Noncirrhotic portal hypertension—Historical perspectives bring clarity to the entity and its management

INTRODUCTION Portal hypertension (PHT) or, more precisely, portal venous hypertension is defined as a pathological increase in pressure in the veins that carry blood from the splanchnic organs (including the spleen) to the liver, which is intrinsically due to a rise in the usually modest (~5 mm Hg) pressure gradient between the portal venous inflow to the liver and the hepatic venous outflow into the inferior vena cava. Unlike the rise in portal venous pressure that results from a rise in systemic venous pressure, when there is no increase in the portal-to-hepatic venous gradient, PHT is almost always caused by increased hepatic resistance to portal venous inflow due to various hepatic and/or extrahepatic pathologic conditions. Occasionally, PHT occurs when portal venous inflow is hugely increased but hepatic resistance is normal, as is seen when there is a splenic arteriovenous fistula.1 However, in conditions not associated with cirrhosis or greatly increased portal inflow, the occurrence of PHT has been particularly perplexing.PHT in the absence of cirrhosis was recognized as an esoteric clinical entity just over a century ago and is generally referred to as noncirrhotic PHT or NCPH (noncirrhotic portal hypertension). This description refers to a heterogeneous assortment of disorders that primarily affect the hepatic vascular system and is classified anatomically based on the site of resistance to blood flow, namely prehepatic, hepatic (presinusoidal, sinusoidal, or postsinusoidal), and posthepatic types. However, like the spectrum of names used worldwide for this condition, various surprising causes for NCPH are still being unveiled. Insight into the somewhat bewildering world of NCPH started in the late 1800s with observations by the distinguished Florentine physician and pathologist Guido Banti (1852–1925),2,3 who was considered the pre-eminent Italian pathologist of the 19th century. Born in Tuscany in the lower Arno River Valley village of Montebicchieri, his medical studies started in Pisa yet he graduated in 1877 in Florence, where he later was appointed both Professor and Chief of the Medical Service and Professor of Pathology. As was not uncommon in that era in medicine, Banti could observe patients in their beds, and later study their corpses at autopsy. For Banti, clinical observation, anatomical evaluation, and laboratory study were 3 links in the same chain. THE EARLY YEARS: CLINICAL ASPECTS In 1886, Gretzl described cases of anemia associated with chronic splenomegaly, for which Griesinger coined the term “splenic anemia.”4 Guido Banti, while performing duties at the Institute of Pathological Anatomy in Florence in 1882, described in detail a series of patients who were characterized primarily by the enlargement of the spleen, leukopenia, and hypochromic anemia in the absence of hematological malignancies (Figure 1),2 which entity has since been known as Banti’s disease. More logically and in keeping with current usage,5 the name should not be a possessive eponym, since Banti neither possessed nor suffered from the disease. Detailed documentation of more patients with similar characteristics and lucid disease progression was later published in 1894, in Banti’s seminal work entitled La splenomegalia con cirrosi del del figato.3 These patients progressed through various clinical stages, distinguished by gastrointestinal bleeding, ascites, and, notably, terminal cirrhosis. However, the next obvious deduction was not made, namely that the cirrhotic liver must be responsible in some way for portal pressure elevation and its many consequences including splenomegaly. What followed instead was the classic error of confusing cause with effect, as he thought that the enlarged spleen was the cause and not the result of the portal pressure elevation. This conclusion was based on the faulty reasoning of the renowned Florentine physician and pathologist Guido Banti, who was somehow misled into reasoning that splenopathy of a toxic spleen (Banti’s disease) injures the liver and causes cirrhosis in a syndrome that he termed hepatosplenopathy, in which an unknown toxin or an infectious agent with a penchant for the spleen initially induces typical lesions, and then through the splenic vein and portal circulation traverses the liver and ultimately causes cirrhosis (Figure 2).6 This pathophysiological complex with the associated anatomicopathological construct represents the progression from Banti’s disease to Banti’s syndrome—suffering the same eponymous linguistic caveat as above and providing the following informative worthwhile literary diversion. For, according to his biographer, Bernard Glassman,7 the twice appointed (in 1868 and in 1874–1880) Tory (Conservative) British Prime Minister and favorite (“Dizzy”) of Queen Victoria, Benjamin Disraeli, 1st Earl of Beaconsfield, KG PC DL JP FRS (1804–1881), disliked definitions. Had Dizzy thrived until 1894 and beyond, he might have had a field day over the confusion wrought by Guido Banti concerning the definitions of the curious and rare entity that he described as both a disease2 and a syndrome.3 Banti’s erroneous hypothesis was not accepted by his colleagues in Europe, but was supported by US and UK colleagues,8 and for the longest while by none other than the most respected physician of the day in Britain and America, William Osler.9,10 Osler described Banti’s disease as “an intoxication of unknown nature characterized by great chronicity with preliminary progressive enlargement of the spleen which cannot be correlated with any known cause, anemia of secondary type with leukopenia, a marked tendency to haemorrhage from the lower esophagus, and a terminal state with cirrhosis of the liver.” Osler later withdrew his