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Cholestasis

BRIC

Cholestasis is defined as a reduction or stoppage in the flow of bile into the intestine caused either by an extrahepatic cause like a blockage (eg. a stone in the bile duct) or by an intrahepatic cause leading to impaired production of bile, like a liver disease.


Presentation

Cholestasis commonly presents with jaundice, pale stools and dark urine. There may be abdominal pain and fever in case of infection or cholecystitis. A common feature of cholestasis is pruritus, which may be disabling or significantly affecting the daily life of the patient. Children may show failure to thrive, hormonal disturbances, and attention deficits. Sometimes, xanthomas may be observed on the trunk and diaper area and in skin folds [8].

Splenectomy
  • The patient abruptly died of sepsis at 3 months of age before a planned splenectomy and ongoing evaluation for liver transplantation.[ncbi.nlm.nih.gov]
Cyanotic Congenital Heart Disease
  • Infants with metabolic liver disease, cyanotic congenital heart disease, congenital syphilis, hepadnaviridae infection, and those who underwent surgery were excluded.[ncbi.nlm.nih.gov]
Clay-Colored Stool
  • Jaundice and Intrahepatic cholestasis of pregnancy (ICP) The increased build-up of bilirubin leads to jaundice, dark colored urine and pale white clay colored stool. This may be seen in very few severe cases of ICP.[news-medical.net]
Jaundice
  • The disease is very well known for episodic flare of jaundice with cholestatic symptoms that are spontaneous or perpetuated by acute insults, followed by self-recovery.[ncbi.nlm.nih.gov]
  • […] during the follow-up period in which jaundice faded after treatment with medical therapy.[ncbi.nlm.nih.gov]
  • Jaundice. Jaundice is an uncommon occurrence in intrahepatic (metabolic) cholestasis, but is common in obstructive cholestasis. Pale stool. This symptom implies obstructive cholestasis.[en.wikipedia.org]
  • RATIONALE: Septo-optic dysplasia (SOD) is a rare congenital disorder that may cause jaundice in infants.[ncbi.nlm.nih.gov]
  • Her physical exam was remarkable for jaundice and scleral icterus without any stigmata of liver disease.[ncbi.nlm.nih.gov]
Scleral Icterus
  • Her physical exam was remarkable for jaundice and scleral icterus without any stigmata of liver disease.[ncbi.nlm.nih.gov]
  • It results in jaundice, which can be detected by scleral icterus at a concentration as low as 2 mg/dL, and by dark urine.[emedicine.medscape.com]
  • Exam revealed a chronically ill-appearing man with a flat affect, scleral icterus, and pronounced jaundice. He was well-oriented to questions but displayed asterixis.[acgcasereports.gi.org]
Hepatomegaly
  • For diagnosis of BA, clinical evaluation, hepatomegaly, stool color, serum gamma-glutamyltranspeptidase (GGT), duodenal juice color, bile acid in duodenal juice, ultrasonography (gallbladder), ultrasonography (griangular cord or strip-apparent hyperechoic[ncbi.nlm.nih.gov]
  • Clinical signs of cholestasis (discolored stools, dark urine) usually appear in the first months of life with recurrent or permanent jaundice associated with hepatomegaly and severe pruritus.[orpha.net]
  • Hepatomegaly is also a common finding. Between episodes patients show no symptoms and the interval between attacks varies from months to years.[orpha.net]
  • Examination revealed cryptorchidism, scleral icterus, and mild hypotonia, but notably no hepatomegaly. He also had extremely dark skin, which the parents reported was not present at birth but had developed quickly after birth.[pediatrics.aappublications.org]
