—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 2 - Vascular Abnormalities associated with Nodular Regenerative Hyperplasia, Suggestive of Hepatoportal Sclerosis

Dale C. Snover
Fairview Southdale Hospital
Minneapolis, MN


Click on each slide thumbnail image for an enlarged view
Clinical History
54 year old female who presented with mild transaminase elevations (approximately 2 – 3 times normal), and an alkaline phosphatase of approximately 2 times normal. The patient also had a low white blood cell count in the range of 3000/µl and macrocytic anemia with platelet counts that varied from low normal to low (lowest recorded being 139,000/µl). From time to time the albumin was low (lowest around 2.5 g/dl). Viral serologies were negative and at the time of biopsy that patient was not diabetic or overweight. Antimitochondrial, antismooth muscle and antinuclear antibodies were negative and her alpha-1-antitrypsin phenotype was PiMM. She was on multiple medications including nitrofurantoin, metoprolol, protonix, ciprofloxacin, amitriptyline, and others. She has had multiple surgical procedures including bilateral knee replacements and rib removals for thoracic outlet syndrome. The major clinical considerations based on this date were primary biliary cirrhosis or other biliary tract disease and a medication reaction. Subsequently to the initial review of this slide, it was discovered that the patient had a prior biopsy approximately one year earlier which had demonstrated steatosis with no evidence of the changes seen in the current biopsy. At that time she had undergone a gastric bypass procedure for obesity, hence her normal weight at the current time. Following the current biopsy upper endoscopy was performed and revealed grade 1 varices.


Case 2 - Figure 1 - Low power view of needle biopsy.
Case 2 - Figure 2 - Portal tracts show minimal inflammation.
Case 2 - Figure 3 - High power view of portal tract.



Case 2 - Figure 4 - Additional high power view of portal tract.
Case 2 - Figure 5 - Low power view of trichrome stain.



Case 2 - Figure 6 - Mild portal expansion on trichrome stain.
Case 2 - Figure 7 - High power view of portal tract on trichrome stain.

Histological features and Differential diagnosis:
This liver biopsy demonstrates a variety of histological findings. At low power there is patchy portal fibrosis with a suggestion of focal bridging, with some bile ductular proliferation in the fibrous portal tracts but very little in the way of inflammation. The most obvious abnormality is in the vasculature. There are numerous irregular vascular spaces within portal tracts, at the periphery of portal tracts abutting directly upon the hepatocellular parenchyma, and in the lobule, where in some areas there are multiple apparent central veins clustering together. In addition, the hepatocytes are somewhat variable from area to area with larger cells with pale cytoplasm near the portal tracts and with smaller cells with more dense eosinophilic cytoplasm in the centrilobular region. A reticulin stain demonstrated thick cell plates in the periportal region consistent with regenerating hepatocytes and atrophic cell plates in the centrilobular regions, a picture of nodular regenerative hyperplasia. The differential diagnosis therefore consists of the differential diagnosis for aberrant vasculature with nodular regenerative hyperplasia (NRH).

The differential diagnosis for the type of vascular changes seen in this biopsy is relatively short, consisting mainly of hepatoportal sclerosis (HPS; idiopathic portal hypertension) and Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia) [1, 2, 3, 4, 5, 6, 7, 8, 9] . Hepatoportal sclerosis is essentially synonymous with the diagnosis of idiopathic portal hypertension as used predominantly in Japan and portal venopathy or non-cirrhotic portal fibrosis in India, and is part of the general category of non-cirrhotic portal hypertension [1, 2, 3, 4, 5, 6, 7] . In both India and Japan this process would appear to be a more common problem than in the United States, although in the USA it has been estimated that HPS accounts for approximately 5% of cases of portal hypertension [1]. From evaluations of resected livers it would appear that the predominant lesion (and rationale for the name) of HPS is sclerosis and obstruction of intrahepatic portal vein branches [1, 2, 6, 10] . This obstruction is very patchy, however, and hence rarely seen in needle biopsy samples obtained in the evaluation of portal hypertension. A number of more generalized but less specific features have also been described including patchy portal fibrosis (with occasional bridging, leading to a pattern of incomplete septal cirrhosis), multiple small thin walled vascular channels within the portal tracts, dilated vascular channels at the interface of portal tracts with the surrounding hepatocellular parenchyma (sometimes referred to as shunt vessels), aberrant veins in the hepatocellular lobule resembling multiple central veins in one lobule, and unlined pools of blood identical to those seen in peliosis. Arterial intimal thickening has also been reported. Nodular regenerative hyperplasia is a feature of many cases.

