Cholestatic Liver Disease

Introduction

Cholestatic liver disease is a condition that occurs due to liver damage and fibrosis because of impairment in bile formation or flow.¹ Now the question arises of what is a bile? Well, bile is a water-soluble fluid that is formed by the liver and aids in the digestion of fats. It is formed by various mechanisms of conjugation with regulation at different levels.

The bile is transported via transported protein in the canaliculus, creating an osmotic gradient. With the help of this gradient, water enters the canaliculi. Understanding the abnormalities in any transporter proteins has led to a clearer picture of the disease presentation.

Due to the failure of bile transport, the bile salt concentration is increased in the liver. The resilient detergent-like effect of these salts causes injury in the membrane and hence impairment of its function. Another mechanism of cholestasis is the physical obstruction at the level of extrahepatic biliary ducts to bile flow.²

The impairment in bile formation or flow can be due to problems in the liver itself (intrahepatic cholestasis) like overuse of drugs, infection, some disease or hormonal effects or it can be due to blockage of bile ducts (extrahepatic cholestasis). This may be due to gallstones, cysts or tumours.

Scientifically, cholestasis is of 2 types. It is represented by primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), but the pathophysiological pathways that cause bile impairment in both diseases are quite distinct. PBC is primarily illustrated by the granulomatous damage to small intrahepatic bile ducts³ whereas PSC is defined by inflammation and fibrosis of the intra and extrahepatic bile ducts, which lead to various bile duct stenosis.⁴

Furthermore, it has been observed that inflammatory bowel disease (IBD) is the main risk factor for PSC patients.⁵ It has been observed that T cells are involved in the damaging of bile ducts in patients with PSC. Hence, it is considered a cytotoxic disorder.⁶ Both of these subtypes are associated with autoimmune triggers for the damage of the bile duct which may further lead to cirrhosis and ultimately liver failure.⁷

Signs and symptoms

The most common symptom of cholestatic liver disease is a pain in the abdomen. However, it is a very common problem to experience pain in the abdomen so doctors associate it with other symptoms like

• Jaundice: It is diagnosed as yellowing of the skin, whites of eyes and mucous membrane. The main reason for this is the increased production of bilirubin. It is a more common symptom in the case of extrahepatic cholestasis⁸
• Pruritus: It is an itchy sensation that provokes the person to scratch. The itchy sensation is more during the daytime as the bilirubin concentration is more due to the consumption of food. At night the itchiness generally decreases⁹
• Fever is also associated with cholestasis
• Fatigue or simply put tiredness is also experienced by most of the cholestatic liver disease patients
• Clinical classifications of deficiency of fat vitamins like A, D, E and K may also be associated with cholestasis as bile is involved in the absorption of these
• Excessive use of medications especially antibiotics
• Family history of the disease or any autoimmune disease¹⁰

Causes and risk factors

Though the main cause of cholestasis is the obstruction in bile formation or secretion and as discussed above it can be due to any reason. However, advances in molecular genetic techniques have facilitated the identification of causative genes, which has better diagnostic accuracy for patients and has led to an increased understanding of the pathways involved in the pathogenesis of liver diseases. Hence, some atypical causes and risk factors of cholestasis are discussed below:

Alagille syndrome (AGS)

It is a multisystem, highly complex, autosomal dominant disorder that is caused by a flaw in the Notch signalling pathway (JAG1 or NOTCH2). This mainly involves the liver, causing considerable cholestasis, which is caused by a scarcity of intrahepatic bile ducts. New therapeutic approaches are under review, including ileal bile acid transporter (IBAT) inhibitors that may involve direct interventions to enhance the Notch signalling pathway in involved tissues.¹¹

Progressive familial intrahepatic cholestasis (PFIC)

It is a condition in which bile transport is affected. Its clinical presentation can fluctuate from early-onset severe liver disease to irregular late-onset due to an external stimulus. Based on clinical presentation, findings of the laboratory, histology of the liver and genetic defect, these are generally classified into three types—PFIC type 1, type 2 and type 3.

