman, in South Africa}(12) also found evidence of roundworms or their remnants in the biliary system, either separate from the stone or as part of the stone, on ultrasound, at surgery or duodenoscopy in many of their patients. Many investigators note that their patients with these stones came mainly from communities in which A. lumbricoides infestation was virtually universal at some stage of childhood and gave personal histories of having been infested. The average age of their patients was usually younger than that of patients with conventional gallstones and fit the fact Ascaris infestation is predominantly a childhood disease.

Furthermore, the investigators who present the most impressive evidence for E. coli infection and for a diet low in protein and fat having roles in the aetiology of Oriental cholangiohepatitis in Japan thought that A. lumbricoides had the dominant role there(21). Maki(20), who outlined the role of E. coli in the formation of calcium bilirubinate stones believed parasites were involved, citing evidence that eggs or fragments of cuticles of Ascaris lumbricoides was identified in 55% of pigmented calcium stones in Japan directly after the Second World War. He quoted Tung et. al. reporting finding roundworm elements forming the kernel of 70% of gallstones examined in Vietnam. Although others claimed that the E. coli may reach the liver through the portal vein, Maki believed that "ascending infection" was the more likely route. He also noted that gallstones produced experimentally, using roundworms, in animals were invariably calcium bilirubinate stones.

Discussion
On hindsight, the problem of explaining cases outside Hong Kong where Clonorchis was not so prevalent in the 1960s is resolved when we realise that Ascaris is also a culprit. It appears that the Clonorchis which inhabits the terminal biliary radicals might have a greater propensity to cause the condition than the Ascaris which is migratory, but because of its wider worldwide prevalence the Ascaris might in fact cause more of the disease overall. Other worms like Fasciolopsis do not appear to cause the disease.

Although I have pointed out that there has been a chorus of agnostics there has been perhaps an even louder chorus of proponents incriminating the worms and I can cite at least 13 papers here of that view and have encountered more (6,7,9,10,14,15,17,18,20,24)

The argument, that portal bacteremia is the initial event leaves many unanswered questions. What causes the portal bacteremia, not in experimental animals, but clinically in patients? Do all patients who have portal bacteremia get Oriental cholangiohepatitis? If not, what is the other crucial factor equivalent to the biliary strictures created in experimental animals? Are we not returning to worms? In that case worms migrating into the biliary tree would in the process bring along the enteric bacteria and ascending infection would be a more logical explanation than portal bacteremia.

The link with poor nutrition is also weak. In a 1990 report, Ho and Ho found no difference in biliary beta glucuronidase activity related to glucaric acid in human gallbladders and no difference in glucaric acid content between those with and those without gallstones(25).

Finally, the changing epidemiology of recurrent pyogenic cholangitis, fits with what we understand about the aetiological role of the parasites involved. Developed countries that have a low prevalence of helminthiasis rarely see the disease but almost all countries where the two worms are prevalent find the disease endemic. In line with a decline in the prevalence of these parasites in Taiwan and Hong Kong, it has been reported that the incidence of Oriental cholangiohepatitis is declining.

It would not be unexpected not to find Ascaris present in many cases as it is a migratory worm and may have left after depositing eggs or cuticles during its sorjourn in the biliary tract, it appears also that the stones that form in the biliary tract can remain asymptomatic or be clinically silent for many years and appear years after the individual is free of ascariasis. Harris noted that the mean duration of residence in the United States among their 45 patients presenting with recurrent pyogenic cholangitis was 6.5 years, "suggesting that subsequent habitation in the United
States has little effect on previously acquired risk factors for development of the disease."(11) This probably accounts for the situation in Japan where the disease was still seen in the 1960-70s whereas parasites were virtually eradicated there in the 1950s - a fact which again might have caused several leading medical scientists to doubt the link of Oriental cholangiohepatitis with parasites.

In summary then, I would argue that poor nutrition, portal bacterimia and other factors may be present incidentally or have a minor role but that they are secondary. Like H. pylori is to peptic ulcer disease - ascariasis and clonorchiasis may be to Oriental cholangiohepatitis. Perhaps careful electron microscopy or DNA analysis of the calcium bilirubinate stones might give us the final proof.

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