Cholestasis

Bile is a primary hepatocyte secretion. It is produced continuously but between meals it is stored in the gallbladder. About 0.5 litres of bile enters the duodenum each day. Cholestasis is the situation where the bile cannot flow from the gallbladder to the duodenum. There are several clinically important sequelae:

1. Retention of conjugated bilirubin and its regurgitation into serum
2. Increased serum concentration of unconjugated bilirubin
3. Hypercholaemia (increased bile salts)

These contribute to the clinical presentation outlined below.

Conditions giving rise to cholestasis broadly fall into two categories:

• Those where there is a mechanical blockage in the duct system - obstructive or extrahepatic cholestasis.
• Those where there are disturbances in bile formation - hepatocellular or intrahepatic cholestasis.

The term obstructive jaundice is usually used to describe extrahepatic cholestasis. See list of associated diseases for conditions giving rise to cholestasis and follow links to find out more about them.

Refer to our dedicated record on Jaundice for more detail about this condition.

• This generally relates to the epidemiology of underlying conditions. Extrahepatic cholestasis accounts for 70% of all cholestasis cases.
• When looking at it as a whole, women are more affected due to the condition of cholestasis in pregnancy (see below). Biliary atresia and drug-induced cholestasis is also more commonly seen in women.
• Newborns and infants are more susceptible and more likely to develop cholestasis as a consequence of immaturity of the liver.

• Jaundice - arises as a consequence of elevated serum conjugated bilirubin. Cutaneous jaundice is usually seen at serum concentrations of about 85.5 μmol/L but scleral icterus can be seen at concentrations as low as 34.2 μmol/L.³ There will be associated pale stools (as no bilirubin reaches the gastrointestinal tract) and dark urine (there is a reflux of conjugated bilirubin into blood which is excreted in the urine).
• Pruritus - manifest by scratch marks (excoriation). This is a common but not universal feature (ranging from absent to severely disabling), the exact pathophysiology of which is not clearly understood. There may be secondary skin infections if scratching is severe and in children, there may be associated poor sleep, attention deficits, poor school performance and a form of hyperkinesis that may have importance regarding energy balance.³
  It is worth noting that the ability to scratch oneself is something that develops over the first 14 months of life and therefore the very young baby may well experience the pruritus of cholestasis but cannot do anything about it. These children invariably go on to scratch themselves as their abilities develop, starting at around 6 or 7 months of age. In the interim, the baby may be miserable, irritable and poor at socialising.
• Hypercholesterolaemia¹ - this is a feature in some types of cholestasis. Unless there is long-standing disease or previous cardiovascular disease, there may not be any clinical manifestations of this (particularly in children). Alternatively, xanthomas may be found - look particularly in the palmar creases, below the breast, on the neck and in the young child: in the nappy area.
• Failure to thrive - in children with cholestatic disease, due to malabsorption, anorexia, poor nutrient use, hormonal disturbances and secondary tissue injury.
• Clubbing

In obstructive cholestasis, there may additionally be:²

• Pain
• Fever
• Palpable or tender gallbladder
• Smooth hepatomegaly

The rates of bile formation and flow cannot actually be measured. Therefore, investigations centre on assessing the serum concentrations of substances released into the bile and imaging of structures involved in the secretion of the bile.

Laboratory tests

The serum concentrations of conjugated bilirubin and bile salts are the most commonly measured parameters. As these are retained to different extents in various cholestatic disorders, their relative levels go some way to helping with diagnosis. The serum bilirubin will help monitor progress. Other findings will typically include:

• A high alkaline phosphatase and gamma-glutamyl transferase (gamma GT) in virtually all obstructive diseases and many hepatocellular diseases. Serum transaminases will also be raised in obstructive cholestasis and to a lesser extent, hepatocellular disease.
• Elevated aspartate transaminase (AST) and alanine aminotransferase (ALT) suggest a more hepatocellular picture.
• Serum albumin and globulin will change little in the acute phase but albumin will decrease and globulin increase in chronic disease.
• Hyperlipidaemia will also be noted in some types of cholestasis where the ability to break down and excrete cholesterol is impaired. There is a picture of hypercholesterolaemia with a normal or low high-density lipo-protein.
• A haematology screen may show anaemia (where there is malignancy) and a raised white cell count (infection e.g. ascending cholangitis). Cholestasis lead to abnormally shaped cells and there may be a deficiency of vitamin K. Reticulocytosis points to pre-hepatic jaundice and it is worth checking the prothrombin time.

