Atypical causes of cholestasis

Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have “silent” progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.     

Drug- and chemical-induced cholestasis

Cholestasis caused by medicinal and chemical agents is an increasingly well-recognized cause of liver disease. Clinical drug-induced cholestatic syndromes producing jaundice and bile duct injury can mimic extrahepatic biliary obstruction, primary biliary cirrhosis, and sclerosing cholangitis, among others. This article updates the various forms of drug-induced cholestasis, focusing on the clinicopathologic features of this form of hepatic injury and on the known or putative mechanisms by which drugs and chemicals lead to cholestasis.     

CHOLESTASIS IN ACUTE ALCOHOLIC LIVER DISEASE

10 of a series of 108 patients with alcoholic liver disease presented with cholestasis associated with non-cirrhotic alcoholic liver disease and without evidence of extrahepatic biliary obstruction. In 7 patients liver histology and the associated conditions presenting as cholestasis were heterogeneous. However, in 3 patients who had been drinking excessively before cholestatic jaundice developed, cholestasis was a major feature of liver histology. The term acute alcoholic cholestasis is suggested for this apparently distinct syndrome of cholestatic jaundice in the absence of hepatitis.     

Familial intrahepatic cholestatic cirrhosis in young adults

Two siblings with intrahepatic cholestatic cirrhosis and their brother, who had a potentially related disease at the time of accidental death, are presented. The onset of disease occurred during adolescence in all 3 cases. The initial sign was mild jaundice or portal hypertension. There was no abnormality in the countenance, cardiovascular system, or vertebral column. Except for the brother who died from an accident, jaundice gradually increased. Death followed due to cirrhosis. Liver biopsy specimens of these 2 patients showed diminution of interlobular bile ducts with no significant cholangitis. At autopsy, the livers of the 2 patients showed biliary cirrhosis without extrahepatic biliary obstruction. In both cases there was an accessory lobe on the right hepatic lobe. Histologically, septal bile ducts showed pronounced papillary proliferations of the epithelium; there was also a decrease in the number of small interlobular bile ducts. Excess copper accumulation in the liver was ascertained. It is suggested that the disease in the 2 autopsied cases is intrahepatic cholestatic cirrhosis due to hypoplasia of the intrahepatic biliary trees.     

Endoscopic decompression may not relieve biliary obstruction caused by polycystic liver disease. Report of a case from malaysia

A 55‐year‐old man with known adult polycystic kidney and liver disease presented to us with a gradual onset of cholestatic jaundice. Gross polycystic disease was noted on liver imaging and endoscopic retrograde cholangiopancreatography (ERCP) confirmed external compression of intrahepatic bile ducts with some dilatation. Despite a well‐placed biliary stent, the jaundice continued to deteriorate until percutaneous aspiration of two of the largest cysts, followed by ethanol injection. His jaundice resolved subsequently and has not recurred to date. The merits of ERCP, biliary decompression and percutaneous cyst drainage in this rare complication of polycystic liver disease are discussed. We conclude that endoscopic biliary drainage is of little value and that cyst drainage with ethanol ablation in the initial stage should be the treatment of choice.     

Benign familial recurrent intrahepatic cholestasis

Three new cases of benign familial recurrent intrahepatic cholestasis in a brother, sister, and mother are reported. These cases emphasize the familial nature of the disorder and the characteristic clinical findings of recurrent attacks, cholestatic jaundice, pruritus with increases in the serum bilirubin, and increased alkaline phosphatase. A normal extrahepatic biliary tree was shown by dye studies, and liver biopsy showed central lobular cholestasis without any inflammation or necrosis. Liver function tests were normal between attacks. This condition must be differentiated from extrahepatic obstruction, parenchymal liver disease, drug-induced cholestatic disease, and other familial types of jaundice.     

Sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease whose aetiopathogenesis is unknown. PSC is frequently associated with inflammatory bowel disease, in particular chronic ulcerative colitis, is most commonly observed in young males and is clinically characterized by fatigue, pruritus and jaundice. The diagnosis is supported by a cholestatic biochemical profile and histological abnormalities, and confirmed by visualization of an abnormal biliary tree. The natural history of the disease is currently being evaluated but is generally recognized to be slowly progressive, leading to complications of chronic cholestasis, portal hypertension and biliary cirrhosis. There is no specific medical treatment, and orthotopic liver transplantation remains the only definitive treatment for patients with end-stage PSC. A more rational approach to medical therapy will ensue upon a better understanding of the aetiopathogenesis of this disease.     

Cholestatic hepatitis following flutamide

Summary Previous reports have indicated that administration of flutamide—a nonsteroidal antiandrogen drug—may induce hepatic toxicity. However, cholestatic hepatitis following flutamide is a rare event. This case report describes a 72-year-old male with metastatic adenocarcinoma of the prostate who underwent bilateral orchiectomy and treatment with flutamide. After seven weeks he developed jaundice and elevated AST and ALT levels. A liver biopsy showed cholestatic hepatitis without signs of biliary obstruction. The patient's clinical symptoms and elevated bilirubin resolved after the flutamide was discontinued. Monitoring of serum liver enzyme tests is advocated during flutamide administration to identify drug-induced liver injury.     

Case Report: Severe cholestatic jaundice induced by Epstein-Barr virus infection in the elderly

Infectious mononucleosis due to Epstein-Barr virus (EBV) is almost always a self-limited disease, most commonly seen in young adults. Hepatitis is a well-recognized complication of EBV infection that usually resolves spontaneously. Jaundice occasionally results from the unusual complication of autoimmune haemolytic anaemia rather than hepatitis. We report a 60-year-old man with severe cholestatic jaundice whose history, liver histology and laboratory findings suggested EBV infection. He also developed significant jaundice related to his hepatitis, but not to autoimmune haemolysis, a situation that led to diagnostic delay. Costly diagnostic laboratory tests and invasive procedures were performed to rule out a malignant extrahepatic biliary obstruction. Physicians need to be aware of this complication and EBV infection should be included in the differential diagnosis of cholestatic jaundice in the elderly.     

Immunocytochemical studies on cholestatic factor in human liver with or without cholestasis

ABSTRACT— The localization of the cholestatic factor (CF) was immunocylochemically investigated in liver biopsy specimens obtained from patients with various liver diseases. CF was detected in seven of nine patients with drug-induced liver injury, three of four with acute viral hepatitis, three of five with alcoholic liver injury and in the two patients with autoimmune hepatitis. Fourteen of these 15 CF-positive patients had jaundice in their clinical courses. CF was stained diffusely in the cytoplasm of hepatocytes throughout the lobules in a granular pattern. Electron-microscopically, it was localized on the ribosomes and polysomes as well as on the filamentous structures around the bile canaliculi. However, CF was not detected in liver specimens from normal controls and patients with primary biliary cirrhosis and extrahepatic biliary obstruction. These findings suggest that CF plays an important role in intrahepatic cholestasis in various liver diseases.     

Recurrent cholestatic jaundice associated with generalized pustular psoriasis: evidence for a neutrophilic cholangitis

Generalized pustular psoriasis can result in systemic complications. We report the case of a woman with relapsing generalized pustular psoriasis and recurring episodes of cholestatic jaundice. Liver biopsy performed during an attack showed a neutrophilic infiltrate surrounding and invading portal triad bile ducts. Ultrasonographic exams and retrograde cholangiography ruled out biliary tract disease. This observation suggests that recurring cholestatic jaundice in pustular psoriasis is related to a neutrophilic cholangitis.     

