Hepatology Research 12 (1998) 169–176

Idiopathic portal hypertension: an overlookedentity

Huma Qureshi a,*, S.J. Zuberi a, Mumtaz Maher b,Waqaruddin Ahmed a, Syed Ejaz Alam a, N.A. Jafarey c

a PMRC Research Centre, Jinnah Postgraduate Medical Centre, Karachi, Pakistanb Department of Surgery, Unit II, Jinnah Postgraduate Medical Centre, Karachi, Pakistan

c Department of Pathology, BMSI, Jinnah Postgraduate Medical Centre, Karachi, Pakistan

Received 9 February 1998; received in revised form 6 May 1998; accepted 14 May 1998

Abstract

Following the criteria laid down by the Japanese Committee on Idiopathic PortalHypertension (IPH), 89 cases of IPH were diagnosed. Though not confirmed, infectionsappeared to play some role in its etiology. Major presenting features were haematemesis andanaemia; one third of cases had haemoglobin of less than 7 g/l; hypersplenism was presentin 14%. Liver function test were within normal range in the majority of the cases. Long termcontrol of rebleeding was achieved satisfactorily with oral propranolol. Of the shuntingprocedures, proximal splenorenal shunt showed better results. It is concluded that IPH canbe managed well with good long term survival. The diagnosis of IPH as the cause of portalhypertension assures an optimistic prognosis. © 1998 Elsevier Science Ireland Ltd. All rightsreserved.

Keywords: Idiopathic portal hypertension; Etiology; Infection; Splenorenal shunt

* Corresponding author.

1386-6346/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved.

PII S1386-6346(98)00052-7

H. Qureshi et al. / Hepatology Research 12 (1998) 169–176170

1. Introduction

In 1889, Banti from Italy reported cases of portal hypertension without cirrho-sis [1]. Later similar findings were reported from India [2]. This entity waslabelled as hepatoportal sclerosis because most of the cases had sclerosis andthickening of portal vein and its branches [3,4]. Boyer et al. [5] reported portalhypertension without cirrhosis from Calcutta and called it as non-cirrhotic portalfibrosis (NCPF) and Basu et al. [6] confirmed this on histology. Okuda et al. [7]from Japan also saw similar cases and called it idiopathic portal hypertension(IPH). In 1981, diagnostic criteria for IPH were laid down by the JapaneseCommittee of IPH [8] which included, (a) demonstration of oesophageal varices,(b) normal to near normal liver function tests (LFTs), (c) reduction in theformed elements of blood, (d) liver scan not typical of cirrhosis and decreasedbone marrow uptake of the isotope, (e) uneven non-cirrhotic liver surface withportal fibrosis on histology, (f) no diffuse nodule formation, and (g) patentportal vein and extra hepatic portal vein branches with raised hepatic vein wedgepressure.

Various etiological agents, like chronic arsenic ingestion [9], intake of indige-nous drugs, food adulterants, herbal and fungal toxins, parasitic and bacterialinfections, have been incriminated in its etiology. Umbilical vein sepsis in infancyresults in ascending infection into the portal system, resulting in portal bacter-aemia and inflammation in the portal vein [5,10,11]. Experimental studies wereconducted to prove this hypothesis and non-pathogenic E. coli were injected inthe portal vein of rabbits; and changes in the liver were observed a few dayslater which were similar to IPH [12]. Similar experiment has been reproduced onguinea pigs in Karachi using Shigella and Salmonella pathogens [13]. AsSalmonella is endemic, and Shigella epidemic in Pakistan, therefore it appearsumbilical vein sepsis and repeated intra abdominal infections with Salmonella,Shigella and other pathogens might be one of the etiological agents for IPH inPakistan.