Imaging

Imaging and further investigation will be guided by the emerging clinical picture:

• Ultrasonography is a good first step to identify obstructive disease; depending on the result, further investigation may be appropriate.
• Endoscopic retrograde cholangiography (ERCP - no dilated ducts seen on ultrasound scan) and percutaneous transhepatic cholangiography (PTC - dilated ducts seen on ultrasound scan) will provide insight into the cause of the obstruction.
• CT may provide some useful information and can complement ultrasonography - particularly in obese individuals where the latter may be challenging.
• Liver biopsy is the single most useful test but it carries risks and many diagnoses can be made before a biopsy is considered.
• Where tumours are found, chest x-ray ±CT will be needed to look for evidence of spread.

• Elevated serum bilirubin in proportion to duration of the cholestasis
• Raised serum alkaline phosphatase to > 3 times its normal upper limit
• Raised gamma GT
• Mildly raised aminotransferases
• Increased urinary bilirubin

Urinary urinobilinogen is excreted in proportion to amount of bile reaching the duodenum so an absence of urinobilinogen suggests complete biliary obstruction.

• Jaundice not due to cholestasis
  • Unconjugated hyperbilirubinemia
  • Dubin-Johnson syndrome
  • Rotor syndrome
  • Carotenaemia
• Dark urine not due to bilirubinuria
  • Haematuria
  • Drug ingestion
  • Dehydration
• Pruritus not due to cholestasis
  • Atopic disease
  • Drug ingestion
  • Behaviour disorder

Generally, the differential diagnosis of cholestasis in neonates and infants is much broader than in older children and adults because the immature liver is relatively sensitive to injury and its response is more limited.³ For example in infants, cholestasis may arise as a result of Gram-negative sepsis, heart failure, metabolic disease or exposure to minimally toxic substances. It is therefore prudent to search beyond the liver for a cause in these patients.

• Obstructive cholestasis - this is usually as a result of a physical obstruction; the most common causes are gallstones and carcinoma of the head of the pancreas. However, paucity of the ducts (e.g. very small bile ducts such as in Alagille syndrome - an autosomal dominant disorder associated with abnormalities of the liver, heart, skeleton, eye, and kidneys and a characteristic facial appearance) may lead to a functional obstruction. Causes can be subdivided into:²
  • Obstruction of the lumen of the bile duct such as gallstones, parasitic (e.g. hydatid disease or round worms) or iatrogenic (e.g. post cholangiography).
  • Obstruction within the wall of the bile duct - sclerosing cholangitis, other types of cholangitis (e.g. infectious cholangitis or associated with Langerhans cell histiocytosis), cholangiocarcinoma, traumatic stricture and congenital stricture (e.g. biliary atresia, choledochal cysts).
  • Obstruction outside the bile duct, pressing into it such as carcinoma of the head of the pancreas or of the ampulla of Vater, pancreatitis, porta hepatis tumours and chronic duodenal ulceration.
• Hepatocellular cholestasis¹
  The most common causes are cirrhosis and drug reactions (e.g. phenothiazines, chlorpromazine, erythromycin, gold salts, anabolic steroids) but other causes include:³
  • Viral or alcoholic hepatitis
  • Sclerosing cholangitis
  • Septicaemia
  • Primary biliary cirrhosis
  • Alpha1-antitrypsin deficiency
  • Inborn errors of bile acid synthesis
  • Total parenteral nutrition (TPN)-associated cholestasis
  There are more uncommon causes of hepatocellular cholestasis including Dubin-Johnson syndrome, benign recurrent intrahepatic cholestasis, Hodgkin's disease: mechanism unknown, inspissated bile in cystic fibrosis, erythropoietic protoporphyria may cause precipitation of protoporphyrins in canalicular ducts, progressive familial Intrahepatic cholestasis and Caroli's disease. Benign intrahepatic cholestasis of pregnancy falls into this category (see below).