Since most of these less specific features are more generalized and hence more likely to be obtained in a needle biopsy, they are the common features one has to deal with when confronted with a biopsy of possible HPS. Unfortunately, very little research has been directed towards determining the specificity of any of these features on biopsy specimens since most of the literature is based on resection specimens, autopsy tissue or wedge biopsies. Perhaps the best studied is nodular regenerative hyperplasia [11, 12] . Nodular regenerative hyperplasia is, in my opinion, more of a histological descriptor rather that a specific diagnosis, and as such should lead to a search for a specific etiology whenever encountered. There have been numerous conditions associated with NRH including collagen vascular diseases, myeloproliferative disorders and medication reactions. NRH is common following bone marrow transplantation, and is very common in HPS. Vascular abnormalities have been found in some cases [12]. The common thread among these conditions is the likely presence of chronic low grade hepatocellular damage, either from the disease itself, from drugs used to treat the disease, or in the case of HPS and other diseases with vascular involvement, from low grade ischemia or possibly focal hypervascularity. This leads to a centrilobular hepatocellular damage and compensatory regeneration, with the result being a nodular liver. Since nodular regenerative hyperplasia is seen associated with so many potential etiologies, if the only histological finding in a biopsy is NRH then the entire potential etiological spectrum needs to be considered to arrive at a final most likely diagnosis/etiology. Perhaps the most important of these are medication related cases since it is theoretically possible that discontinuation of the medication may result in resolution of the NRH. If a biopsy is taken to evaluate portal hypertension and the only finding is NRH, and the clinical history fails to provide an etiology (such as a medication), then the differential diagnosis should include the possibility of HPS, although in the end distinction of HPS from pure NRH (if the latter exists) is more academic than practical since therapy is likely to be symptomatic only. Since NRH is a generalized process and most of the other changes of HPS can be focal, size of biopsy is very important in assessing the probability of missing additional vascular lesions in a biopsy demonstrating only NRH, and that concern should be mentioned in that biopsy report if the biopsy is particularly small.

The most common and potentially useful vascular changes seen in a biopsy are the "shunt vessels" seen at interface of portal tracts and parenchyma. These are thin-walled somewhat ectatic vessels which seem to lie between the fibrous portal area and parenchyma. When seen in a non-cirrhotic liver these vessels strongly suggest the possibility of HPS although the specificity of these lesions has not been rigorously tested. I say that because one occasionally encounters a biopsy from a totally non-fibrotic liver which demonstrates this lesion in one or two portal tracts, in which case it is generally ignored. To the best of my knowledge no systematic review of these changes in a general biopsy population has been undertaken, although Nakanuma et al did find these changes to a minor extent in a small control sample of patients without portal hypertension [6]. Therefore, when I see these changes as prominent findings I will suggest the diagnosis of HPS, and suggest that evaluation be undertaken for evidence of portal hypertension. For example, the patient who provided the biopsy in the current case was being evaluated because of alkaline phosphatase elevations, which is a common biochemical abnormality in both NRH and HPS. She underwent upper GI endoscopy because of the biopsy findings and mild esophageal varices were seen. This provides supportive evidence for the diagnosis and indicates that followup of the patient for worsening of portal hypertension is indicated. As implied above, vascular abnormalities similar to these are not uncommonly seen in cirrhotic livers and in that context have no diagnostic importance.