As the liver functions tests in IPH are almost normal or marginally deranged,therefore most of these patients survive well once bleeding from varices is con-trolled [5,10,14,15]. Death from decompensation, subacute bacterial peritonitis(SBP) and liver failure is rare. Determination of the cause of portal hypertensionis important because prognosis is good in IPH and variable in cirrhosis. In IPH,treatment options vary from beta-blockers [16,17] to sclerotherapy and or band-ing [18,19], to shunt. Of the beta-blockers, non-selective beta-blockers show abetter response in preventing a rebleed [20]. Generally, shunts are discouraged incirrhosis because of a high frequency of encephalopathy, but in IPH, a betterresponse has been found by Nundy and Tandon [21] with proximal splenorenalshunt.

The present study was done to determine the frequency, the most reliable testsfor its diagnosis, and the response to various treatment modalities in patientswith IPH.

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2. Patients and methods

Informed consent was obtained from each patient and the study protocolconformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflectedin a prior approval by the appropriate institutional review committee.

All patients with endoscopically proven esophageal varices were subjected to thefollowing investigations to determine its pathology, i.e. cirrhosis or idiopathicportal hypertension. The tests included CP, platelets, prothrombin time, liverfunction tests (LFTs) with proteins, ultrasonography of liver and spleen, measure-ment of portal venous diameters, associated ascites and gall stones. Endoscopy inall subjects was done in a fasting state using an Olympus XQ endoscope. The sizeand color of varices [22], associated gastric varices [23], portal hypertensive gas-tropathy and peptic ulcer were also noted. Liver biopsy was done from the standardsite using a Surecut modified menghini’s needle. Sections were stained with H&Eand reticulin stains to see distribution of fibrosis.

Hepatic vein free and wedged pressures were taken in a fasting state usingSeldinger’s technique and a Swan Genz catheter. In some patients, pressures wererepeated after sublingual administration of isosorbide dinitrate [24] to see itsefficacy in lowering portal pressures. Hepatic vein wedged pressure is often repre-sentative of portal pressure in cirrhosis, but is an under estimation of portalpressure in IPH [25].

Treatment for the prevention of a rebleed consisted of either using propranololtwice a day for long-term, or performing injection sclerotherapy using Cooksdisposable injector and absolute ethanol as a sclerosant [26]. Injection were mostlygiven intravariceally and were repeated every 15 days till complete eradication ofthe varices. Tc99 colloid dynamic and static scintigraphy of liver and spleen wasdone to differentiate cirrhosis from IPH. Patients were placed under gamma camerain a supine position with liver, spleen and heart lying in anterior image. Then, 4 mcof technicium was given intravenously (i.v.) as a bolus dose. Films were taken at0.5-s intervals for 240 s. An anterior and posterior image of the liver and spleen wastaken for the static image. Slope of the integral and ratio of the slope of the integralwere calculated to differentiate IPH from cirrhosis [27].

Patients were followed up to see the mortality and morbidity.

2.1. Statistical analysis

Data were analyzed with statistical package EPI-INFO Ver 5.0. Calculate meanfor continuous variable and percentages were calculate for qualitative variable.

3. Results

From 1987–1994, of 464 cases with endoscopically proven esophageal varicesseen at the research centre, 89 cases were diagnosed as IPH. There were 51 malesand 38 females whose ages ranged from 15 to 85 years (mean 33916). Sixty five

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(73%) cases were below 40 years of age. Main presenting symptom was haemateme-sis in 93 cases, of whom 27 cases presented with the first bleed and in 41 cases thiswas a recurrent bleed. Fifteen patients came without a present GI bleed but theyhad a past history of bleed and six patients had never bled. On examinationsplenomegaly was found in 74 cases only, and hepatomegaly in 19 cases. Only sevencases had pedal oedema and four had a history of bleeding from gums or nose orecchymosis (Table 1). Thirty one patients had a history of suffering from jaundicein the past. Four patients (5%) had a history of undergoing laparotomy for variousreasons and occurrence of malaria/typhoid could be confirmed in only threepatients (Table 1). Liver biopsy was done in 80 cases; of these 42 showedmicroscopic features of IPH, mostly comprising of sinusoidal dilatation andperiportal fibrosis with thickened intrahepatic portal vein branches. No significantchange was reported in 34 cases indicating the absence of cirrhosis. The tissue wasinadequate for diagnosis in four cases.

