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Progress report

Hepatosplenic schistosomiasis: a clinicalreview

Hepatosplenic schistosomiasis refers to the major complication of chronicinfection with Schistosoma mansoni, S japonicum and S mekongi,schistosomal portal hypertension. Hepatosplenic schistosomiasis is usually,but not invariably, associated with enlargement of the liver and spleen, andreversible hepatosplenomegaly may occur in early infections not compli-cated by the development of portal hypertension. This paper broadlyexamines current knowledge concerning hepatosplenic schistosomiasis,emphasising clinical aspects. It draws on the author's experience in EastAfrica,1 and is concerned mainly with schistosomiasis mansoni. Infectionwith S japonicum and S mekongi, both restricted to parts of the Far East,are not specifically discussed. Clinical aspects of hepatosplenic schisto-somiasis cannot be considered distinct from the epidemiology, pathologyand pathogenesis of the condition, and these are briefly reviewed.

Epidemiology

It has been estimated that over 200 million people world wide harboursome form of schistosomal infection.2 Probably 100 million individualssuffer from schistosomiasis mansoni or ja onica, of whom several millionmust have hepatosplenic disease. Warren suggests that 60% of Africanslive in areas where transmission of schistosomiasis is possible, and that40% of such people are infected.The two major schistosome species affecting man in Africa are S

haematobium and S mansoni. Chronic infection with S haematobiumresults in a variety of genitourinary problems, but there is no evidence thatit causes liver disease. Infection with S intercalatum occurs particularly inCentral and West Africa.4 This species of schistosome is of relatively highinfectivity but low pathogenicity, although heavy infections have beenassociated with severe intestinal involvement and hepatosplenomegaly. Shaematobium and S intercalatum are not further considered.

Hepatosplenic schistosomiasis in Africa results from infection with Smansoni. According to a recent review,2 transmission of S mansoni doesnot occur in Tunisia, Algeria, Morocco, Mauritania, Guinea-Bissau,Niger, the Congo Republic (Brazzaville), Somalia, and Mauritius. It isprevalent throughout much of the rest of Africa, although its distributionvaries greatly within different regions, countries and even small districts.Such variations have a major impact on local patterns of disease, andproblems of clinical diagnosis and management must be related to someunderstanding of medical geography. In unselected patients seen inNairobi, hepatosplenic schistosomiasis was the cause of portal hyperten-sion in one third of 85 patients with documented oesophageal varices.

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Schistosomiasis mansoni is also endemic in certain parts of South America,especially Brazil, and in a few islands of the Caribbean.2

PathologyThe original description of clay pipestem fibrosis by Symmers5 is stillconsidered accurate, but the term cirrhosis is no longer used as nodularregeneration and diffuse distortion of hepatic lobular architecture are notfeatures of hepatosplenic schistosomiasis. The liver is enlarged, although itmay be of normal size or even small, and the surface in severe cases isirregular and bosselated. Sometimes the left lobe is disproportionatelyenlarged. Round or stellate white lesions are seen on the cut surface, theclay pipestem lesions described by Symmers, which result from massiveportal fibrosis.5On light microscopy, ova are seen in the portal and periportal regions,

initially surrounded by eosinophilic granulomata. The portal tracts showvarying amounts of fibrosis and generally contain an inflammatoryinfiltrate which often includes eosinophils. Schistosomal pigment may bepresent, resembling malarial haemozoin. The presence of pigment in theliver biopsy of an individual expected to have attained relative immunity tomalaria should always raise the possibility of S mansoni infection. The liverparenchyma is normal and lobular architecture is essentially maintained.A variety of subtle changes are frequently seen in tropical liver biopsies

which in temperate areas would be considered abnormal. These includeportal inflammation, mild stellate fibrosis emanating from the portal tracts,Kupffer cell hyperplasia and variation in the size and number of nuclei inparenchymal cells ('parenchymal cell unrest').6 These non-specific changesfrequently accompany the pathological appearances of hepatosplenicschistosomiasis described above.A study of vinylite casts of the intrahepatic vessels of cadavers with

hepatosplenic schistosomiasis showed extensive destruction and distortionof small portal branches.7 Such lesions were especially marked in theperiphery of the liver, and corresponding histological sections oftenshowed occluded or apparently absent portal vein radicles. Arterialbranches were increased in size and number, explaining the normal hepaticblood flow maintained in the majority of patients with hepatosplenicschistosomiasis.The pathology of hepatosvlenic schistosomiasis has been well reviewed

by Cheever and Andrade, Warren,9 McCully et al,'0 Edington andGilles, 1I and Edington. 12