One could argue that use of the term hepatoportal sclerosis in a case such as this is overly speculative, and in point of fact without the diagnostic lesion of a sclerosed portal vein I do not render an unequivocal diagnosis of hepatoportal sclerosis but rather provide a more descriptive diagnosis such as "vascular abnormalities associated with nodular regenerative hyperplasia, suggestive of hepatoportal sclerosis". In the literature the definition of "idiopathic portal hypertension" is very generic, generally requiring only a clinical picture of portal hypertension without evidence of cirrhosis or other defined conditions generally associated with the production of portal hypertension. The problem with that definition of "idiopathic portal hypertension" in a case such as the current one is that the patient was not recognized as having portal hypertension at the time of the biopsy, but only afterwards. Therefore sometimes the pathologist must recognize the histopathological features which allow a suggestion of this diagnosis rather than the other way around. Another approach to the terminological problem of HPS is to use the more generic terms of "non cirrhotic idiopathic portal hypertension" or "non-cirrhotic portal fibrosis" [4, 7] . This approach has been used in several reports which attempted to subclassify this general category (non-cirrhotic portal hypertension) by histological features into groups such as HPS, periportal fibrosis, incomplete septal cirrhosis and nodular regenerative hyperplasia or combinations of these [6, 7, 13, 14, 15] . In general this exercise points out that while subclassification is possible on large resection specimens or wedge biopsies, the clinicopathological features of the cases are similar, and hence aside from the differential diagnosis of nodular regenerative hyperplasia mentioned above, the subclassification does not provide much useful information. In addition, subclassification applied to complete livers and is probably not possible for needle biopsies due to sampling error. It has been argued that the current classification and terminology is inadequate, however at the current time from a management perspective choosing a single term would seem prudent [13, 14] . In my daily practice I us the term HPS and mention idiopathic portal hypertension as a synonym to assist clinicians in retrieving relevant references if needed.

The etiology of HPS remains somewhat of a conundrum. Several rare but etiological agents have been reported to cause a lesion similar to HPS, including arsenic and vinyl chloride and toxic oil syndrome, however these certainly do not account for many if any cases in general practice in this country [16, 17] . Early literature pointed out the frequency of this disease in "underdeveloped" countries and suggested that it might represent a sequela of untreated pelvic infections and subsequent thrombosis or thromboembolization of portal vein branches. Although this is an intriguing idea, and on occasion fresh thrombi are seen in both portal and central veins in these cases, the fact that this is also one of the most common causes of portal hypertension in modern Japan, a country not generally considered "underdeveloped" argues against the infectious possibility in many cases. A recent study suggested an association with a variety of prothrombotic disorders, again raising the spectre of intrahepatic thrombosis as an initiating factor [7]. Since the vascular lesions (without the sclerosed portal veins) are very similar to the findings of hereditary hemorrhagic telangiectasia one might consider some congenital abnormality, however the fact that this condition in our patient appears to have developed over the course of a year following a biopsy taken for obesity related steatosis indicated that at least in some cases it is an acquired condition. Our particular patient is intriguing in this regard. Steatohepatitis is not a recognized cause of HPS. One might speculate that our cases was induced somehow by the gastric bypass procedure that the patient underwent, although I was not able to identify similar cases in the literature. It is possible, however, that the gastric bypass surgery induced intrahepatic portal vein thrombosis, leading to this condition.

In summary, HPS and HPS-like changes are something which should be considered in all biopsies taken to evaluate for portal hypertension if there is no evidence of cirrhosis in the biopsy, and may sometimes provide an explanation for idiopathic elevation of alkaline phosphatase. Appropriate suggestions for evaluation of these patients or patients with nodular regenerative hyperplasia should be made in the surgical pathology report.

Diagnosis: Vascular abnormalities associated with nodular regenerative hyperplasia, suggestive of hepatoportal sclerosis.

References

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