Cholestasis is a condition where bile cannot flow from the liver to the duodenum. Bile formation is a secretory function of the liver. It begins in bile canaliculi that form between two adjacent surfaces of liver cells (hepatocytes) similar to the terminal branches of a tree. The canaliculi join each other to form larger and larger structures, sometimes referred to as Canals of Hering, which themselves join to form small bile ductules that have an epithelial surface.
- pale stools
- dark urine
- yellowish pigmentation of the skinn (jaundice)
- failure to thrive (due to malabsorption of fat)
- itchiness (pruritus)
The effects of pruritus are age-dependent. The ability to scratch is not yet developed in young infants. The cutaneous signs of scratching begin to appear, usually around the ears or the nasal bridge, in infants aged 6-7 months. From there, they expand over the head, then the trunk, and finally to the limbs by the time the baby reaches age 12-14 months. The mutilating scratching observed in older patients does not appear until well after the first birthday. The fact that young infants do not scratch does not mean that they do not itch. Cholestatic babies are often irritable and do not socialize well. Young infants with those signs almost invariably proceed to scratching as they age, and irritability probably represents their response to pruritus.
Vitamin E deficiency causes neurological problems due to poor nerve conduction. Vitamin E deficiency symptoms include peripheral neuropathy and ataxia (damaging of nerves necessary for using muscles or sensing the environment), skeletal myopathy (muscle weakness to non-functioning of skeletal muscles), retinopathy (non-inflammatory damage to the eye), and impairment of the immune response. Complete blindness, cardiac arrhythmia, and dementia may occur in patients in whom vitamin E deficiency has been prolonged and severe. Deficiency can also cause anaemia due to oxidative damage to red blood cells.
Sources: Medscape, Wikipedia, National Institute of Health
Bile is secreted by the liver to aid in the digestion of food lipids and at the elimination of certain waste products (hemoglobin, cholesterol). When bile enters the small intestine it emulsifies fats so digestive enzymes can digest them more efficiently.
In chronic cholestasis the flow or the formation of bile is impaired. The two basic distinctions of cholestasis are obstructive and metabolic cholestasis. In obstructive cholestasis, a mechanical blockage in the duct system occurred, for example from a gallstone. In metabolic types of cholestasis, a disturbance in bile formation occurred because of genetic defects or it was acquired as a side effect of medications. This results in bile salts, pigments, and lipids to accumulate in the blood stream instead of being eliminated through the digestive tract. The main organs affected are the liver and the intestine, secondary effects can involve every organ system. Albeit chronic cholestasis in itself is not a primary cause of death, it is the cause of considerable morbidity mainly due to liver disease and systemic illness.
The differential diagnosis of cholestasis in neonates and infants is much broader than in older children and adults. This is because the immature liver is relatively sensitive to injury, and the response of the immature liver is more limited. Cholestasis develops in response to a wide variety of insults. Although the reasons for this are not entirely clear, it is considered the result of immaturity of several critical mechanisms of bile formation. So-called physiologic cholestasis of infancy results from immaturity of these mechanisms. This is better termed physiologic hypercholemia and is characterized by the elevation of serum bile salt concentrations in healthy infants to a level equal to many adults with pathologic cholestasis.
This developmental condition probably helps to establish the infant's sensitivity to various insults that would not produce cholestasis in adults, such as gram-negative sepsis, heart failure, metabolic disease, and exposure to minimally toxic substances. Because of this, looking beyond the liver for the cause of cholestasis in newborns or young infants is wise. If no other cause is found and liver disease is suspected, a more focused diagnostic investigation can be undertaken.
Deficiencies of the fat soluble vitamin E is therefore a complication often observed in patients presenting with this condition. Vitamin E is one of the most important lipid-soluble antioxidant nutrients. It also acts through immunomodulation on lymphocyte proliferation and production of prostaglandin E2.
Vitamin E deficiency can lead to progressive demyelinisation affecting the nervous system and consequently leads to neurological abnormalities like peripheral neuropathy, ataxia and skeletal myopathy.
Other vitamins that are also malabsorbed in chronic cholestasis are the fat soluble vitamins D, K and A.
Sources: Wikipedia, Medscape
In chronic cholestasis, careful attention must be paid to prevent fat-soluble vitamin deficiencies. This is accomplished by administering fat-soluble vitamins and monitoring the response to therapy
Cholestasis can be diagnosed through the measurement of the blood concentration of serum bilirubin, conjugated bilirubin or total serum bile salts.
Newer methods of measuring bilirubin in serum have resulted in the discovery of a fraction of serum bilirubin that is covalently bound to albumin, known as delta bilirubin or biliprotein. This fraction may account for a large proportion of total bilirubin in patients with cholestatic jaundice but is absent in patients with nonconjugated hyperbilirubinemia. This complex is formed in plasma by a nonenzymatic process that involves acyl migration of bilirubin from its glucuronide ester with the formation of an amide linkage between 1 propionic acid side chain and a lysine residue of plasma albumin. The presence of large quantities of delta bilirubin indicates long-standing cholestasis. Any amount of delta bilirubin in cord blood or the blood of a newborn is an important sign indicating cholestasis that antedates birth.
Ultrasonography of liver and bile ducts, cholangiography and abdominal CT scanning are used to identify anatomic causes of obstructive cholestasis (eg. gallstones). Liver biopsy is the single most useful test to determine the cause of cholestasis, but requires a high degree of expertise in interpretation.
Ursodeoxycholic acid is the most frequently used pharmacological agent in children with chronic cholestasis, which is administered at dosages between 10 and 30 mg/kg/day. Ursodeoxycholic acid mainly increases bile flow and has a membrane-stabilizing effect, reducing the toxicity of more hydrophobic bile acids. The antibiotic rifampicin, applied between 10 and 20 mg/kg/day, is very efficient in relieving pruritus. Similar effects are obtained using nonabsorbable ion exchange resins (e.g. cholestyramine). In addition, these molecules decrease the serum cholesterol levels contributing to reduce xanthomas. Ultraviolet light might also help against pruritus.
Supplementation of vitamin E is important against malnutrition, because apparently effective doses are beyond the maximum dietary intake. Replacement recommendations according to disease state are 15-25 IU/kg/d for chronic cholestasis.
The Recommended Dietary Allowance (RDA) of alpha tocopherol according to age is as follows:
- Age 0-6 months - 3 mg
- Age 6-12 months - 4 mg
- Age 1-3 years - 6 mg
- Age 4-10 years - 7 mg
- Adults and elderly individuals - 8-10 mg
Sources: Medscape, Alvarez (2008, Ann Nestlé; 66:127-135)