  • He had no tender hepatomegaly, but had extensive excoriations on his torso and extremities induced by pruritus. He had temporal wasting and loss of adipose tissue in his arms and abdomen.[acgcasereports.gi.org]
Recurrent Jaundice
  • Images: Related links to external sites (from Bing) Ontology: Cholestasis of pregnancy (C0268318) Concepts Disease or Syndrome ( T047 ) MSH C535932 SnomedCT 950004 , 235888006 English CHOLESTASIS OF PREGNANCY , Cholestasis of pregnancy , recurrent jaundice[fpnotebook.com]
  • Intrahepatic cholestasis of pregnancy Also known as recurrent cholestasis of pregnancy, obstetric cholestasis, cholestasis of pregnancy, recurrent jaundice of pregnancy, cholestatic jaundice of pregnancy, idiopathic jaundice of pregnancy, prurigo gravidarum[dermcoll.edu.au]
  • Keywords Bile Acid Primary Biliary Cirrhosis Primary Sclerosing Cholangitis Intrahepatic Cholestasis Serum Bile Acid Disease name and synonyms Intrahepatic cholestasis of pregnancy Obstetric cholestasis Recurrent jaundice of pregnancy Pruritus gravidarum[ojrd.biomedcentral.com]
Biliary Colic
  • Hepatitis Consequences Jaundice Pruritus Biliary colic Ascending cholangitis Blood culture. Malabsorption, especially Vitamin K deficiency Osteomalacia Biliary cirrhosis[rcpa.edu.au]
Pruritus
  • RESULTS: All three patients had an intractable pruritus with different underlying etiologies of cholestasis. All three patients showed significant improvement in pruritus, with none or minimal pruritus in one patient with primary biliary cirrhosis.[ncbi.nlm.nih.gov]
  • The pruritus of cholestasis is a maddening complication of liver disease. Increased opioidergic tone contributes to the pruritus of cholestasis, as evidenced by the amelioration of the symptom by opiate antagonists.[ncbi.nlm.nih.gov]
  • KEYWORDS: LDL-apheresis; arthrogryposis-renal failure-cholestasis syndrome; bile acids; cholestasis; lipoprotein-apheresis; pruritus[ncbi.nlm.nih.gov]
  • Ultraviolet B phototherapy has been successfully used to treat pruritus.[emedicine.medscape.com]
Excoriation
  • There is no rash but the skin may show scratch marks (excoriations) or become yellow (jaundiced). This condition typically develops late in pregnancy and resolves within days after the baby is born.[dermcoll.edu.au]
  • These are called excoriations and may be complicated with bacterial infections as well. The itching sites may sometimes bleed due to excessive scratching. Due to chronic itching the nails of the patient may also appear shiny and smooth.[news-medical.net]
  • He had no tender hepatomegaly, but had extensive excoriations on his torso and extremities induced by pruritus. He had temporal wasting and loss of adipose tissue in his arms and abdomen.[acgcasereports.gi.org]
  • 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.[patient.info]
Neglect
  • However, it is usually prone to neglect and misdiagnosis in infants with cholestasis because endocrine disorder such as panhypopituitarism is rare in the cause of infantile cholestasis.[ncbi.nlm.nih.gov]
Dark Urine
  • Dark urine Possible causes: pregnancy androgens birth control pills antibiotics (such as TMP/SMX) abdominal mass (e.g. cancer) biliary atresia and other pediatric liver diseases biliary trauma congenital anomalies of the biliary tract gallstones acute[en.wikipedia.org]
  • It can also be accompanied by: jaundice pale stools dark urine abdominal pain nausea See your doctor if you have itching in pregnancy.[healthline.com]
  • It results in jaundice, which can be detected by scleral icterus at a concentration as low as 2 mg/dL, and by dark urine.[emedicine.medscape.com]

