Bile Cast Nephropathy Due to Hepatitis A-induced Hyperbilirubinemia: A Case Report and Literature Review

Bile cast nephropathy (BCN) or cholemic nephrosis (CN) is a form of acute renal dysfunction that occurs in the setting of hepatic dysfunction and hyperbilirubinemia. We present a case of a 58-year-old woman with a four-day history of intractable nausea, vomiting, and yellowish discoloration of her skin and eyes. Laboratory workup was notable for elevated total bilirubin (mainly direct), liver enzymes, creatinine, and blood urea nitrogen (BUN). The ultrasonography (US) of the abdomen showed hepatic steatosis. The hepatitis panel was remarkable for hepatitis A IgM. She was initially treated with supportive therapy. However, her bilirubin levels reached over 20 mg/dl, creatine was >8 mg/dl, and her estimated glomerular filtration rate (eGFR) was <10. Kidney biopsy showed pigmented casts consistent with BCN. She was started on hemodialysis with significant improvement in her symptoms and liver enzymes. This case underscores the importance of a broad differential diagnosis in cases with hyperbilirubinemia and acute kidney injury. BCN requires renal biopsy for a definitive diagnosis, and these patients usually require hemodialysis.


Introduction
Cholestasis secondary to liver disease can lead to kidney injury. The mechanism of renal dysfunction in cholestatic liver disease may be attributed to several factors. These include hemodynamic changes such as intravascular depletion, hepatorenal syndrome, or acute tubular necrosis (ATN) [1]. Elevated bilirubin levels can cause direct cytotoxicity to renal tubular cells. In severe cases, the bile acids can precipitate into casts and cause ATN, which may result in renal failure requiring renal replacement therapy [2,3]. This condition is known as bile cast nephropathy (BCN) or cholemic nephrosis (CN). This entity of kidney disease has not yet received much attention in the medical field. Bile casts on renal biopsy in a patient with hyperbilirubinemia and elevated creatinine are pathognomonic for BCN or CN [4]. The tubular injury in this disease can be reversible, so timely detection is critical to determining prognosis in these patients [5]. We report a case of BCN in a patient who developed acute kidney injury secondary to hyperbilirubinemia due to hepatitis A.
The case was presented as a poster presentation at the American College of Gastroenterology (ACG) in Charlotte, North Carolina in 10/2022.

Case Presentation
A 58-year-old woman presented with a four-day history of intractable nausea, vomiting, and yellowish discoloration of her skin and eyes. She denied abdominal pain, fever, chills, hematemesis, hematochezia, diarrhea, or constipation. Her medical history included type 2 diabetes mellitus, hypothyroidism, hypertension, and hyperlipidemia. The patient had traveled to Arizona two months earlier but denied any sick contacts, insect bites, herbal supplements, use of antibiotics, drugs, alcohol/tobacco, or tattooing.
The patient was hemodynamically stable on presentation. Physical exam was notable for scleral icterus. The abdomen was not tender without rebound tenderness or rigidity. Laboratory values were remarkable for elevated total bilirubin, mainly direct, elevated liver enzymes, and high INR ( Table 1). In addition, creatinine and blood urea nitrogen (BUN) were elevated ( Table 1). Urine analysis was remarkable for elevated urobilinogen.  CT scan of the abdomen and pelvis without contrast revealed evidence of hepatic steatosis. IgM against hepatitis A was positive, while IgM anti-HEV, HBsAg, and anti-HCV were negative. The management included supportive therapy. In the following days, bilirubin levels reached over 20 mg/dl, creatine was >8 mg/dl, and her estimated glomerular filtration rate (eGFR) was <10. The patient was initiated on hemodialysis with significant improvement in her symptoms. Percutaneous ultrasonography (US)-guided left kidney core biopsy showed acute tubular injury with frequent pigmented casts, consistent with BCN or CN ( Figure 1). A Fouchet stain for bile was positive within focal intralobular casts ( Figure 2).   On the day of discharge, liver enzymes improved, but bilirubin remained elevated ( hemodialysis was scheduled, a follow-up appointment was arranged, and the patient was discharged home. Repeat laboratories three months later showed normalization of liver enzymes, total bilirubin, and kidney functions ( Table 1).

