Cholestasis and jaundice

Published on 09/04/2015 by admin

Filed under Gastroenterology and Hepatology

Last modified 22/04/2025

Print this page

This article have been viewed 5297 times

Chapter 32 CHOLESTASIS AND JAUNDICE

• Biliary, hepatocellular and systemic conditions may all cause cholestasis and jaundice.

• Elevated bilirubin and cholestatic enzymes (ALP and GGT) suggest a biliary cause. Elevated bilirubin and transaminases (ALT and AST) suggest a hepatocellular cause.

• Imaging with abdominal ultrasound is essential to evaluate for the presence of biliary obstruction and parenchymal liver disease, giving useful information about both the underlying cause for cholestasis and any complications of liver disease.

• A liver screen should be performed to narrow the differential diagnosis for cholestasis.

• Treatment of cholestasis is primarily aimed at treating the underlying cause.

• Pruritis is a troublesome symptom of cholestasis, and can occur with elevated bile acids, even when the bilirubin is within normal range. There is a range of specific treatments available.

• Cholestatic disorders contribute to mortality and morbidity and are, in some settings, an important indication for liver transplantation.

INTRODUCTION

Cholestasis and jaundice are common clinical occurrences which flag the presence of an underlying disease process. Diseases of the liver and biliary tree are a significant cause of morbidity and mortality and an important indication for liver transplantation in certain settings. This chapter outlines an approach to dealing with this common problem.

Definitions

Cholestasis can be defined as ‘the excess of biliary substances in the blood’. Cholestasis may be accompanied by jaundice and/or deranged liver biochemistry. Although cholestasis commonly occurs in the context of biliary obstruction, it may occur without evidence of biliary pathology.

CAUSES OF CHOLESTASIS

Cholestasis can broadly be divided into that caused by mechanical obstruction, and that caused by non-obstructive or hepatocellular causes. Table 32.1 lists the causes of cholestasis. Mechanical obstruction may develop in either the extrahepatic biliary tree or the smaller intrahepatic bile ducts. Non-obstructive intrahepatic cholestasis may arise from parenchymal disease affecting the small bile ducts and canaliculi or conditions affecting the hepatocytes directly (causing an excess of bile products to be formed). Considering the possible underlying causes of cholestasis will guide the history, examination and investigation of a patient with cholestasis. Important causes to consider include the following.

TABLE 32.1 Causes of cholestasis

1. Cholelithiasis and choledocholithiasis: cholelithiasis (stones in gall bladder) is common, occurring in up to 25% of Caucasian population, and more in certain ethnic groups. Choledocholithiasis (stone in bile duct) complicates 15%–20% of patients with cholelithiasis. Major risk factors for cholelithiasis include age, female gender, family history, obesity, diabetes and hyperlipidaemia. States with elevated oestrogen and progesterone (pregnancy, oral contraceptives and hormone therapy) are also lithogenic.

2. Malignancy: malignancies (primary and secondary) can cause cholestasis both by mechanical obstruction (e.g. large intrahepatic tumours, cholangiocarcinomas or pancreatic tumours) or by disruption of normal hepatocyte function (hepatocyte destruction).

3. Primary sclerosing cholangitis (PSC): an idiopathic inflammatory disorder of bile ducts characterised by small and large bile duct strictures, portal fibrosis and cirrhosis. Patients have abnormal liver function tests at diagnosis, but only approximately half of the patients are symptomatic at this time. Coexisting inflammatory bowel disease is found in 62% of the patients. High-dose ursodeoxycholic acid has been used to manage cholestasis and endoscopic therapy for dominant bile duct strictures, however the role of these therapies requires further investigation. The risk of developing cholangiocarcinoma is high.

4. Primary biliary cirrhosis (PBC): an autoimmune disease of the bile ducts, occurring predominantly in women, which if untreated can progress to fibrosis and cirrhosis. Antimitochondrial antibodies are found in 95% of patients with PBC. Ursodeoxycholic acid is the only treatment established to modify disease progression in PBC.