Endoscopy was done in 88 cases, in one case it was not done as the patient wasreferred after a shunt. Sixty six patients had grade II–III and 11 had bleedingvarices. Nineteen cases had associated portal hypertensive gastropathy simulatinggastritis, 16 had associated gastric varices on the lesser curve or fundus and sevenhad peptic ulcer (DU 5, GU 2). Ultrasonography showed normal echogenicity in 64cases, 76 had splenomegaly, 18 ascites, and 15 gall stones.

Tc99-labelled static and dynamic scintigraphy was done in 14 cases. Ratio of theslope of the integral was used to differentiate IPH from cirrhosis. In 11 cases, theratio was more than 1, suggesting the diagnosis of IPH, while in three it was lessthan 1 indicating cirrhosis.

Hepatic vein free and wedged pressures were done in ten cases. Mean free andwedged pressures were 9 and 15 mmHg (range 2917, and 9932 mmHg),

Table 1Epidemiology and clinical features of idiopathic portal hypertension

JapanIndiaPakistanParameters

89 75 612Number of casesFMSex preponderance M

33 33 36Mean age (years)5 13 20Past history of abdominal surgery (%)

776Recurrent diarrhoea (%) —a

UrbanRural/urban Urban—b

Clinical features93 52Haemetemesis 35

32Anaemia 749774Splenomegaly 100 76

Hepatomegaly 19 31 ——7Pedal oedema 9

4Bleeding diathesis — 6

a Diarrhoea due to various cause is endemic in Pakistan.b Not possible due to migrating patterns.

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respectively. Mean pressure gradient, i.e. wedged pressure minus the free pressurewas 7 mmHg (range 2915 mmHg).

Haematology included haemoglobin, total leucocyte count and platelet counts.Anaemia was found in 97% of cases; of these 32% cases had severe anaemia (Hbless than 7 g) and 14% had hypersplenism (TLCB4000, plateletsB50000). Liverbiochemistry showed a bilirubin of less than 2 mg in 97% cases, normal to nearnormal ALT (B50) in 77% and an over 3.5 g albumin in 73% cases suggesting wellpreserved liver functions.

Management was done in different phases. In the initial phase of the study whenpropranolol was not introduced as a portal pressure lowering drug and sclerother-apy were not available, 28 cases were managed conservatively using volumereplacement regimen. In the next phase, tablet propranolol 40 mg twice daily wasgiven to 20 patients once bleeding was controlled with conservative management. Inthe final stage sclerotherapy was done in 27 cases as an emergency or electivemeasure to control bleeding or prevent a rebleed. Rebleeding frequency was 43%,20% and 49% in the three groups. All rebleeds were treated with sclerotherapy tocontrol bleeding. Various shunting procedures like proximal splenorenal shunt (11cases), mesocaval shunt (three cases) were done in 15 cases. Of 11 cases withsplenorenal shunt, eight are alive and have completed 4 years follow-up, twoexpired due to causes unrelated to shunt (pneumonia/unknown) at 18 and 24months, and one is lost to follow-up. Of three mesocaval shunts, all expired withinthe immediate postoperative period due to GI bleeding. One case underwentportacaval shunt and expired within postoperative period due to GI bleeding. Thebest results were achieved with proximal splenorenal shunts showing a 4-yearsurvival of 73%.

Follow-up was available in 51 cases; of these 41 were alive and ten expired. Causeof death was massive exsanguinating GI bleed in most of the cases.

4. Discussion

Over 7 years, 89 cases of IPH were seen at this Centre. The actual frequency ofIPH is likely to be high, as all cases of portal hypertension admitted in the hosthospital are not seen at this Centre.