Pathogenesis and relation to intensity of infection

There is agreement that obstruction to portal blood flow probably occurs atthe level of smaller portal tracts, and that the macroscopic clay pipestemlesions are not themselves the cause of portal hypertension.71314Controversy surrounds the role of granulomata in causing chronic portalfibrosis. Warren'5 firmly associates granulomatous reaction to eggs withthe development of fibrosis and subsequent portal hypertension. Evidenceagainst this are the observations that broad fibrosis may be seen distantfrom any granuloma,16 that in the absence of Symmer's fibrosis ova do notalways accumulate in portal areas even in heavily infected cases,3 and that

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in experimentally infected chimpanzees fibrosis preceded egg deposition inthe portal tracts. 17 A further interesting observation is that excess collagenmay be deposited independent of any granuloma in the space of Disse,producing fibrosis at the level of the sinusoids.'8

Genetic factors probably predispose certain individuals to developinghepatosplenic schistosomiasis. In Brazil, hepatosplenic schistosomiasis wasfound more frequently in whites than in blacks with similar levels ofinfection,'9 and was also shown to be more common in patients of bloodgroup A.20 A report from Egypt associated histocompatibility antigens(HLA) Al and Bs with a greater likelihood of developing hepatosplenic

21schistosomiasis.2Intensity of infection appears to be the main variable determining the

development of hepatosplenic schistosomiasis. Pathological studies inBrazil" and Egypt3 showed that hepatosplenic schistosomiasis was presentin patients with the heaviest worm loads. Epidemiological surveys inBrazil23 24 and St Lucia25 support this relationship between intensity ofinfection and clinical manifestations. In Kenya,26 in an essentially non-malarious village in Machakos District, prevalence and intensity ofinfection were high and intensity correlated with hepato- and spleno-megaly. In a similar study on the malarious shores of Lake Victoria,27however, where rates and levels of schistosomal infection were lower, aninverse relationship existed between infection intensity and splenomegaly.In another malarious area, the West Nile region of Uganda, 8 prevalenceand intensity of infection were high, and splenomegaly was common but notrelated to egg output. It was suggested in these latter studies thatsimultaneous stable malaria, itself associated with a high frequency ofsplenomegaly, might mask hepatosplenic schistosomiasis or depress thehost response to schistosomal infection. The weakness of such epidemio-logical studies is that they assume that hepatosplenomegaly is schistosomalin origin, when in fact hepatosplenic schistosomiasis can only be diagnosedwith certainty after detailed investigation.

It seems reasonable to conclude that frequency and severity of diseasecorrelate with prevalence and intensity of infection, but all such general-isations apply to groups rather than to individuals, and other factors mayplay a significant role.

Clinical features

Hepatosplenic schistosomiasis affects both sexes and all age groups,including children. Patients are often young and usually look well, mostfrequently seeking medical attention for discomfort from splenomegaly orafter an episode of upper gastrointestinal bleeding. Previous symptoms ofintestinal schistosomiasis are often lacking, and in Nairobi' less than onethird of patients with histologically diagnosed hepatosplenic schisto-somiasis gave a previous history of dysentery.

Splenomegaly in schistosomiasis is congestive in nature, a consequenceof portal hypertension, but also results from reticulo-endothelial hyper-plasia.29 Not every patient with schistosomal splenomegaly has establishedportal hypertension, and enlargement of the spleen is a well recognisedfeature of acute schistosomiasis ('Katayama fever').30 In Nairobi,' oeso-phageal varices could be demonstrated in 12 of 22 patients presenting with

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chronic splenomegaly in whom liver biopsy showed significant schisto-somal involvement and no other pathology. These two groups of patientswith schistosomal splenomegaly did not differ in any other obvious way.The rest of this discussion concerns patients with established schistosomalportal hypertension.