Workup

  • Blood analysis: Elevated serum bilirubin levels, total serum bile salt concentration levels and total serum cholesterol level are found. Serum lipoprotein-X levels are elevated in conditions leading to obstructive cholestasis. Increased levels of of serum alkaline phosphatase, serum 5'-nucleotidase, and serum gamma-glutamyl transferase (GGT) are observed. Hematology screen may show anemia in case of malignancy. Leukocytosis is present in case of infection. Cholestasis often leads to abnormally shaped cells. In case of prehepatic jaundice, reticulocytosis may be seen and prothrombin time should be checked.
  • Abdominal ultrasound and CT: Anatomic causes of obstructive cholestasis can be detected with ultrasonography and CT scan of liver and bile ducts. 
  • Hepatoiminodiacetic acid [HIDA] scanning is used to identify anatomic causes of obstructive cholestasis and to differentiate between hepatocellular and obstructive cholestasis. 
  • Endoscopic retrograde cholangiography or endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography are useful to identify anatomic causes of obstructive cholestasis. Operative cholangiography, when done is definitive in detecting the cause. 
  • Liver biopsy when possible, can lead to definitive diagnosis. 
  • Urea, electrolytes and creatinine derangement signifies acute renal damage may be present. 
Hypertriglyceridemia
  • Abstract We present a 6-week-old male infant with persistent hyperbilirubinemia, hypertriglyceridemia, elevated creatine kinase levels, and transaminitis since the second week of life.[pediatrics.aappublications.org]

Treatment

Medical therapy is largely ineffective in cholestasis. However, ursodeoxycholic acid (20-30 mg/kg/d) has been used in children to increase bile formation and antagonize the effect of hydrophobic bile acids on biological membranes. Children with chronic cholestasis may be given phenobarbital (5 mg/kg/d). Dietary substitution for treatment of fat malabsorption is recommended. Vitamin supplementation in chronic cholestasis, oral absorbable, fat-soluble vitamin formulation A, D, E, and K are given to children. Osteopenia, if present, is treated with bisphosphonates. Pruritus is treated with phototherapy, ursodeoxycholic acid, colestyramine, rifampicin and external biliary drainage. Surgical treatment is indicated for underlying causes that are amenable to surgery [9] [10].

Prognosis

Cholestasis can give rise to secondary liver disease like hepatic fibrosis, metabolic bone disease like osteopenia and osteoporosis, and life threatening bleeding tendencies in children. Prognosis depends on the underlying condition giving rise to cholestasis. Although cholestasis itself does not result in death, it causes significant morbidity due to the widespread systemic effects.

Etiology

Cholestasis is classified as acute or chronic, and based on the localization of the interference of bile flow or formation, as extrahepatic (obstructive) and intrahepatic (hepatocellular) cholestasis.

Acute extrahepatic cholestasis is caused by obstruction to the bile ducts due to malignancy, benign bile duct stricture, bile duct compression, bile duct stones, gallstones and infectious cholangitis.

Drugs, viral infections, sepsis and cholestatic conditions can lead to acute intrahepatic cholestasis. Acute cholestasis may also occur as a part of paraneoplastic syndrome due to the release of inflammatory mediators from cancer cells. Other obstructive causes are Alagille syndrome and nonsyndromic ductal paucity.

Primary biliary cirrhosis and primary sclerosing cholangitis are considered causes of chronic cholestasis. Some other causes of hepatocellular cholestasis are drug-induced, alpha-1-antitrypsin deficiency, inborn errors of bile acid synthesis and cholestasis associated with total parenteral nutrition. Drugs that can cause cholestasis are antibiotics, contraceptive pills, anabolic steroids, cimetidine, chlorpromazine, imipramine, prochlorperazine, terbinafine, and tolbutamide. Intrahepatic cholestasis of pregnancy is reversible, influenced by hormones and develops in late pregnancy in women with genetic predisposition [2] [3] [4].

Epidemiology

More than 70% of all cholestasis cases have extrahepatic causes. Although there is not differences between men and women in the incidence of cholestasis induced by genetic diseases, overall women are more affected due to cholestasis in pregnancy. Biliary atresia and drug-induced cholestasis also occur more in women. Pediatric cholestasis is also more common as newborns and infants have an immature liver [5] [6].

Sex distribution
Age distribution

Pathophysiology

In hepatocellular cholestasis bile is present within hepatocytes and canalicular spaces leading to hepatocellular injury. Bile plugging of the interlobular bile ducts, bile duct proliferation in association with centrilobular cholate injury and portal expansion is found in obstructive cholestasis.