Common Bile Duct Obstruction Caused by Hydatid Daughter Cysts—Management by Endoscopic Retrograde Sphincterotomy

Four patients with cholestatic jaundice due to ruptured hydatid liver cyst into the biliary tract underwent endoscopic retrograde sphincterotomy with clearance of the bile ducts. Prompt relief of jaundice followed the produced and no complications occurred. After the procedure all patients received medical treatment (Meben-dazole) for 3–4 months and were well at a mean follow-up of 8 months. We conclude that endoscopic retrograde sphincterotomy is a safe and effective treatment for cholestatic jaundice caused by hydatid daughter cysts obstructing the bile ducts. This method may serve as an alternative to surgery in selected, high risk, patients.     

Sepsis‐associated liver injury: Incidence,classification and the clinical significance

Aim: Although it is a common complication of sepsis, sepsis‐associated liver injury has not been substantially recognized, because its diagnostic criteria and clinical implications are unclear. We aimed to elucidate the incidence, manifestation, disease type classification and prognosis of sepsis‐associated liver injury. Methods: The subjects were 588 patients admitted to our hospital for sepsis between 2001 and 2010. They were classified into “normal liver function”, “sepsis‐associated liver injury” and “sepsis‐not‐associated liver injury” groups. Sepsis‐associated liver injury was classified as either “cholestatic”, “hepatocellular” or “shock liver.” Each of these three subgroups was further classified into “with jaundice” or “without jaundice”. The primary end‐point was the “poor prognosis ratio”, defined as the proportion of patients whose prognosis was “unchanged”, “worsened” or “died”. Results: Among the 449 subjects except for sepsis‐not‐associated liver injury (n = 139), the incidence of sepsis‐associated liver injury was 34.7% (156/449), including 75 cholestatic (48.1%), 34 hepatocellular (21.8%) and 47 shock liver (30.1%) cases. Jaundice was a complication in 25 (33%), six (17.6%) and four (8.5%) patients in each group, respectively. The poor prognosis ratio was higher in males (37.5%) and in the elderly (47.7%); it was 48.0%, 38.2% and 62.8% in the cholestatic, hepatocellular and shock liver groups, respectively, and higher than the normal liver function (18.4%) group (P < 0.0001). It was also higher in patients with jaundice (68.6%) than in those without (45.5%) (P < 0.0001). Conclusion: Sepsis‐associated liver injury, especially with jaundice, is a significant predictive sign of poor prognosis in patients with sepsis.     

Occurrence of an abnormal lipoprotein in patients with liver disease

An abnormal lipoprotein, containing a high proportion of unesterified cholesterol and phospholipid, has previously been described as occurring in the serum of patients with obstructive jaundice, and has been called lipoprotein X. Using an immunoelectrophoretic method for the detection of lipoprotein X in serum, the sera of 97 patients with liver disease have been screened and the associated biochemical features measured.

Lipoprotein X was found in 45% of cases of liver disease with cholestatic features, and was not detected in cases of liver disease without cholestasis. The incidence of lipoprotein X in different causes of cholestatis varied, and while it was commonest in cases of extrahepatic obstruction of recent onset, occurring in 75% of cases, it was also found in primary biliary cirrhosis in 48% of cases, and in cholestatic hepatitis, less commonly.

The cause of the appearance of lipoprotein X is unknown, but analysis of associated biochemical features suggested a relationship to physical biliary obstruction rather than a derangement of liver cell function.

     

Tubercular biliary hilar stricture: A rare case report

Localized hepatic tuberculosis (TB) with or without bile duct involvement is a rare form of hepatobiliary tuberculosis; accounting for less than 1% of all tuberculous infections. We report an uncommon case of cholestatic jaundice with disseminated TB in an immunocompetent male who presented with simultaneous involvement of liver and biliary system.     

