intrahepatic%20cholestasis
INTRAHEPATIC CHOLESTASIS
Cholestasis is bile formation and/or bile flow impairment that manifests as fatigue, pruritus and jaundice.
It can be classified into intrahepatic or extrahepatic cholestasis.
Extrahepatic cholestasis develops from mechanical blockage in the duct system or hepatocellular defects.
Intrahepatic cholestasis may be due to functional defects hepatocellularly or from obstructive lesions of the intrahepatic biliary tract distal from the bile canaliculi.

Diagnosis

  • The first critical step in diagnosing is differentiating intrahepatic and extrahepatic cholestasis
  • History and physical examination are essential diagnostic processes for the experienced clinician to predict the nature of cholestasis
  • A diagnosis of intrahepatic cholestasis may be made if imaging studies do not demonstrate mechanical obstruction
    • However, clinical judgment should be pursued and repeat ultrasound or another imaging procedure should be performed if the patient has a history that suggests an extrahepatic cause (eg early pancreatic or ampullary carcinoma)
  • Testing for serum antimitochondrial antibodies (AMA) is the recommended next step after confirming diagnosis of chronic intrahepatic cholestasis
    • If this test reveals high-titer AMA and a cholestatic serum enzyme profile, a diagnosis of primary biliary cirrhosis, which is the major cause of small-duct biliary diseases, can be made

Classification

Primary Biliary Cirrhosis (PBC)

  • It is a presumed autoimmune disease that is chronic and progressive in nature
  • It is characterized by destruction of small to medium bile ducts, leading to cholestasis and frequently, end-stage liver disease
  • Symptoms include fatigue, pruritus and/or jaundice, but most patients are asymptomatic at the time of diagnosis
  • Histological features of florid bile duct lesions confirm diagnosis of PBC
  • Please refer to the Primary Biliary Cirrhosis Disease Management Chart for more information

Primary Sclerosing Cholangitis (PSC)

  • A chronic cholestatic liver disease that is characterized by an inflammatory and fibrotic process affecting both intrahepatic and extrahepatic bile ducts
  • It leads to irregular bile duct obliteration, including formation of multifocal bile duct stricture
  • It is likely an immune-mediated, progressive disorder that eventually develops into portal hypertension and hepatic decompensation, liver cirrhosis and liver failure
  • Etiology is unknown, but there is evidence that genetic susceptibility factors are involved
  • At first presentation, the patient is asymptomatic
  • Symptoms that typically occur are pruritus, pain in the right upper abdominal quadrant, fatigue, weight loss, and episodes of fever and chills
  • Diagnosis can be made when the patient has:
    • Elevated serum aminotransferase levels, typically to levels 2-3 times upper limits of normal (ULN), although normal levels can be observed in some patients
    • Magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) that shows bile duct changes with multifocal strictures and segmental dilatations
      • Magnetic resonance cholangiography is the preferred primary diagnostic imaging study over ERCP
    • Clinical findings of hepatomegaly and splenomegaly
    • Autoantibodies that include perinuclear antineutrophil cytoplasmic antibodies (pANCA), antinuclear antibodies (ANA) and smooth muscle antibodies (SMA)
    • Detailed cholangiographic assessment result of mural irregularities and diffusely distributed multifocal, short, annular strictures alternating with normal or slightly dilated segments producing a “beaded” pattern
    • At the time of PSC diagnosis, a screening ileocolonoscopy is recommended to screen for PSC-associated inflammatory bowel disease

Intrahepatic Cholestasis of Pregnancy (ICP)

  • A reversible cholestatic condition during pregnancy characterized by:
    • Intense pruritus without skin rash that usually occurs in the 2nd or 3rd trimester of pregnancy
    • Elevated serum alanine aminotransferase (ALT) activities and fasting serum bile acid levels
    • Symptoms resolve after delivery (within 4-6 weeks)
  • Potential fetal risks include spontaneous or iatrogenic prematurity, asphyxial events during delivery, intrauterine death
  • Genetic predisposition, environmental and hormonal factors have been implicated in the pathogenesis
  • Risk factors include advanced maternal age, previous history of cholestasis secondary to oral contraceptives, and a family or personal history of intrahepatic cholestasis
  • If no other cause of liver dysfunction is found for the symptoms and LFT abnormalities, a diagnosis can be made:
    • Transaminases and gamma-glutamyl transferase (gamma-GT) increase
    • Bilirubin rarely increased
    • Bile acids are the most sensitive indicator for cholestasis of pregnancy and may precede the abnormalities of other serum liver tests
    • Increased bile acids with increased cholic acid levels and decreased chenodeoxycholic acid levels

Immunoglobulin G4-associated Cholangitis (IAC)