In uncomplicated cases of hepatosplenic schistosomiasis features of livercell failure are rare, so that stigmata of chronic liver disease usuallyassociated with cirrhosis are lacking. Gynaecomastia, spider naevi, andpalmar erythema (difficult, anyway, to see on black skin), jaundice, alteredhair distribution, neuropsychiatric manifestations and a bleeding diathesisare not seen except in terminal disease.The spleen may be visibly enlarged and sometimes fills much of the

abdomen. It may result in 'hypersplenism' with pancytopaenia detectableon a peripheral blood smear, but this is rarely of clinical significance.Anaemia is unusual but may result from occult gastrointestinal blood loss.The shortened red cell survival associated with splenomegaly is generallyof minor importance. The spleen is firm and smooth to palpation, andwhen it is very large more than one notch may be evident. The liver is alsousually enlarged, although not to the same degree as the spleen, and isabnormally firm.

Portal hypertension in hepatosplenic schistosomiasis is presinusoidal intype,3' so that splenic pulp and portal vein pressures are raised whilewedged hepatic vein pressure is normal. Because liver function is wellmaintained, gastrointestinal bleeding is well tolerated in hepatosplenicschistosomiasis provided adequate resuscitative measures are instituted,unlike in cirrhosis where liver failure is often precipitated. The maindanger of variceal haemorrhage in hepatosplenic schistosomiasis isexsanguination, a real possibility when medical facilities are limited andaccess to hospital is difficult.

It remains uncertain what exactly causes oesophageal varices to bleed.Portal hypertension is considered present when the portal vein pressure israised to 5 mmHg above inferior vena caval pressure, when the intrasplenicpressure is above 15 mmHg or when the portal vein pressure measureddirectly at surgery is above 30 cmH20.32 While portal hypertension is aprerequisite for the development of a collateral circulation, in cirrhosis riskof bleeding cannot be directly correlated with exact portal vein pressure,although haemorrhage is unlikely in cases where the portal vein pressure isless than 10 mmHg above inferior venal caval pressure.33 Large varicesappear more likely to bleed than small ones, although above a criticaldiameter there is no relationship between bleeding risk and the size ofoesophageal varices.33 Whether such observations apply also to hepato-splenic schistosomiasis has not been studied.

In Nairobi,' 52% of patients with hepatosplenic schistosomiasis gave aprevious history of haematemesis or melaena. As with other forms ofpresinusoidal portal hypertension, ascites is most often absent although itsformation may be precipitated by gastrointestinal bleeding. Ascites wasseen in about one-third of our patients with hepatosplenic schistosomiasis.

Diagnosis

Diagnosis requires understanding of the various causes of the related but

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distinct clinical problems of chronic undiagnosed splenomegaly and portalhypertension in the tropics. The differential diagnosis of chronic spleno-megaly in Africa is wide.34 Individual cases may result from causescommon in industrialised, temperate areas, but the majority are related tothe tropical environment. Tropical splenomegaly syndrome ('hyper-reactive malarial splenomegaly'),1 35 schistosomiasis, visceral leishmaniasisand, more rarely, trypanosomiasis, are important causes resulting fromparasitic infections. Other conditions such as tuberculosis, brucellosis, andcertain haemoglobinopathies are seen world wide but occur morefrequently in tropical Africa. Non-schistosomal forms of portal hyper-tension such as cirrhosis and portal vein occlusion are also common, andidiopathic portal hypertension is probably more frequent than in thedeveloped world.1

Firm diagnosis requires proof of schistosomal infection, demonstrationof portal hypertension and determination of its cause. Infection may bediagnosed parasitologically or immunologically. Faecal examination is bestcarried out using a concentration method such as the Kato technique,36although in heavy infections ova may be readily detected in a single wetsmear. In light infections examination of snips of rectal mucosa taken witha curette through a proctoscope is more sensitive.36 Material thus obtainedis compressed between two glass slides and examined immediately underthe low power lens of a light microscope. Quantification of egg excretion isof interest but not clinically important in individual cases. Paradoxically,patients with advanced hepatosplenic schistosomiasis may have low faecalegg counts, the result of previous treatment, senescence of worms, and,perhaps, shunting of ova to the lungs via the collateral circulation.