Idiopathic adulthood ductopenia: case report and review of the literature

The clinical and pathological findings of idiopathic ductopenia were studied in a 30-year-old woman who initially manifested jaundice and pruritus. Serum biochemical tests of liver function indicated severe and progressive cholestasis. Viral hepatitis markers and circulating autoantibodies were absent. The patient had a normal cholangiogram and lacked evidence of inflammatory bowel disease. Histological examination of a liver specimen showed severe cholestasis and absence of interlobular bile ducts. Severe jaundice and intractable pruritus developed in the patient and served as the indications for liver transplantation 4 months after initial examination. Transplantation resulted in prompt and complete resolution of the jaundice and pruritus. Two types of idiopathic adulthood ductopenia associated with different prognoses are recognized. Patients with type 1 idiopathic adulthood ductopenia are asymptomatic or manifest symptoms of cholestatic liver disease. They tend to have less destruction of the intrahepatic bile ducts on liver biopsy specimens. Their clinical course ranges from spontaneous improvement to progression to biliary cirrhosis. In contrast, patients with type 2 idiopathic adulthood ductopenia generally manifest initial symptoms of decompensated biliary cirrhosis, have extensive destruction of the intrahepatic bile ducts on liver biopsy, and frequently require orthotopic liver transplantation.     

Hepatic tuberculosis presenting as cholestatic jaundice. A case report.

We report three cases of hepatic tuberculosis with cholestatic jaundice. All three patients presented with cholestatic jaundice, anorexia, fever and weight loss. All had hepatomegaly. No biliary obstruction was detected. Two patients had evidence of extra hepatic tuberculosis but one had no such evidence. Diagnosis of hepatic tuberculosis was confirmed by liver biopsy. Little is known about tuberculous affecting the liver and the general belief is that it is a histopathological entity only, but these cases are a reminder of the unusual manifestation of a very common condition. All the cases recovered with anti-tuberculous treatment.     

Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease

Chronic cholestasis often results in premature death from liver failure with fibrosis; however, the molecular mechanisms contributing to biliary cirrhosis are not demonstrated. In this article, we show that the death signal mediated by TNF-related apoptosis-inducing ligand (TRAIL) receptor 2/death receptor 5 (DR5) may be a key regulator of cholestatic liver injury. Agonistic anti-DR5 monoclonal antibody treatment triggered cholangiocyte apoptosis, and subsequently induced cholangitis and cholestatic liver injury in a mouse strain-specific manner. TRAIL- or DR5-deficient mice were relatively resistant to common bile duct ligation-induced cholestasis, and common bile duct ligation augmented DR5 expression on cholangiocytes, sensitizing mice to DR5-mediated cholangitis. Notably, anti-DR5 monoclonal antibody-induced cholangitis exhibited the typical histological appearance, reminiscent of human primary sclerosing cholangitis. Human cholangiocytes constitutively expressed DR5, and TRAIL expression and apoptosis were significantly elevated in cholangiocytes of human primary sclerosing cholangitis and primary biliary cirrhosis patients. Thus, TRAIL/DR5-mediated apoptosis may substantially contribute to chronic cholestatic disease, particularly primary sclerosing cholangitis.     

Vitamin A deficiency in chronic cholestatic liver disease: Is vitamin A therapy beneficial?

Chronic cholestatic diseases are progressive diseases of the biliary tract that cause hepatic fibrosis and ultimately lead to liver failure. Liver transplantation is the sole curative option currently available, and because of high morbidity and mortality rates of these diseases, new therapeutic approaches are needed. Vitamin A is a nutrient essential for health as it regulates many processes, including epithelial growth and immunological processes. Vitamin A is primarily stored in hepatic stellate cells, and during liver injury, through an unknown mechanism, these cells lose vitamin A and convert into collagen‐producing myofibroblasts, which contributes to hepatic fibrosis. Vitamin A deficiencies in chronic cholestatic diseases have been frequently reported, and therefore, retinoid metabolism has attracted a lot of attention. Retinoids have been shown to attenuate or even prevent hepatic fibrosis, and to regulate hepatic immunological response to cholestatic injury in different rodent models of chronic cholestasis. Recently, their potential as therapeutic drugs in primary sclerosing cholangitis patients was analyzed. The aim of this review is to summarize the existing knowledge and hypotheses about vitamin A role and the disease progression in cholestatic liver disease.