Case 2 -
Vascular Abnormalities associated with Nodular Regenerative Hyperplasia, Suggestive of Hepatoportal Sclerosis
Dale C. Snover
Fairview Southdale Hospital
Click on each slide thumbnail image for an enlarged view
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.
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)
. 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
. 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 . 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
. 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
. 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
. 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 . 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"
. 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
. 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
. 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
. 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 . 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.
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