5. Drug-induced cholestasis: this can occur with a number of pharmacological agents and may be associated with variable degrees of hepatitis. The offending drug should be promptly discontinued. In some circumstances, drug induced cholestasis may progress to vanishing bile duct syndrome, veno-occlusive disease or liver failure.

6. Hepatocellular causes: any acute or chronic hepatocellular injury can cause cholestasis (e.g. viral or alcoholic hepatitis). This is characterised by a predominant elevation in the serum transaminases and the cholestasis usually resolves sometime after the resolution of the underlying acute hepatocellular injury.

7. Congenital: a choledochocele is a cystic dilatation of the common bile duct, which may cause intermittent biliary obstruction. It is rare, occurring in approximately 1:100,000–150,000 live births. About 80% are diagnosed before 10 years of age, classically presenting as a triad of right upper quadrant pain, a mass and jaundice. In adults this is a rare presentation with abdominal pain and tenderness being the most common features. Endoscopic and surgical therapies are possible.

8. Inherited defects of bilirubin uptake, glucuronidation and transport:

a Unconjugated hyperbilirubinaemia:

i. Gilbert’s syndrome: the most common inherited disorder of bilirubin glucuronidation. Diagnosed in young adults who present with mild icterus or isolated hyperbilirubinaemia. Impaired conjugation of bilirubin is due to reduced bilirubin UDP glucuronosyl transferase activity.

ii. Crigler-Najjar syndrome (Type I & II): congenital non-haemolytic jaundice with glucuronosyltransferase deficiency. A rare, autosomal recessive disorder of bilirubin metabolism presenting as neonatal jaundice (kernicterus).

b Conjugated hyperbilirubinaemia: characterised clinically by mild icterus presenting in the second decade of life.

i. Dubin-Johnson syndrome: rare condition except in Sephardic Jews (incidence is 1:3000) due to altered excretion of bilirubin into the bile ducts.

ii. Rotor syndrome: due to defective hepatic storage of bilirubin.

c Defects in canalicular transport: a range of molecular defects can result in impaired transport of bile acids, phospholipids and ions that express as progressive familial forms of cholestasis.

9. Haemolysis: although haemolysis due to any cause leads to an excess of biliary substances in the blood (unconjugated hyperbilirubinaemia) and may cause clinically evident jaundice, it is not usually associated with cholestatic symptoms. An exception to this is haemolytic disease of the newborn which causes kernicterus, a condition with significant risks to the neonate.

ASSESSMENT

History

Fatigue is the most common symptom of chronic cholestasis. Other symptoms include jaundice, pruritis and steatorrhoea. There may be a history of haemorrhage due to poor vitamin K absorption or bone pain and fractures due to poor vitamin D and calcium absorption (in cases of chronic cholestasis resulting in hepatic osteodystrophy or osteoporosis).

Specific questioning will help determine the underlying aetiology of the cholestasis.

• Enquire about the presence, site and character of abdominal pain. The absence of pain is also relevant. Ask about associated nausea, vomiting and the timing of these symptoms.

• Fevers, chills and rigors suggest hepatobiliary obstruction or an infectious aetiology.

• Enquire about constitutional symptoms suggestive of underlying malignancy (weight loss, appetite change) and perform a specific systems review for other symptoms of malignancy.

• Ask about intercurrent conditions, especially:

– Metabolic disorders

– Autoimmune disorders

– Inflammatory bowel disease

– Cardiac disease

– Haematological conditions.

• Take a family history with particular focus on liver disease, autoimmune diseases, malignancies, neonatal jaundice or cholestasis of pregnancy.

• A thorough drug history (including complementary and over-the-counter drugs) is essential to evaluate for the possibility of a drug-induced cholestasis.