When the present data was compared with that of India [28] and Japan [29](Table 1), it was observed that in the Indo-Pakistan subcontinent IPH is predomi-nantly a male disease, while in Japan it was found more in females. Mean age in allthese studies was in the 30s, indicating that the younger age group is affected more.Involvement of younger age group also confirms the possibility of early exposure tothe etiological agent (infection, food contamination etc.). Past history of abdominalsurgery appears to play some role in the etiology of IPH in Japan, where 20% casesof IPH had abdominal surgery; similarly in India 13% had surgery. In Pakistansurgery does not seem to play a major role in the etiology of IPH as only 5% hadthis history in the past. Recurrent diarrhoea, typhoid and other intra-abdominalinfections cause portal pyaemia and ascending cholangitis and result in inflamma-

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tory reaction in the intra and extrahepatic portal vein branches, resulting inthickening and fibrosis/sclerosis of portal vein and its branches. This hypothesisappears to play a major role in the occurrence of IPH in Pakistan, because thehygienic and sanitary conditions in Pakistan are less than satisfactory and water-re-lated infections like diarrhoea, dysentery, typhoid and hepatitis A and E areendemic, and malaria is also rampant in Pakistan [30,31]. It was difficult to obtainthe actual history of dysentery, diarrhoea or malaria in our cases as this was acommon occurrence which was not worth noting in most of the cases. A 76%frequency of diarrhoea seen in the Indian series may be a representative figure forPakistan also. The disease affects the urban population. Urbanization, use of wellwater and contamination of edible material and exposure to carcinogens appears tobe the cause of disease in urban population. Frequent migration from rural tourban areas in Pakistan made documentation of rural/urban setting impossible.

When comparing the presenting features between the three countries (Table 1), itwas observed that haematemesis and anaemia were the major presenting features inthis study while splenomegaly and anaemia (hypersplenism) were the major findingsin India and Japan. The liver surface of IPH cases is uneven, knobbly, with anatrophic right lobe and enlarged left lobe; therefore, during laparotomy most ofthese cases are labelled as cirrhosis. A Wedge biopsy when taken shows fibrosis(normally found in the subcapsular area) misleading the diagnosis. A proper trucutbiopsy is therefore recommended in diagnosing this entity. Cirrhotic liver is fine tocoarsely nodular and firm to hard when felt.

Transient ascites is seen after a GI bleed in the majority of patients with portalhypertension following a bleed. This collection is often secondary to changes in theosmotic pressure and volume in the intravascular versus interstitial space. In IPH,the ascites resolve within few weeks either on its own or following a short course ofdiuretics. Discontinuation of diuretics in these subjects does not cause recollectionof the fluid. This is contrary to cirrhosis where discontinuation of diuretics resultsin recollection of fluid.

Though sclerotherapy is good in controlling the acute bleed and preventing arebleed, it requires expertise and is expensive. Generally, the patients default onceacute bleed has been controlled with sclerotherapy, and are seen again mostlyduring a rebleed or with symptoms of hypersplenism (anaemia, splenomegaly).Propranolol is cheap and easily available. Most patients comply to twice a daydosage and remain bleed free. Studies done by Lebrec and Nouel [16], Kiire [17]and this centre [26] showed excellent results with beta-blockers during a 2-yearfollow-up. Westaby et al. [21] used a selective beta-blocker, metoprolol and did notget the expected results, suggesting that non-selective beta-blockers are better thanselective beta-blockers in lowering portal pressures. Reduced levels of cate-cholamines are said to produce a better response in IPH [32]. A combination ofbanding and beta-blockers are likely to improve the morbidity/mortality in IPH,because banding is a relatively pain-free, complication-free procedure [19], and thenumber of session required to obliterate the varices are also less.

Splenorenal shunt is the treatment option for patients with hypersplenism orthose who are non-responders to beta-blockers or sclerotherapy.

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Idiopathic portal hypertension is not a diagnostic dilemma, but is often missed inPakistan because of lack of awareness about its presence. Once diagnosed, betterlong-term prognosis can be expected in most of the cases once portal hypertensionis controlled either medically or surgically.

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