The mutation is present in the ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene (BSEP protein) and ABCB4 gene (MDR3 protein) in types 1, 2 and 3 respectively.¹² The main problem in PFIC1/2 has impaired bile salt secretion whereas it is decreased biliary phospholipid secretion in PFIC3.

Treatment mainly includes nutritional care by providing fat-soluble vitamins, medium chain triglycerides and adequate calories to the body. As pruritus is the main clinical presentation, it is generally taken care of by the use of prescribed medications.⁹ Furthermore, gene therapy, mutation-targeted pharmacotherapy and hepatocyte transplantation are being explored as future therapeutic options.¹³

Bile acid synthesis defects (BASDs)

These are unusual metabolic disorders. As discussed above, bile acids are chemical compounds found in the liver that have various functions in the body including causing the flow and excretion of bile and helping in the absorption of fat and fat-soluble vitamins in the intestine. These acids are formed from cholesterol.

Hence, bile acid synthesis functions as the key pathway in breaking and eliminating cholesterol from the body. The inability to form functional bile acids causes the accumulation of abnormal bile acids and intermediary metabolites within the body. The main symptom of BASDs is decreased or no flow of bile from the liver (cholestasis) and fat-soluble vitamin malabsorption.¹⁴ Studies have shown that BASDs is caused by mutations in specific genes which are inherited in an autosomal recessive pattern.¹⁵

Niemann-Pick type C disease (NPC)

It is an inborn error of metabolism defined by a defect in cholesterol trafficking from the lysosome. It is also inherited in an autosomal recessive manner. Defects in variants on NPC1 or NPC2 genes cause NPC.

These genes encode proteins which help in moving out of unesterified cholesterol from the lysosome to other cellular organelles and membranes. The clinical spectrum is highly variable and ranges from a severe prenatal presentation to an adult onset. The initial symptoms of the disease are neonatal cholestasis (NC) which is generally combined with hepatomegaly and spleen enlargement.¹⁶

Aagenaes syndrome

Lymphedema cholestasis syndrome 1 (LCS1), or Aagenaes syndrome, is a rare inborn, autosomal recessive hereditary disease. It is characterized by cholestasis as there is a decline in bile flow, classically from birth. Liver function usually improves with time, but in some circumstances, cholestasis can cause cirrhosis and ultimately liver failure.¹⁷ Some cases of Aagenaes syndrome have been linked to genetic changes in the LSC1 gene on chromosome 15q.¹⁸

Zellweger syndrome

It is a rare autosomal recessive peroxisomal disorder that is associated with multiple peroxisome malfunctions. Among the several peroxisomal genes, it is mostly linked to mutations in PEX1 and PEX6. In the early perinatal period, liver involvement may not be significant, although some infants may show symptoms of conjugated hyperbilirubinemia.

Hepatosplenomegaly and impaired hepatic biosynthetic function may be present even in patients without jaundice. Histologically, the liver often shows decreased numbers of small intrahepatic bile ducts and fibrosis.¹⁹

Diagnosis

Liver function tests

Total and fractionated direct bilirubin levels should be performed in serum. In cholestasis, primarily increased levels of bilirubin are observed. Also, in cholestasis, the level of serum alkaline phosphatase is 3 times above the upper normal limit. The levels of ALT or AST are generally normal or show a mild increase in cholestatic jaundice. Serum albumin is usually decreased in patients with liver cirrhosis or chronic liver disease.²⁰

Haematology

• Increased leukocyte levels in the blood are usually observed in cholangitis and malignancy
• Acute severe anaemia or Chronic anaemia can be observed in liver cirrhosis or malignancy
• Increased prothrombin time can be observed in patients with cholestasis which quickly reverses with supplementation of vitamin K in contrast to cirrhosis patients

Radiological Assessment

• Abdominal ultrasound can be of assistance when one needs to identify if there is any kind of biliary ductal dilation. It can also help to differentiate between hepatocellular causes of biliary obstruction in which ducts will be dilated with cholestasis in which ducts will be normal size
• If dilated biliary ducts are observed on primary ultrasound, then magnetic resonance cholangiopancreatography can be used to evaluate bile ducts to identify any stone or stricture vs. malignancy