support from the notion that a primary splenic disorder causes PHT, but not before surgeons (from Harvey Cushing to William Mayo) removed the offending spleens with gusto, despite recurrent hemorrhage and late mortality.9FIGURE 1: Prof Guido Banti and his landmark work “Dell’ anemia splenica,” on Banti’s disease published in Florence, Italy, in 1883. (A) Book cover. (B) Guido Banti. (C) Frontispiece of the book. Panels (A) and (C) reprinted from Banti.2 Courtesy of Royal College of Physicians of London. Source for Panel (B): Wellcome Collection.FIGURE 2: From clockwise left, (A) Banti’s description and illustration of splenic pathology in Banti’s disease; (B) Operative wedge biopsy of spleen showing nodularity in the absence of fibrosis or cirrhosis; (C) Studies showing that NCPH differed extensively with respect to natural history when compared to cirrhosis with portal hypertension. Panel (A) reprinted from Banti.2 Courtesy of Royal College of Physicians of London. Panels (B) and (C) reprinted with permission from Zeegen et al.6.Banti also described the primary splenic pathology as fibroadenie or fibrosis affecting the Malpighian bodies, with initial destruction occurring around tufts of intrahepatic hepatic arterioles. An interesting therapeutic intervention later developed for reducing the splenic size and improving Banti’s disease was the “Ascoli Method,”11 which comprised injecting small aliquots of epinephrine hydrochloride (0.01 to 0.10 mg) intravenously on each of 20 successive days. That splenomegaly was a consequence of circulatory disturbance and may not be primarily a disease of the spleen was put forth by Dock and Warthin in 1904.12 Banti’s disease has had a long history of conflicts and controversies over its pathogenesis and classification, giving rise to many kind and unkind criticisms and publications spanning many pages. EARLY CLASSIFICATION SYSTEMS OF NCPH Cauchois in 1908 assuredly refuted Banti’s concept when he described a similar group of patients in whom the cause was identified as a portal or splenic vein thrombosis, thereby airing the initial descriptions of another etiology for NCPH, namely portal vein thrombosis, which he called extrahepatic portal vein obstruction or EHPVO.13 This was further consolidated by various investigators who described Banti’s disease complex in many patients with “pyelithrombotic phlebitis,” which led to the conclusion that splenic enlargement, subsequent hematological aberrations, and development of PHT were due to obstruction in the portal vasculature leading to “congestive splenomegaly” with greatly increased pressure in the splenic vein.14 Investigators found that clinical and histopathologic features described by Banti were also associated with various other disease conditions, some even in the absence of portal venous system obstruction.15,16 Thus, the term Banti’s disease was discarded and a more appreciable terminology, “Banti syndrome,” took its place.17,18 Initial descriptions and classification of NCPH—Banti’s syndrome—were mainly founded on the morphologic bases of splenic histology and segregated into fibrous/fibroadenic variants (Banti’s classification). This congestive type included chronic thrombotic occlusion of splenic or portal vein or that associated with cirrhosis,14,19,20 or a siderotic type (Gamna’s) of splenic disorder.14,19,20 Further classifications were based on the affected primary organ tissue, including Naegeli’s, McNee’s, and Michel-Minot’s descriptions featuring infections, granulomatous diseases, diseases affecting myeloid and lymphatic structures, reticuloendothelial system, vascular system, and various malignancies.15,21–24 The most acceptable classification of Bantian syndromes associated with portal hypertensive features was by Paul Klemperer in 1936.25 His detailed monograph describes splenomegaly due to a circulatory disturbance, which was essentially NCPH secondary to portal vein or splenic vein occlusion. The pathogenetic feature of “early fibrosis around the follicular artery,” also called fibroadenie by Guido Banti, was described as a characteristic of early splenic vein thrombosis, while the finding of “periarterial haemorrhage, which progresses to fibrosis in the vicinity of Malpighian corpuscle” was notable in chronic PVT. In advanced stages of the chronic portal vein and splenic vein thrombosis with cavernomatous transformation, advanced fibrosis of the splenic pulp was classically described.25 Nonetheless, the for splenomegaly of Banti’s syndrome in from in which the Banti’s disease as of known causes as and or toxic causes due to and and as that of congestive splenomegaly with or liver disease and or The group of patients in has to the NCPH that in his that of the of etiology with the of other while the of cases to is to and ultimately even in current the is still in patients known causes and associated with heterogeneous disease THE EARLY YEARS: in described in the spleen in patients with cirrhosis. splenic as pulp which with of the in fibrosis of the This was with Banti’s of of the in which the were and with secondary to primary liver disease and this was early of vascular around the or its by Banti and later by in their initial descriptions of there are in pathophysiological descriptions that must to a heterogeneous disease like NCPH from Guido Banti’s but confusing description that considered the spleen as the primary of However, other investigators started to a for the liver in disease pathogenesis the obvious that chronic liver disease was and that primary to cirrhosis which of the spleen, which progresses and to the development of PHT and associated features described by Banti. a systemic disease affecting the liver and spleen for was initially described in cases associated with or in whom chronic and Banti’s disease were thought to in the same as described in by at