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An Unusual Case of Cholestatic Hepatitis

Ahmad M. Al-Taee, Anas K. Gremida, Amanda C. Cheung, Jinping Lai, Brent Neuschwander-Tetri

Ahmad M. Al-Taee, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, the United States
Anas K. Gremida, Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, New Mexico, the United States
Amanda C. Cheung, Brent Neuschwander-Tetri, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, Saint Louis, Missouri, the United States
Jinping Lai, Department of Pathology, University of Florida, Gainesville, Florida, the United States

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Ahmad Al-Taee, MD, Department of Internal Medicine, Saint Louis University School of Medicine, 3635 Vista Ave, FDT 14th floor, St Louis, Missouri 63110, the United States.
Email: altaeeam@slu.edu
Fax: +877-992-9414

Received: May 10, 2017
Revised: June 28, 2017
Accepted: June 30, 2017
Published online: August 21, 2017

ABSTRACT

Renal cell carcinoma can present with a variety of paraneoplastic syndromes. Reversible hepatic dysfunction in the setting of non-metastatic renal cell carcinoma is a rare paraneoplastic phenomenon that was first described by Stauffer in 1961. This clinical entity is characterized by reversal of liver chemistry abnormalities after resection of the primary tumor. Here we present an unusual case of non-metastatic hepatic dysfunction secondary to renal cell carcinoma, also known as Stauffer’s syndrome, in a 55-year old patient who presented with liver synthetic dysfunction and notable hyperbilirubinemia. Unlike earlier reports, the icteric variant of Staffer’s syndrome has been emerging as the predominantly reported variant in the recent literature. Moreover, poor correlation between the severity of hepatic dysfunction and the liver biopsy findings was noted. The variable and non-specific presenting symptoms and signs as well as the need for extensive evaluation for abnormal liver chemistry usually results in a delay in the diagnosis of the primary tumor. Therefore, physicians need to be familiar with this clinical entity as a possible reversible etiology of liver chemistry abnormalities in patients with renal and other solid tumors as this may guide further investigations, lead to earlier diagnosis and treatment of the primary tumor, and ultimately improve outcomes.

Key words: Stauffer’s syndrome; Non-metastatic hepatic dysfunction; Renal cell carcinoma

© 2017 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Al-Taee AM, Gremida AK, Cheung AC, Lai J, Neuschwander-Tetri B. An Unusual Case of Cholestatic Hepatitis. Journal of Gastroenterology and Hepatology Research 2017; 6(4): 2411-2415 Available from: URL: http: //www.ghrnet.org/index.php/joghr/article/view/2072

INTRODUCTION

Non-metastatic hepatic dysfunction secondary to renal cell carcinoma, also known as Stauffer’s syndrome, was first described by Stauffer in 1961[1]. The pathophysiology has not been completely elucidated so far. Surgical resection of the primary tumor is characteristically associated with reversal of liver chemistry abnormalities[2].

Case Presentation

A 55-year-old Caucasian male with a past medical history of type 2 diabetes mellitus and benign prostatic hyperplasia presented to the emergency room with the chief complaint of worsening abdominal pain as well as pruritus for three months prior to presentation. Home medications included insulin glargine, insulin lispro, and tamsulosin. He denied any new or recent medications including antibiotics, over-the-counter medications, and herbal supplements. Past surgical history included a cholecystectomy nine years ago. On presentation, vital signs were Unremarkable. Physical examination was notable for scleral icterus, jaundice, multiple excoriations over the forearms and shins, and tenderness to palpation over the right upper abdominal quadrant.

Initial laboratory workup was notable for elevated conjugated bilirubin, alkaline phosphatase, gamma glutamyltransferase, and prothrombin time (Table 1). Aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, serum creatinine, hemoglobin, and platelet count were all within normal limits. Neutrophilia, lymphopenia, and monocytosis were also noted although the absolute total white blood cell count was normal. Urinalysis showed a positive urobilinogen and glycosuria. Workup for liver chemistry abnormalities was unremarkable (Table 2).

Table 1 Laboratory results upon patient presentation.
Lab TestResultReference Range
Total bilirubin20.9 mg/dL0.2 - 1.2 mg/dL
Conjugated bilirubin12.5 mg/dL0.0 - 0.5 mg/dL
Alkaline phosphatase327 Units/L40 - 150 Units/L
Gamma glutamyltransferase185 Units/L9 - 64 Units/L
Alanine aminotransferase (ALT)34 Units/L0-55 Units/L
Aspartate aminotransferase (AST)29 Units/L5-34 Units/L
Prothrombin time18.7 seconds12.1 - 14.8 seconds
International normalized ratio (INR)1.60.9-1.1
Albumin2.5 g/dL3.4 - 5.0 g/dL
White blood cell count with differential8.9 x103/uL3.5-10.5 x103/uL
Neutrophils81%35-70%
Lymphocytes11.30%20-50%
Monocytes18%3-15%

Table 2 Work up for abnormal liver enzymes.
Lab TestResultReference Range
Antinuclear antibodiesNegativeNegative
Anti smooth muscle antibodiesNegativeNegative
Anti mitochondrial antibodiesNegativeNegative
Urine ceruloplasmin35 mg/dL< 20 mg/dL
Herpes Simplex PCR and IgMNegativeNegative
Epstein Barr virus PCRNegativeNegative
Cytomegalovirus PCRNegativeNegative

Computed tomography and magnetic resonance imaging of the abdomen showed no abnormalities of the liver or biliary tree; however, a 2.5-cm enhancing exophytic solid and cystic mass arising from the lower pole of the left kidney was incidentally noted (Figure 1). Due to persistent liver chemistry abnormalities without an identified etiology, he underwent a percutaneous liver biopsy which revealed portal and periportal neutrophilic inflammatory infiltrate with bile duct and ductular proliferation as well as centrilobular hepatocanalicular cholestasis consistent with cholestatic hepatitis (Figure 2).