  • IgG4-related systemic (or sclerosing) disease with biliary manifestations characterized by:
    • Elevated serum IgG4
    • Infiltration of IgG4-positive plasma cells in bile ducts and liver tissue
    • Markedly overexpressed T helper 2 (Th2) and T regulatory (Treg) cytokines
  • Often associated with autoimmune pancreatitis and other fibrosing conditions
  • Diagnosis can be made (based on recent proposal) if a patient with biliary stricture in the intrahepatic, proximal extrahepatic and/or intrapancreatic bile ducts:
    • Has recently undergone pancreatic/biliary surgery or core biopsy of the pancreas showing diagnostic features of autoimmune pancreatitis
    • Shows classic imaging findings of AIP and elevated IgG4 or
    • Fulfills two of the following criteria (elevated serum IgG4; suggestive pancreatic imaging findings; other organ manifestations including sclerosing sialadenitis, retroperitoneal fibrosis or gastrointestinal involvement and abdominal lymphadenopathy with infiltration of IgG4-positive plasma cells; >10 IgG4-pos. plasma cells per high power field in bile duct biopsies) and shows an adequate response to a 4-week course of corticosteroid treatment to allow stent removal without relapse of obstructive cholestasis, to reach serum liver tests <2x ULN, and to present decreasing IgG4 and CA 19-9

Secondary Causes of Intrahepatic Cholestasis

Alcoholic Liver Disease

  • Chronic alcohol consumption that results to a broad spectrum of liver injury, ranging from simple steatosis to alcoholic hepatitis, chronic hepatitis with hepatic fibrosis and cirrhosis
  • The clinical jaundice and histological features of intrahepatic cholestasis may present in all stages of alcoholic liver disease
  • Please refer to the Alcoholic Liver Disease Disease Management Chart for more information

Non-alcoholic Liver Disease

  • Patient has alcoholic liver disease histopathological features but with no or little alcohol consumption
  • Believed to be the hepatic manifestation of the metabolic syndrome that is frequently accompanied by obesity, type 2 diabetes, and hyperlipidemia
  • Encompasses a histopathological disease spectrum from bland steatosis to nonalcoholic steatosis hepatitis with significant inflammation and fibrosis progressing to cirrhosis
  • Patients are mostly asymptomatic and, while hepatomegaly is common, jaundice is rarely seen
  • Laboratory workup may show modest elevation of serum aminotransferase and gamma-GT, normal or mildly increased alkaline phosphatase (AP) and rarely hyperbilirubinemia

Chronic Viral Hepatitis

  • Presence of intrahepatic cholestasis clinical or laboratory signs usually indicate severe progressive liver disease or an acute exacerbation of hepatitis B virus infection
  • Cholestatic presentation is infrequently seen in chronic hepatitis C virus infection
    • Most patients with cholestasis display advanced disease, present with pruritus, and show bile duct injury in the setting of advanced fibrosis

Granulomatous Hepatitis

  • Inflammation of the liver tissue that is chronic, exudative and proliferative that occurs due to infections, systemic diseases or drugs
  • There is a variable degree of cholestasis in granulomatous liver disease
    • Clinical symptoms may range from none to intractable pruritus
    • Morphological features causing intrahepatic cholestasis include periportal granulomatous infiltrates associated with damaged bile ducts, nodular regenerative hyperplasia and ductopenia 
  • Nodular inflammatory infiltrates (granulomas) consisting of macrophages, epithelioid cells, lymphocytes and fibroblasts are the histological feature

Drug-induced Cholestatic Liver Injury (DILI)

  • It is an isolated elevation of serum AP >2x ULN or an ALT/AP ratio (both elevated above ULN) <2
  • It is based on two major mechanisms:
    • Inhibition of hepatocellular transporter expression and/or function with alteration of bile secretion at the hepatocellular level
    • Induction of an idiosyncratic or hypersensitive reaction at the bile ductular/cholangiocellular level with ductular/ductal cholestasis, which can also interfere with hepatocyte bile secretion
  • There are no specific diagnostic tests, thus diagnosis requires clinical suspicion, a careful drug history, consideration of the temporal relationship between drug intake and liver disease and exclusion of other disorders

History

  • Skin should be inspected to differentiate scratching lesions from other skin disorders such as eczema and pruritic eruption of pregnancy
  • History of fever with rigor and right abdominal pain may suggest cholangitis
  • Presence of extrahepatic disease has to be recorded
  • History of prior biliary surgery increases likelihood that biliary obstruction is present
  • Family history of cholestatic liver disease suggests a possibility of hereditary disorder
  • Thorough occupational and drug history is imperative and any medications taken within 6 weeks of presentation may be incriminated

Laboratory Tests

Biochemical Markers

  • Early biochemical markers in often asymptomatic patients include:
    • Increases in serum alkaline phosphatase (AP)
    • Increases in gamma-glutamyltransferase (gamma-GT) 
  • At more advanced stages, conjugated hyperbilirubinemia is the biochemical marker present

Imaging

Ultrasonography

  • Abdominal ultrasonography is commonly the first test to exclude dilated intra- and extrahepatic ducts and mass lesions due to its sensitivity, specificity, portability and it is inexpensive and non-invasive
  • Endoscopic ultrasound (EUS) is used for the detection of bile duct stones and lesions causing extrahepatic obstruction
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