who was to study at by William to of However, subsequent descriptions of the which by then had been in of by and that characteristics of classic Banti’s disease with splenic and liver could be distinguished from Banti’s syndrome in more than in the absence of other and of systemic affecting the liver and including chronic and or were also as as Banti’s description of NCPH, which he could affect from to the The natural history of the disease and its progression was into 3 stages as described by initial with splenomegaly, and a distinguished by liver enlargement, of the and the with of the liver.” was due to or hepatic caused by the progressive hepatic and subsequent liver from the splenomegaly, the The associated with Banti’s disease were the spleen and liver, with almost in the splenic and portal The spleen was enlarged and than a with of the in the Malpighian and fibroadenie by Banti (Figure where the around the or its and the characteristic of the was The progressive of the in the into As early as the of the a chronic of the splenic and portal veins was Nonetheless, the fibroadenie of the pulp was found to be associated with other splenic Nonetheless, Banti’s descriptions of the spleen were further found to be associated with other conditions as liver in and thrombosis cirrhosis. and of cases by Banti could not any Thus, the and toxic nature and the splenic as of the disease that was by Banti were Banti’s disease a with heterogeneous but with a natural history and associated PHT features in the absence of showing the of in and The features and the Malpighian with permission from YEARS: CLINICAL ASPECTS In Banti’s was included patients with splenomegaly due to and patients in whom an etiology for splenomegaly and PHT could not be This group was later described by various in a of conditions, which to be known as but still the In described pathologic in portal veins to PHT and coined the term or splenomegaly in the absence of This was later by of the of the and in where he described a series of patients with splenomegaly of cirrhosis or portal vein from the that Banti’s disease was a secondary of any chronic splenic vein hypertension. Thus, the term “splenic in Banti’s disease was to be by “congestive to be in NCPH was the and in an but in who had his eponymous which an over the developed by in and in In the of that the intrahepatic was the site of the pathogenesis of PHT in description of syndrome of portal was the for and colleagues described many patients with the syndrome of splenomegaly with leukopenia, and associated with the development of increased circulation between the portal and venous In group described more cases following Banti’s disease natural history that the splenic vein pressure was over the venous pressure in with splenomegaly and PHT in the absence of liver disease. Thus, a Bantian syndrome that was to pathophysiological that affect obstruction to blood the portal into In investigators at the was in with the Medical published the of a with bleeding, in whom the found the of PHT, but and of the portal increased splenic pulp pressure, and hepatic vein wedge pressure in the of hepatic and for this coined the term PHT for Banti’s However, was not until to a of a century that in coined the term in the absence of for the of portal In from described a series of patients with PHT from cirrhosis. from in in a by the of Medical coined the term noncirrhotic portal fibrosis to patients with PHT cirrhosis or his in or until when the name was to the Professor of at similar patients and the term In the study by and coined the term portal of the liver for The and intrahepatic portal vein were characterized by The from and other referred to NCPH as THE YEARS: NCPH from the where was that NCPH was a PHT syndrome any of which and the described a of cirrhosis in which by were associated with PHT, and he called which some investigators as of cirrhosis and colleagues in the described the of PHT with of the liver, from an In transformation, the liver to the and transformation, in the absence of advanced from are with nodularity and fibrosis with or and colleagues in described the of PHT in patients with an entity that was described in by as and later for which Paul at the Institute for in the more Thus, NCPH was described as and in the while was known as portal and various other uncommon in the In the most cause of NCPH in the world is history of the of and of NCPH is in of of noncirrhotic portal hypertension into The in many studies have that conditions associated with NCPH, including clinical and some pathologic features the same This the that disorders a and are of a spectrum associated with a In this in and a which that a thrombotic occurring and the portal vein in In in the same was that the intrahepatic portal venous system led to in the in the Portal of the that in the of intrahepatic venous obstruction and increased splenic blood are in disease. The from that the vascular of portal into in vascular The between NCPH and in the and in the is that the was as a syndrome with PHT as the primary and not secondary to other of the of NCPH The various that result in NCPH, or are associated with to as fibrosis of intrahepatic portal of and infections, leading to portal and and causes with an and of of NCPH also from various liver or and of the liver with of which both intrahepatic resistance and portal pressure in the absence of cirrhosis and The fibrosis included the and and of a over in which intrahepatic portal fibrosis and The of PHT was portal vein or occlusion of the with and which was similar to Banti’s description of NCPH, with and the or of in the classic of NCPH was by and colleagues in by chronic of (in to In this in in the intrahepatic portal veins as early as at a The same group also that was in a of into the portal This a or the type of the by the splenic an