Serodiagnostic techniques in schistosomiasis have been reviewed bySmithers and Doenhoff.37 The enzyme linked immunosorbent assay(ELISA) has been the most successful immunodiagnostic technique for Smansoni infection. While cheap, easy to do and highly sensitive, it lacksspecificity.39 Cross reaction with S haematobium infection occurs. Inaddition, in schistosomiasis, infection does not necessarily signify path-ology, and serology is incapable of distinguishing between simple infec-tions and hepatosplenic disease. In a study of splenomegaly and portalhypertension in Kenya, De Cock1 concluded that a negative ELISAreliably excluded hepatosplenic schistosomiasis but that a positive result inan endemic area gave no applicable diagnostic information. Serodiagnosismay become more specific in the future with the development of morehighly purified antigens.40

In patients with splenomegaly, diagnosis of portal hypertension can bemade by the radiological or endoscopic demonstration of oesophagealvarices. Barium swallow examinations are easy to carry out and interpretbut less sensitive than upper gastrointestinal endoscopy. This latterinvestigation may sound unrealistically sophisticated in developingcountries but is in fact easily applicable. In Kenya, Thomas et ap1 showedthat endoscopy was cheaper and more reliable than barium studies for thediagnosis of oesophageal varices. Other African centres have publishedtheir experience with endoscopy42 and the technique, within the com-petence of any specialist physician after suitable training, could havesignificant impact. The initial cost of the instruments and their main-tenance pose difficulty.

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Measurement of portal vein pressure is of little clinical value. Demon-stration that the portal vein is patent is required before the therapeuticcreation of a portacaval shunt, and excludes portal vein occlusion as thecause of oesophageal varices. Splenoportovenography is a simple tech-nique but may be complicated by haemorrhage. Superior mesentericangiography with study of the venous phase is safer but requiresangiographic facilities restricted to major referral centres. Ultrasound is anon-invasive technique that has recently been used to assess portalhypertension in hepatosplenic schistosomiasis. The investigation ofportal hypertension is covered in standard texts.32

Liver biopsy continues to play a central role in diagnosis. In endemicareas, the finding of ova in stool does not prove that portal hypertension isschistosomal in origin. Even liver biopsy may be misleading, becausegranulomata and haemozoin pigment may be frequent findings inapparently healthy individuals. Dusek et al44 have discussed difficulties ofhistological diagnosis of hepatosplenic schistosomiasis based on needlebiopsy of the liver. Certain diagnosis of hepatosplenic schistosomiasis,rather than of simple infection, depends on observation of significantportal fibrosis.

TREATMENT

Treatment is aimed at eradicating schistosomal infection and dealing withthe complications of portal hypertension. It is unlikely that establishedfibrosis can regress to any significant degree, but treatment of infection isimportant to prevent progression. As splenomegaly is not purely con-gestive, specific chemotherapy sometimes causes reduction in splenicenlargement.

SPECIFIC CHEMOTHERAPYThis has been reviewed recently by De Cock.45 The most familiar drugs arepraziquantel, oxamniquine, hycanthone and niridazole.

Praziquantel is effective against all major schistosome species and is welltolerated in advanced disease. Two oral doses of 25-30 mg/kg at an intervalof four hours are usually adequate treatment for S mansoni infection.Praziquantel damages the schistosome integument and interferes withinorganic ion transport and glucose metabolism. Side effects are rare andnot serious. They include skin rash, fever, pruritus, abdominal discomfort,nausea, headache, and dizziness. This drug is currently the treatment ofchoice for all forms of schistosomiasis.Oxamniquine is also well tolerated in advanced hepatosplenic schisto-

somiasis. The usual dose is 20 mg/kg/day orally for three consecutive days.The drug is effective only against S mansoni. Drowsiness, dizziness andheadache are the major adverse effects, and orange discolouration of theurine sometimes occurs. Its mode of action is unknown. Currently, the useof oxamniquine and praziquantel may be severely limited in thedeveloping world by their expense.Hycanthone should be avoided in hepatosplenic schistosomiasis or other

forms of liver disease because of occasional cases of fulminant hepaticfailure. Reports of mutagenicity also cause concern. Nevertheless, insimple infections the drug continues to be used with the approval of expertconsultative groups. Problems should be exceptional with a reduced

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dosage of 1*5 mg/kg body weight, given once only by intramuscularinjection.