• Ask about the level of alcohol consumption (in grams per day) and illicit or recreational drug use. Risk factors for viral hepatitis and human immunodeficiency virus (HIV) should be elicited (intravenous drug use, tattoos, blood product transfusions, foreign travel, infectious contacts, occupation, sexual history).

Physical examination

Start with general inspection. Scleral icterus is first visible when the serum bilirubin is greater than twice the upper limit of normal. There may also be generalised jaundice (yellowing of the skin). Check for scratch marks (suggesting pruritis), bruising (vitamin K deficiency) and muscle wasting (malabsorption, malignancy).

Then check the nursing observations. Check for fever, hypotension and tachycardia which suggest sepsis/infection. Assess if the patient is orientated to time, person and place. Examine for asterixis (hepatic flap) and fetor, which suggest hepatic encephalopathy. Check for signs of chronic liver disease (palmar erythema, spider naevae, gynaecomastia, dilated abdominal wall veins). Examine for lymphadenopathy in all lymph node groups.

Examine the abdomen for organomegaly and masses. A small shrunken liver with splenomegaly suggests chronic liver disease. An enlarged liver suggests acute hepatitis, hepatic congestion, primary biliary cirrhosis or an infiltrating process (malignant or non malignant). A nodular liver suggests malignancy, cystic disease or cirrhosis.

The presence of a palpable gall bladder in a patient with painless jaundice is worrying (Courvoisier’s sign)—this suggests compression of both the cystic duct and bile duct, usually due to malignancy of the head of the pancreas. A tender gall bladder suggests cholecystitis—if there is associated jaundice, a gallstone in the common bile duct (choledocholithiasis) is likely. Choledocholithiasis alone causes abdominal pain, but rarely tenderness on examination unless there is associated pancreatitis or cholecystitis.

Check for shifting dullness (ascites), which, if present, suggests hepatic decompensation.

Investigations

Basic laboratory tests: biochemistry (liver function tests, electrolytes and creatinine), full blood count and coagulation profile. Note the degree of hyperbilirubinaemia and the presence of hypoalbuminaemia and coagulopathy (which together suggest hepatic decompensation). Disorders of the bile ducts predominantly cause elevation in gamma glutamyltransferase (GGT) and alkaline phosphates (ALP). In disorders affecting hepatocytes, the serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) predominantly may be elevated. There is often mixed liver function test derangement, in which case further investigations may be necessary to narrow the differential diagnosis (see Chapter 30).

Non-invasive imaging modalities

Ultrasound is an essential basic imaging modality to investigate for biliary and hepatic parenchymal pathology. The size and echogenicity of the liver, the presence of biliary duct dilatation, cholelithiasis/choledocholithiasis and the gall bladder may all be assessed. The pancreas and spleen should also be assessed for size and space occupying lesions, and Doppler flow studies of the hepatic and portal veins performed to check for thrombosis or other impedance to blood flow. The presence and volume of ascites should also be noted.

Computed tomography (CT) scans or magnetic resonance cholangiopancreatography (MRCP) may be needed to further characterise abnormal findings.

Invasive imaging modalities (with therapeutic capability)

Endoscopic retrograde cholangiopancreatography (ERCP)

ERCP allows imaging of both the pancreatobiliary tree as well as therapeutic intervention with sphincterotomy, biliary dilatation, biliary duct balloon trawl, lithotripsy and stenting. The complications of pancreatitis, cholangitis, bleeding and perforation should be weighed against benefits of the procedure.

Percutaneous transhepatic cholangiography (PTC)

This ultrasound-guided procedure is an alternative or adjunct in patients who will not tolerate ERCP, or in those patients in whom ERCP is technically difficult (e.g. in cases of non-dilated biliary system or abnormal anatomy). Biliary stenting and percutaneous biliary drainage is also possible with this method.

Endoscopic ultrasound (EUS)

EUS has been used to image the hepatobiliary tree, pancreas and adjacent structures. Its precise role in the investigation and management of cholestatic disorders is under evaluation.