These patients need referring for investigation, diagnosis and treatment. Thereafter, management depends on the underlying problem. Cholestasis per se is not responsive to medical treatment;³ the underlying cause has to be sought and addressed. Similarly, it is worth noting that some of the secondary effects of cholestasis that would usually be managed successfully with conventional treatment are not responsive and only resolve with treatment of the underlying cause of cholestasis. This includes:

• The pruritus of cholestasis which is not mediated by histamines and therefore anti-histamines will be ineffective. There are a few options in the interim:
  • External biliary drainage
  • Cholestyramine
  • Phototherapy
  • Ursodeoxycholic acid (UDCA)
  • Rifampicin
• The asthma-type picture which sometimes emerges in these patients.
• Hypercholesterolaemia - dietary measures will do little positive and may be counter-productive, particularly in children where cholestasis may give rise to secondary malnutrition.
  These patients have complex dietary needs, especially where the disease is long-standing and particularly in the paediatric population. Whilst the fat intake needs to be reduced, the protein and calorie intake needs to be maintained. There may also be problems in the assimilation of fat-soluble vitamins (A,D,E,K). It is advisable to involve a dietician at an early stage.
• Osteopenia should be excluded in patients with chronic cholestasis (see complications).⁴ If this is present, bisphosphonates are the drugs of choice.

• Retention of biliary salts results in injury to cellular membranes throughout the body but hepatocytes are most affected (and therefore the problem is exacerbated). Thus cholestasis can give rise to secondary liver disease such as hepatic fibrosis.
• A well-described peripheral complication of chronic cholestasis is metabolic bone disease (osteopenia, osteoporosis and occasionally osteomalacia) - sometimes referred to as hepatic osteodystrophy.⁴
• Bleeding tendencies - particularly nosebleeds (which may be life-threatening) - affect the paediatric patient group.³
• Individuals with chronic cholestasis may develop an asthma-type wheeze which is not responsive to conventional asthma therapy and which disappears with treatment of the cholestasis.
• There may be complications from investigative procedures (e.g. cholangitis post ERCP, bleeding post biopsy).

This relates to that of the underlying problem.

This depends on the underlying cause.

Description

Also known as intrahepatic cholestasis of pregnancy (ICP), obstetric cholestasis is a multifactorial condition affecting 0.7% of pregnancies (1.2-1.5% of women of Indian-Asian or Pakistani descent). It is characterised by intense pruritus in the absence of a skin rash and abnormal liver function tests (particularly AST and ALT elevation) in the absence of other causes and which resolve following delivery. The importance relates to the risks associated with this condition:

• There is an increased risk of fetal distress and sudden intrauterine death.⁶
• There is an increased risk of premature birth (spontaneous and iatrogenic).⁷
• There is no current evidence supporting the claims of increased risk of caesarean section or post-partum haemorrhage.

Presentation

• Intense pruritus ± excoriation, affecting any part of the body but particularly the palms of the hands and soles of the feet.
• It is often worse at night and may interfere with sleep.
• Some women develop other signs associated with cholestasis (see above).
• There may be generalised malaise and fatigue.
• The itching may precede the LFT abnormalities by days or weeks.

Diagnosis

Other causes of liver dysfunction and itching need to be excluded. Think of gallstones, hepatitis, EBV, CMV, an autoimmune process (anti-smooth muscle and antimitochondrial antibodies) and organise a liver ultrasound scan. Other conditions to rule out are pre-eclampsia and fatty liver of pregnancy. Monitor LFTs weekly over this period of investigation.

If no other cause is found for the symptoms and LFT abnormalities, a diagnosis can be made on the basis of symptoms and liver function tests: transaminases, gamma GT (both raised) and bilirubin (infrequently raised).
More recently, the total bile acid level has been proposed as an alternative diagnostic marker.⁷

Management

• Monitoring - LFTs should be monitored weekly. If they return to normal or soar (into the 100s), the diagnosis needs to be revised. Following the delivery, wait at least 10 days before re-checking to avoid the confounding factor of the normal fluctuations in LFTs during this time following normal pregnancies. There are no current guidelines regarding specific fetal monitoring that might reduce the risks described above.
• Treatment - topical emollients are safe for both mother and baby but their efficacy is unproven. Ursodeoxycholic acid (UDCA) is the mainstay of medical management, with noted positive effects on both maternal and fetal outcome as well as on pruritus.⁶ Vitamin K can be offered (daily supplement of water-soluble preparation), particularly if there is steatorrhoea or a prolongation of the prothrombin time.
• Delivery - there is not currently data supporting the blanket recommendation of the popular practice of inducing an early labour and delivery (aimed at reducing a late stillbirth). However, each case should be considered individually.

Outcome

This is a condition that should settle spontaneously following delivery. Follow-up should be long enough to ensure a normalisation of LFTs. If, after six months, there is no improvement, further specialist input will be required. Women will have to counselled that there is a significant risk of recurrence (reports vary between 60% and 90%).