Niridazole should no longer be used in view of its high frequency of sideeffects. Neuropsychiatric disturbances may occur when the unmetaboliseddrug reaches the brain, as in the presence of portasystemic collaterals.

MANAGEMENT OF PORTAL HYPERTENSIONTwo related problems require consideration, the management of acutevariceal haemorrhage and long term measures to prevent recurrentbleeding. Variceal haemorrhage has been the subject of a recentinternational symposium.46 The continued discussion about modalities oftreatment that have been in use for many years emphasises the therapeuticuncertainties that surround this field.

Patients should be managed at as intense a level of care as possible.Early efforts are directed at assessment of the patient, estimation of bloodvolume depletion and resuscitation. If possible, emergency endoscopyshould be done to determine that bleeding is variceal in origin. Blood istransfused as required to maintain cardiac output and a stable haematocrit.Vasopressin infusion acts to constrict splanchnic arterioles thus reducingportal blood flow. Its long acting analogue, glypressin, may be moreeffective.47 The simultaneous administration of nitroglycerin has recentlybeen shown to enhance the effects of vasopressin and to reduce is sideeffects.48 Oesophageal balloon tamponade using the Sengstaken-Blakemore tube or the Linton-Nachlas tube may give useful temporarycontrol of bleeding. This dramatic medical emergency can stretch theresources and skills of even the best equipped institutions, and mayoverwhelm available facilities in many endemic areas.Long term intervention to prevent further haemorrhage may be surgical,

endoscopic, or pharmacological. Portal decompression by the surgicalcreation of a portacaval shunt is effective in preventing further bleeding,but is complicated by a high rate of hepatic encephalopathy.49 This isdisappointing as well as somewhat difficult to explain in view of the wellmaintained liver function in most cases of hepatosplenic schistosomiasis. Itpresumably results from reduction in hepatic blood flow with deprivationof hepatotrophic factors contained in portal blood. Exhaustive review ofthe different procedures possible is beyond the scope of this paper, butRaia and colleagues50 51 have suggested that the distal splenorenal shunt,in which hepatic blood flow is better maintained, results in a lower rate ofencephalopathy. This procedure also lessens the risk of egg embolisation tothe lungs associated with the traditional portacaval shunt. Long termresults in cirrhosis have generally failed to show marked benefit fromchoosing the distal splenorenal rather than the traditional portacavalshunt. For the time being, therefore, it seems premature to unhesitatinglyrecommend this more difficult operation.Splenectomy alone does not affect portal hypertension, and even when

combined with gastro-oesophageal devascularisation is associated with ahigh rate of rebleeding. Oesophageal transection using a stapling gun52 is atemporising measure which is often followed by further bleeding whenvarices redevelop. It is, however, a simpler operation than a shunt and maybe life saving when medical treatment is failing in acute haemorrhage.

Endoscopic sclerotherapy is becoming the favoured treatment for

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oesophageal varices.5>56 Although technically difficult when bleeding isactive, sclerotherapy can stop acute haemorrhage and lower the incidenceof rebleeding, and in the long term it reduces bleeding risk and mayimprove survival. Most workers use a flexible endoscope, although manytechnical details remain controversial, such as the frequency of injections,the choice and volume of sclerosant and whether injections should be intra-or paravariceal. Any trained endoscopist should be able to learn thetechnique, and little equipment is needed over and above the endoscope,the light source and the needle for injection. Encouraging results havebeen published of two Egyptian controlled trials of sclerotherapy,57 58 inwhich a large number of patients with hepatosplenic schistosomiasis wereincluded, and one uncontrolled study.59 There is no role for prophylacticsurgery in the management of portal hypertension, but whether prophy-lactic sclerotherapy should ever be considered deserves further study.60