Discussion
BCN is a form of acute renal dysfunction in the setting of liver dysfunction and hyperbilirubinemia [3]. Jaundice-related nephropathy can lead to renal failure, referred to as CN [2]. The pathophysiology of BCN remains unclear, but several hypotheses exist. In humans, cholesterol is a precursor to the production of bile acids in the liver [6]. These bile acids go through enterohepatic circulation, are excreted in the bile, released into the intestines, and then recycled back to the liver [7]. These bile acids can also leak into the systemic circulation, where they are delivered to the kidneys and reabsorbed into the circulation by the proximal convolute tubules (PCT) and delivered to the liver. Once cholestasis develops, liver cells upregulate pumps that help eliminate excess bile. In addition, a similar process takes place in the PCT of the kidneys to excrete bile [4]. This excess of bilirubin is thought to cause oxidative damage to kidney tubular cells by disrupting mitochondrial phosphorylation. This process can lead to tubular hypertrophy and hyperplasia, as suggested by Holmes in 1953, who performed autopsies on 68 patients with hyperbilirubinemia, with 73.5% having these findings [8]. In addition, tubular obstruction can also occur due to bile cast deposition. This process is enhanced by the ability of bile acids to promote cast formation by altering pH via inhibition of Na+/H+, Na+/K+, and Na+/Cl transporter [4].
A literature review of BCN secondary to hepatitis A-induced hyperbilirubinemia revealed four cases ( Table  2). All cases involved male patients, and their ages ranged from eight to 35 years; however, in our case, the patient was a 58-year-old female. The most common presenting manifestations were fever and jaundice. Laboratories showed elevated ALT, AST, bilirubin, and creatinine.  Kidney biopsy is considered the gold-standard method for diagnosing BCN [13]. A recent review by Tinti et al. [14] showed that several cases of CN were diagnosed via the identification of bile casts on renal biopsy, underscoring the necessity of using histological identification as the gold standard for diagnosing BCN. Interestingly, Chediak et al. [15] reported that transjugular renal biopsy (TJRB) is a better option than transcutaneous renal biopsy because the latter approach reaches the renal cortex while the former can identify lesions in the distal nephron where bile casts appear to be developing. The Hall (or Fouchet) histochemical stain shows green to yellow bile casts obstructing the renal tubules ( Figure 2) [16]. All cases in our review ( Table 2) underwent renal biopsy, and three specifically mentioned Fouchet stain.
Tinti et al. [14] suggested that low albumin levels and acidosis may serve as bile cast-promoting factors (BCPFs). This study also suggested that bile casts in urine sediment analysis could aid diagnosis. In addition, it is essential to distinguish hepatorenal syndrome from BCN since both disorders occur in patients with liver disease. Nayak et al. [6] aimed to study the incidence of BCN at postmortem autopsies in patients admitted with a diagnosis of acute kidney injury secondary to hepatorenal syndrome. BCN was identified in 72.1% of patients with acute or chronic liver disease and 27.4% of patients with decompensated cirrhosis [6].
There are currently no established treatment guidelines for BCN. Treatment aims to lower bilirubin levels to prevent kidney dysfunction [4]. Hemodialysis is often used, especially when the patient needs it to improve kidney function [4]. All cases in the review ( Table 2), including our patient, required hemodialysis with improvement in the clinical symptoms and laboratory values. In some instances, however, hemodialysis does not lower bilirubin levels sufficiently [4]. In these situations, other extracorporeal methods can be used. These include molecular adsorbents recycling system (MARS), coupled plasma filtration adsorption (CPFA), and plasmapheresis (XXII) [7]. Plasmapheresis has reportedly been used successfully in patients with BCN [7]. In addition, certain drugs, including steroids, cholestyramine, ursodeoxycholic acid, and lactulose, have been suggested, but these have been proven to be minimally effective [4]. However, ursodeoxycholic acid has been shown to alleviate CN in mice [2].