Table 32.2 summarises the sensitivity and specificity of the range of imaging modalities available for detecting choledocholithiasis.

TABLE 32.2 Sensitivities and specificities of imaging modalities used to detect cholelithiasis, choledocholithiasis and biliary obstruction

Liver screen

If basic investigations exclude obstructive causes for cholestasis, investigations for parenchymal or intrahepatic causes may be needed. The following liver screen should be considered.

• Viral causes:

– Hepatitis A IgM, HBsAg (hepatitis B surface antigen), HBcAb (hepatitis B core antibody), HBeAg (hepatitis B e antigen) and HBeAb (hepatitis B e antibody)

– Hepatitis B DNA PCR (polymerase chain reaction) and/or hepatitis C RNA PCR and genotype if serology positive

– Epstein-Barr virus (EBV) IgG and IgM, cytomegalovirus (CMV) IgG and IgM.

• Autoimmune causes:

– Antimitochondrial antibody (AMA), antineutrophil cytoplasmic antibody (ANCA), anti-liver/kidney microsomal antibody (Anti-LKM Ab), anti-smooth muscle antibody

– Gamma globulin level.

• Malignant causes:

– Alpha-fetoprotein (AFP), human chorionic gonadotrophin (β-hCG), electrophoresis (EPG), immunoelectrophoresis (IEPG), carbohydrate antigen (CA 19-9).

• Metabolic causes:

– Fasting glucose, insulin, C-peptide

– Fasting cholesterol and triglycerides

– Thyroid function tests

– Copper and caeruloplasmin

– Iron studies

– Alpha₁-antitrypsin level (and genotype if level reduced).

– Blood film, lactate dehydrogenase (LDH), reticulocytes, haptoglobins, Coombs test.

Liver biopsy

Percutaneous liver biopsy is considered the gold standard for diagnosis of liver disease. A liver biopsy may be necessary before committing a patient to specific treatments with significant adverse effects or toxicity. Liver biopsy is also useful to determine disease severity and prognosis by evaluating extent of fibrosis or cirrhosis. Specialty consultation should be considered before a liver biopsy because of the risks associated with the procedure (see Chapter 33).

MANAGEMENT

1. Treat underlying cause:

• In cases of mechanical obstruction, consider endoscopic retrograde cholangiopancreatography (ERCP) to relieve dominant strictures, malignant obstruction or choledocholithiasis

• Systemic conditions: treat heart failure, malignancies, etc

• See chapters on treating specific underlying disorders.

2. Remove exacerbating/precipitating factors:

• Hepatotoxic drugs

3. Treat complications of chronic cholestasis:

• Treat cholangitis with antibiotics

• Correct nutritional/vitamin deficiencies

• Treat any manifestations of hepatic decompensation (see Chapter 47).

4. Symptomatic treatment (see Table 32.3):

a For mild cholestatic pruritus—nonspecific measures:

• Antihistamines: promethazine 10–20 mg b.d. and 25–75 mg nocte (sedating), or loratadine or cetirizine 10 mg daily (non-sedating).

b For moderate to severe pruritus, or mild pruritus that does not respond to simple measures:

• Cholestyramine (4 g daily) or

• Colestipol (15–30 g daily in 2–4 divided doses) or

• Ursodeoxycholic acid (15 mg/kg daily in two divided doses).

TABLE 32.3 Mechanism of action of drugs to manage cholestasis

Cholestyramine	Cholestyramine resin combines with bile acids forming a complex that is excreted in the faeces. This non-systemic action results in a partial removal of the bile acids from the enterohepatic circulation, preventing their reabsorption
Colestipol	An oral hypolipidaemic that binds bile acids in the intestine, i.e. works like cholestyramine
Ursodeoxycholic acid (UDCA)	A hydrophilic bile acid. The assumption is that replacing the bile acid pool UDCA may reduce hepatocyte damage
Rifampicin	May decrease pruritus by competing with bile acids for hepatic uptake, thereby minimising bile acid toxicity to the hepatocyte. May also induce microsomal enzymes that promote 6-alpha-hydroxylation and subsequent glucuronidation of toxic bile salts
Phenobarbitone	Sedative properties
Opioid antagonists	Opiate receptors may be implicated in pathogenesis of pruritis therefore blocking these receptors theoretically may improve symptoms