Great interest was stimulated by work from France6' showing that betaadrenergic blockade reduced portal pressure and the frequency of varicealhaemorrhage. The remarkable results with propranolol achieved byLebrec and colleagues6' have not been reproduced by others,62 but work inthis area continues. Patient selection may be one cause of discrepantresults. The French subjects were predominantly suffering from alcoholiccirrhosis and were in good condition. Beta blockade has not been formallystudied in hepatosplenic schistosomiasis. Because in this condition thevascular problem of portal hypertension can be examined distinct from theoften confusing issue of liver cell failure, hepatosplenic schistosomiasiswould be an ideal model in which to study this pharmacological approachto portal hypertension. For the time being, the use of beta adrenergicblockade for the prevention of variceal haemorrhage is best restricted tocontrolled clinical trials.

Complications and associations

DECOMPENSATED HEPATOSPLENIC SCHISTOSOMIASISEndstage hepatosplenic schistosomiasis may be complicated by features ofhepatocellular failure, ascites often being the most obvious clinical sign.While this may all result from severe schistosomiasis, the possibility ofother coexistent liver disease must be remembered. In Nairobi,' two of 25patients considered to have schistosomal portal hypertension also hadhistological evidence of cirrhosis. Areas endemic for schistosomiasis have ahigh prevalence of hepatitis B virus (HBV) infection. Work from Brazil63and from Egypt'" suggests that HBV infection may be more frequent inpatients with hepatosplenic schistosomiasis than in controls, and thatpatients with hepatosplenic schistosomiasis who have chronic HBV infectiondevelop more severe liver disease. Presumably their basic disease is madeworse, in addition to which they may develop chronic active hepatitis orcirrhosis. This possible association between HBV infection and hepato-splenic schistosomiasis deserves further attention.

RENAL INVOLVEMENT, SALMONELLOSISProteinuria has frequently been noted in hepatosplenic schistosomiasis,and nephropathy associated with hepatosplenic schistosomiasis has beenhistologically documented both in man and in experimental animals.65 66

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Although studies are few, clinically significant renal disease is probablyuncommon in hepatosplenic schistosomiasis.An association also exists between chronic salmonellosis and schisto-

somiasis.67 68 The bacteria may be harboured by the parasite itself,68 andantischistosomal chemotherapy may have to be given for antibiotics to beeffective in eradicating the bacterial infection. Salmonellosis seemsparticularly associated with cases of hepatosplenic schistosomiasis wherenephropathy is also present, and it is possible that the bacterial infectionalters the clinicopathological course of the renal lesions.

Conclusions

Although hepatosplenic schistosomiasis affects only a small proportion ofall those with schistosomal infection, study of the condition is appropriatebecause it is patients with hepatosplenic schistosomiasis who make thegreatest demands on medical facilities. As a disease of the liver,hepatosplenic schistosomiasis has been neglected by academic hepato-logists, although its study could increase understanding of many aspects ofliver disease. Portal hypertension, and recent non-surgical therapeuticapproaches, can be examined uncomplicated by liver cell failure. Thequestion of HBV infection in hepatosplenic schistosomiasis requiresclarification. Hepatosplenic schistosomiasis is of interest to clinicalimmunologists, and allows study of hepatic fibrogenesis.70 Not least, itdeserves attention because it is one of the world's most prevalent forms ofliver disease.The prognosis of the rural African patient with hepatosplenic schisto-

somiasis is uncertain. Variceal haemorrhage in a small Third Worldhospital is a formidable challenge. It is to be hoped that clinical research inthe management of these patients will be encouraged in tropical institu-tions.

This article was adapted from a background paper, 'Clinical features ofhepatosplenic schistosomiasis in Africa', prepared by request for theWHO Expert Committee on the Epidemiology and Control of Schisto-somiasis. I am grateful to Ruth Nao for secretarial help. Reprints will notbe available.

K M DE COCKUniversity of Southern California.Liver Unit,Rancho Los Amigos Hospital,7601 East Imperial Highway,Downey,California 90242, USA.

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