There is increased cholesterol content of membranes leading to imapirment of the functioning of integral membrane proteins. Retention of bile salts results in injury to biological membranes throughout the body, with most damage to the liver. Bile salts may be a mediator of hepatic fibrosis as well. Injury to red blood cells can result in spur-cell hemolytic anemia [7].

Prevention

There is no definitive way to prevent cholestasis, but timely diagnosis and treatment can prevent debilitating and serious complications. The possibility of cholestasis should be borne in mind in patients undergoing total parenteral nutrition, or who are pregnant or have any of the known associated genetic conditions. Vaccination against viral hepatitis can prevent the related cases of cholestasis.

Summary

As the bile flow from the gallbladder into the duodenum is hindered, cholestasis leads to retention of bile and regurgitation of unconjugated bilirubin and bile salts into the serum, leading to major effects on all organ systems. Jaundice, pruritus, nausea, vomiting, and pain are frequent symptoms. Management consists of treatment of underlying cause and treatment of pruritus [1].

Patient Information

  • Definition: Cholestasis is the term used when the flow of bile from the gall bladder into the small intestine is slowed or blocked.
  • Cause: The liver related causes can be infections, pregnancy, alcoholic liver disease, cancers, and primary biliary cirrhosis. The causes that are outside liver are commonly bile duct tumors, stones, pancreatic diseases, and cysts. 
  • Symptoms: The white of your eyes may look yellowish. There may be yellow tinge to the skin and dark colored urine. Commonly the stool may be clay colored or white and you may have digestion problems. There can be nausea and vomiting and pain in the upper part of the abdomen. You may have itching
  • Diagnosis: Some blood tests will be done to see the level of contents of bile in the blood and other enzymes that show the functioning of the liver. Ultrasound and CT scan of the abdomen may be done. A test called endoscopic retrograde cholangiopancreatography (ERCP) may be useful. 
  • Treatment and follow-up: Treatment involves treating the cause of the bile flow obstruction like removal of stones and treatment of infection. Although completely resolved bile duct stones and such acute problems may not cause require frequent follow-ups, you must continue regular follow up for chronic diseases according to your physician’s recommendation, and consult a doctor for any recurrence of symptoms. 

References

Article

  1. Sellinger M, Boyer JL. Physiology of bile secretion and cholestasis. Prog Liver Dis. 1990;9:237-59.
  2. Karlsen TH, Vesterhus M, Boberg KM. Review article: controversies in the management of primary biliary cirrhosis and primary sclerosing cholangitis. Aliment Pharmacol Ther. 2014;39(3):282-301.
  3. Kimmings AN, Van deventer SJ, Obertop H, Rauws EA, Gouma DJ. Inflammatory and immunologic effects of obstructive jaundice: pathogenesis and treatment. J Am Coll Surg. 1995;181(6):567-81.
  4. Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2014;124(1):120-33.
  5. James OF, Myszor M. Epidemiology and genetics of primary biliary cirrhosis. Prog Liver Dis. 1990;9:523-36.
  6. Mathias A, Wax JR, Pinette MG, Cartin A, Blackstone J. Progressive familial intrahepatic cholestasis complicating pregnancy. J Matern Fetal Neonatal Med. Jun 1 2009;1-3.
  7. Elferink RP, Groen AK. The mechanism of biliary lipid secretion and its defects. Gastroenterol Clin North Am. Mar 1999; 28(1):59-74, vi.
  8. Gossard AA, Talwalkar JA. Cholestatic liver disease. Med Clin North Am. 2014; 98(1):73-85.
  9. Beuers U, Kremer AE, Bolier R, Elferink RP. Pruritus in cholestasis: facts and fiction. Hepatology. 2014;60(1):399-407.
  10. Festi D, Montagnani M, Azzaroli F, et al. Clinical efficacy and effectiveness of ursodeoxycholic acid in cholestatic liver diseases. Curr Clin Pharmacol. May 2007; 2(2):155-77.

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Last updated: 2017-08-09 17:39