If these fail, consider:

• Rifampicin 150 mg b.d. (monitor liver function tests for drug induced/idiosyncratic liver derangement)

• Phenobarbitone 90 mg q.i.d. (alternative to rifampicin—has the disadvantage of somnolence during the first few weeks of use).

c Refractory pruritis: these patients may need an acute pain team consultation or consideration for use of investigational techniques:

• Opioid antagonists, e.g. naloxone

• Plasmapheresis

• Phototherapy

• Extracorporeal albumin dialysis

• Emerging therapies – pharmacologic modulation of xenobiotic/nuclear receptors.

Liver transplantation should also be considered in refractory cholestatic pruritis.

a Biliary reconstruction

• High mortality from surgery, especially if cirrhotic.

b Liver transplantation—85% five-year survival. Indications include:

• Haemorrhage due to oesophageal varices or portal gastropathy

• Intractable ascites

• Recurrent bacterial cholangitis

• Progressive muscle wasting

• Hepatic encephalopathy

• Refractory cholestatic pruritis.

c Pregnant women: obstetric liaison is essential (see Chapter 48).

• Pregnant women are susceptible to all the usual causes of cholestasis as listed above.

• Cholestasis of pregnancy: severe cholestasis with significant symptoms may occur from 20 weeks gestation. The cholestasis resolves following delivery of the baby. Ursodeoxycholic acid may improve symptoms and may also improve fetal outcome especially if serum bile acids exceed 40 μg/mL:

– Ursodeoxycholic acid 15 mg/kg orally, daily in two divided doses, or

– Cholestyramine 4 g daily.

SUMMARY

Both cholestasis and jaundice can arise due to biliary, hepatocellular and systemic conditions. Biochemical clues may suggest the underlying mechanism for the cholestasis: elevated bilirubin and cholestatic enzymes (ALP and GGT) suggest a biliary cause; elevated bilirubin and transaminases (ALT and AST) suggest a hepatocellular cause (Figure 32.1). Imaging with abdominal ultrasound gives useful information about both the underlying cause for cholestasis and any complications of liver disease. A full liver screen will narrow the differential diagnosis for cholestasis. Treatment of cholestasis is primarily aimed at treating the underlying cause, but a range of symptomatic treatments is available. In particular, pruritus is a troublesome symptom of cholestasis, and can occur with elevated bile acids, even when the bilirubin is within normal range.

FIGURE 32.1 The evaluation of cholestasis.

CT = computed tomography; ERCP = endoscopic cholangiopancreatography; EUC = electrolytes, urea, creatinine; FBC = full blood count; LFTs = liver function tests; MRCP = magnetic resonance cholangiopancreatography; PTC = percutaneous transhepatic cholangiography.

One must appreciate that cholestatic disorders contribute to mortality and morbidity and, in some settings, these disorders are an important indication for liver transplantation.

FURTHER READING

Balistreri WF, Bezerra JA, Jansen P, et al. Intrahepatic cholestasis: summary of an American Association for the Study of Liver Diseases single-topic conference. Hepatology. 2005;42:222-235.

Demery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinaemia. N Engl J Med. 2001;344:581-590.

Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology. 2006;40:467-474.

Glasova H, Beuers U. Extrahepatic manifestations of cholestasis. J Gastroenterol Hepatol. 2002;17:938-948.

Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Eng J Med. 2005;353:1261-1273.

Levy C, Lindor KD. Drug-induced cholestasis. Clin Liver Dis. 2003;7:311-330.

Related

Gastroenterology and Hepatology