Due to the appearance of the renal cystic mass with Bosniak 4 classification, the patient underwent surgical resection of the renal mass. The perioperative course was uncomplicated, notably without any decompensation of liver or renal function. Histologic examination of the tumor revealed clear cell renal cell carcinoma with no vascular or capsular invasion. Liver chemistry abnormalities had normalized three months post-operatively (Figure 3).

Figure 1 Coronal (A) and axial (B) sections of the computed tomography of the abdomen revealing an enhancing exophytic mass (white arrows) arising from the lower pole of the left kidney which was later confirmed to be clear cell renal cell carcinoma.

Figure 2 A-D, Liver biopsy showing portal ductular proliferation, mild edema, periductal and periductular neutrophils infiltrate (H&E stain, A, 100X; B, 400X); Trichrome stain showing portal edema and periportal fibrosis (C, 100X); and CK19 immunostain showing extensive periportal ductular proliferation (D, 100X).

Figure 3 The trend of liver chemistry abnormalities before and after resection of the left renal mass. Liver enzymes normalized about a month after surgical resection of the renal mass.

DISCUSSION

Cholestasis in the setting of malignancies is usually due to metastatic disease with widespread hepatic infiltration or compression of the hepatobiliary tree. Less frequently, cholestasis may be due to a paraneoplastic syndrome rather than metastatic disease. In addition to renal cell carcinoma (RCC), hepatic dysfunction in the absence of liver metastasis has been described in patients with prostate cancer[3,4], bronchogenic carcinoma[5], soft tissue sarcoma[6,7], bladder cancer[8], thymoma[9], and lymphoproliferative malignancies[10,11].

Non-metastatic hepatic dysfunction (NMHD) in the setting of RCC is a rare paraneoplastic phenomenon that was first described by Stauffer in 1961 in a case series of five patients and was referred to as “nephrogenic hepatomegaly”[1]. Although the term “Stauffer’s syndrome” has been typically used to refer to NMHD secondary to renal tumors, other reports have also used this term to describe NMHD secondary to non-renal tumors[3-8]. The hallmark features described by Stauffer included: 1. liver dysfunction in presence of RCC, 2. absence of liver metastasis, 3. absence of other causes of liver disease, and 4. resolution of hepatic dysfunction after resection of the primary.

Although the pathophysiology of Stauffer’s syndrome has not been fully elucidated, several mechanisms have been proposed. Interleukin-6 has been suggested as a major contributor, as its plasma levels were found to be elevated in up to 80% of patients with RCC-related paraneoplastic syndromes[12]. More recently, there has been a growing interest in exploring autoimmune mechanisms in patients with paraneoplastic syndromes and solid tumors[13,14]. Further investigating the pathophysiology of Stauffer’s syndrome would be challenging as it is rarely encountered in clinical practice. This raises the need to establish a national registry that provides means to report cases and collect blood samples for further analysis.

Data on the outcome, prognosis, and significance of Stauffer’s syndrome is limited. Previous anecdotal reports suggested that RCC patients with hepatic dysfunction had significantly worse prognosis than those without hepatic dysfunction[2,15]. It has also been suggested that the occurrence of Stauffer’s syndrome may be an early indicator of recurrence after surgical resection or tumor metastases[15,16].

The initial reports by Stauffer and others have described the classic, or anincteric, form of the NMHD in the setting of renal tumors[1,17]. In comparison, the first case of the cholestatic, or icteric, variant of Stauffer’s syndrome was reported by Dourakis et al in 1997[18]. Since then, a total of 7 case reports describing the icteric variant of Staffer’s syndrome were found on our review of the literature[19-25]. Direct hyperbilirubinemia was also noted in the patient described above. This adds to the growing body of literature on the icteric variant of Stauffer’s syndrome. Moreover, our patient had evidence of hepatic dysfunction in the form of coagulopathy. However, histologic examination of the liver revealed intact hepatic parenchyma with inflammatory cellular infiltrate and periportal fibrosis. This confirms the lack of correlation between the severity of hepatic dysfunction and the liver biopsy findings in patients with Stauffer’s syndrome.

Non-metastatic hepatic dysfunction in the setting of renal cell carcinoma is a diagnosis of exclusion that is made after an extensive non-revealing abnormal liver chemistry workup. The variable and non-specific presenting symptoms and signs as well as the need for extensive evaluation for abnormal liver chemistry usually results in delay in the diagnosis and management of the primary tumor. Therefore, physicians need to be familiar with this clinical entity as a possible reversible etiology of liver chemistry abnormalities in patients with renal and other solid tumors as this may guide further investigations, lead to earlier diagnosis and treatment of the primary tumor, and ultimately improve outcomes.

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Peer reviewer: Hany Shabana

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