hypothesis of which in splenomegaly and PHT and the of portal circulation in which portal due to the of into the portal system of the through an in a in portal pressure in the absence of hepatic on clinical and The NCPH differed from in many was in in from and between the and of while was in in the with with portal hypertensive of and the same patients with were more to with and the most in other variants of the of portal into various intrahepatic pressure were was that patients with had pressure between and intrahepatic and the between intrahepatic and hepatic venous which with hepatic The may be or in patients with NCPH, in a gradient despite as the was that for the of NCPH, the between the and hepatic venous was and mm wedge hepatic pressure may be normal, but portal vein be (Figure in the portal and splanchnic circulation in compared to patients with NCPH and portal noncirrhotic portal NCPH, noncirrhotic portal the other cause of is generally considered a disorder of chronic portal vein leading to PHT and the is a cause of PHT and gastrointestinal in in in to noncirrhotic the most cause of PHT in the is from PVT. The intrahepatic secondary to cirrhosis or by liver and not the of portal and the development of PHT, both of which are in In to of the cause of may and are seen in primary with or the are in The feature of a of the portal at the liver that may and the features in and in and is occurs in to of a with the of portal which is a associated with other of patients have pressure but and intrahepatic the of and NCPH and more and the initial disease natural history system by an on for NCPH in from et to this system for the disease through stages from absence of to which features the of thrombosis in intrahepatic or of the portal vein in and progressive liver In the for of the for the of which to splenomegaly, or of PHT, a system, liver or elevation in and the absence of cirrhosis on the of and with further and descriptions of portal hypertensive conditions not associated with NCPH was ultimately into namely affecting the liver at the sinusoidal, and noncirrhotic PHT was a put forth by et in which both clinical and of the disease. was defined as an increased portal venous pressure gradient with neither a known cause of liver disease nor PVT. The included any of the clinical of PHT or ascites, and increased of cirrhosis on liver of chronic liver disease NCPH as chronic and primary as as the absence of other causes of NCPH as liver or with portal and hepatic veins on These diseases were not classically included even feature NCPH due to their natural history that from the descriptions by Banti at the of the 19th and and were considered for NCPH that intrahepatic of small and portal venous leading to increased intrahepatic resistance to portal blood and PHT in the absence of In the of NCPH, patients with the same clinical and features but some may be PHT at the of patients with features but no clinical of PHT, a term vascular disease characterized by of the small of portal was from a to portal and and from a clinical of as or NCPH which was by the This classified patients into patients with chronic and of liver PHT and patients with PHT in the absence of defined by liver on which in patients with PHT may the of cirrhosis This description also included patients the disease developed chronic PVT. a and yet should also be in patients with or chronic of a study that the compared to the clinical of patients with was more associated with PHT, including the of and were associated with and the spectrum of early and late of and current over the of is that NCPH refers to a heterogeneous group of liver disorders that primarily affect the liver vascular system and are classified anatomically based on the site of resistance to blood flow, that as prehepatic, hepatic (presinusoidal, sinusoidal, or postsinusoidal), and of for and the of and used to NCPH has their and The term conditions associated with NCPH, which are characterized by of the small of portal veins from a of as portal portal and or from a clinical of as and Nonetheless, this classification variants but not the clinical of the spectrum associated with NCPH that in clinical and of in and study in NCPH is in of in and classification over the in NCPH, noncirrhotic portal PHT has seen of and of confusion since its description by Guido Banti at the of the 19th century. of NCPH and its into disease conditions that were later and further was of the work of and on this heterogeneous group of disorders for early and due to its for and still not for this but disease As The put in the of a rare disease in which the patients may the is to NCPH, from to and is still for to In keeping with other in this the who to to of his to the of his and in this is another of more than to ago at when was a of the and he was a in the late on for the and his typical The led to his to late and in his was in the his in to his the of a the of his on the to to his he a are not the Prof is the Professor of and of the Institute of and in which he was in the of the of is also the of the on and at and of the of Medical is with for liver diseases, bleeding, liver and liver has more than publications to his on liver diseases, and in various medical has 20 including in and has been the of the of for the of the and of the of the his many and he has been with a by the of which to the like is the of the of which is for of a of or not with to of a and that he was a of have had the of with a and in the of and at The in from his clinical and in liver disease and and including the he has been in as a and have the and of Portal have led through the of the reasoning over the of this most an to the of the and the in that of The of this disorder is a of a of in an the of and have from this as each each of the many for the same publications from the and to to caveat for of this