Liver Histology

• It is generally performed in the case of intrahepatic cholestasis to assess different underlying etiologies

Treatments

Management of cholestatic liver disease depends mainly upon the underlying etiology and type of cholestasis. Some of the drugs:

Ursodeoxycholic acid (UDCA)

It is the main anti-cholestatic drug for many cholestatic liver diseases like intrahepatic cholestasis of pregnancy, PBC and for liver involvement in cystic fibrosis. However, UDCA alone is quite ineffective for the treatment of PSC. UDCA has many sites of action to reduce the cholestasis.

It decreases the bile acid-mediated toxicity due to its anti-apoptotic nature and also by the initiation of a bicarbonate-rich biliary choleresis.²¹ UDCA also upregulates the bile acid–transporting systems and decreases bile acid synthesis. By and large, this UDCA shows anti-cholestatic abilities at distinct disease stages on the hepatocytic and bile duct levels.²²

Hence, its use is recommended by the American Association for the Study of Liver Diseases (AASLD)²³ and also by the European Association for the Study of the Liver (EASL).²⁴

Obeticholic acid (OCA) and another farnesoid X receptor (FXR) agonists

FXR is the main integrator of bile acid homeostasis. On activation, it causes a significant decrease in cellular bile acid levels. FXR is a kind of a nuclear hormone receptor and transcription factor that is biologically triggered by hydrophobic bile acids such as chenodeoxycholic acid.

OCA is a semi-synthetic derivative of natural chenodeoxycholic acid. It has approximately 100-fold more affinity for FXR.²⁵ It has been used commonly as a second-line treatment in PBC patients who either do not respond or cannot tolerate UDCA. In the POISE clinical trial also it was observed that twelve-month OCA treatment along with UDCA decreased the AP below the 1.67 upper limits of normal in 47% of the patients.²⁶

Only the above-mentioned drugs are commonly used as medications for the cholestatic liver disease. However, many other drugs are still under clinical trials to function as potential therapeutic agents against the disease.

Cholestatic liver disease and pregnancy

Cholestasis of pregnancy is a very common liver disease. It generally appears as an itch in late pregnancy. It is also acknowledged as intrahepatic cholestasis of pregnancy (ICP) or obstetric cholestasis. Epidemiologically, it has been reviewed that it is more prevalent in South American and Scandinavian countries.

Furthermore, the risk factors that promote ICP are multiparity, advanced maternal age, and some preceding history of cholestasis because of the use of oral contraceptives.²⁷ The characteristic symptom of ICP as discussed above is an itch or is scientifically defined as pruritus, but it is often accompanied by fatigue, epigastric pain, anorexia, and even jaundice. Bile acids are usually elevated in ICP while levels of AST and ALT range from normal to 10 to 20 times higher than normal.²⁷

Furthermore, the limited studies on fertility and pregnancy in PSC that are available in the literature suggest that PSC has no negative effect on pregnancy.²⁸ In fact, it has been observed that PSC is not linked to stillbirth or fetal loss or any kind of congenital malformation and even to pregnancy outcomes like the number of off-springs etc.^29,30

In the case of PBC also younger women show more symptoms than older women.³¹ However, in the largest population-based study including PBC patients, it was observed that the disease has no connection with decreased fertility.^32,33

Summary

Both PSC and PBC are gradually advancing chronic liver diseases that are initiated by the destruction of the bile duct leading to fibrosis and ultimately cirrhosis. However, studies are still limited to understand the pathogenesis of the disease. Also, the treatments or the drugs available to the patients are very restricted.

UDCA is the only approved and effective anti-cholestatic drug that is available in the market for these patients. With a greater understanding of the molecular pathways and the immunological attributes involved in disease occurrence and progression, a range of compounds both natural and synthetic have entered the clinical stage. In near future, it may be a possibility to fight this disease at an early stage as endeavours are ongoing to investigate newer diagnostic and therapeutic methods.