Cholestasis


Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are:
  • obstructive type of cholestasis, where there is a mechanical blockage in the duct system that can occur from a gallstone or malignancy, and
  • metabolic type of cholestasis, in which there are disturbances in bile formation that can occur because of genetic defects or acquired as a side effect of many medications.
Classification is further divided into acute or chronic and extrahepatic or intrahepatic.

Signs and symptoms

The signs and symptoms of cholestasis vary according to the cause. In case of sudden onset, the disease is likely to be acute, while the gradual appearance of symptoms suggests chronic pathology. In many cases, patients may experience pain in the abdominal area. Localization of pain to the upper right quadrant can be indicative of cholecystitis or choledocholithiasis, which can progress to cholestasis.
Pruritus or itching is often present in many patients with cholestasis. Patients may present with visible scratch marks as a result of scratching. Pruritus is often misdiagnosed as a dermatological condition, especially in patients that do not have jaundice as an accompanying symptom. In a typical day, pruritus worsens as the day progresses, particularly during the evening time. Overnight, pruritus dramatically improves. This cycle can be attributed to an increase in the concentration of biliary elements during the day due to food consumption, and a decline at night. Pruritus is mostly localized to the limbs, but can also be more generalized. The efficacy of naltrexone for cholestatic pruritus suggests involvement of the endogenous opioid system.
Many patients may experience jaundice as a result of cholestasis. This is usually evident after physical examination as yellow pigment deposits on the skin, in the oral mucosa, or conjunctiva. Jaundice is an uncommon occurrence in intrahepatic cholestasis, but is common in obstructive cholestasis. The majority of patients with chronic cholestasis also experience fatigue. This is likely a result of defects in the corticotrophin hormone axis or other abnormalities with neurotransmission. Some patients may also have xanthomas, which are fat deposits that accumulate below the skin. These usually appear waxy and yellow, predominantly around the eyes and joints. This condition results from an accumulation of lipids within the blood. If gallstones prevent bile flowing from the pancreas to the small intestine, it can lead to gallstone pancreatitis. Physical symptoms include nausea, vomiting, and abdominal pain.
Bile is required for the absorption of fat-soluble vitamins. As such, patients with cholestasis may present with a deficiency in vitamins A, D, E, or K due to a decline in bile flow. Patients with cholestasis may also experience pale stool and dark urine.

Causes

Possible causes:
Drugs such as gold salts, nitrofurantoin, anabolic steroids, sulindac, chlorpromazine, erythromycin, prochlorperazine, cimetidine, estrogen, and statins can cause cholestasis and may result in damage to the liver.

Drug-induced cholestasis

Acute and chronic cholestasis can be caused by certain drugs or their metabolites. Drug-induced cholestasis falls under drug-induced liver injury, specifically the cholestatic or mixed type. While some drugs are known to cause DILI in a predictable dose-dependent manner, most cases of DILI are idiosyncratic, i.e., affecting only a minority of individuals taking the medication. Seventy-three percent of DIC cases can be attributed to a single prescription medication, commonly antibiotics and antifungals, anti-diabetics, anti-inflammatory, and cardiovascular drugs, psychotropic drugs. The exact pathomechanism may vary for different drugs and requires further elucidation.
Typical symptoms of DIC include pruritus and jaundice, nausea, fatigue, and dark urine, which usually resolve after discontinuation of the offending medication.
Clinically, DIC can manifest as acute bland cholestasis, acute cholestatic hepatitis, secondary sclerosing cholangitis, or vanishing bile duct syndrome. Bland cholestasis occurs when there is obstruction to bile flow in the absence of inflammation or biliary and hepatic injury, whereas these features are present in cholestatic hepatitis.Bland cholestasis is almost always caused by anabolic steroids or estrogen contraceptive use, while many drugs may cause cholestatic hepatitis, including penicillins, sulfonamides, rifampin, cephalosporins, fluoroquinolones, tetracyclines, and methimazole, among others.
Antibiotics and antifungals that commonly cause DIC are penicillins, macrolides, trimethoprim/sulfamethoxazole, and tetracyclines. Due to its clavulanic acid component, penicillin amoxicillin-clavulanate is the most common culprit of cholestatic liver injury. Flucloxacillin, which is commonly prescribed in the UK, Sweden, and Australia, is another penicillin frequently implicated in DIC. Cholestasis induced by penicillins usually resolves after withdrawal. Macrolides with cholestatic potential include erythromycin, clarithromycin, and azithromycin, and prognosis is likewise favorable with these drugs. Trimethoprim/sulfamethoxazole is the fourth most common antibiotic responsible for DILI in North America. However, DIC is comparatively less common with low-dose tetracyclines like doxycycline. Other cholestatic antimicrobials include the antifungal terbinafine, notable for its potential to cause life-threatening cholestatic injury, and quinolones, which have been linked to cholestatic hepatitis and vanishing bile duct syndrome.
Among psychotropic drugs, chlorpromazine is known to cause cholestatic hepatitis. Tricyclic antidepressants and SSRIs causing cholestasis have also been reported. Anti-inflammatory drugs with cholestatic potential include the immunosuppressant azathioprine, which has been reported to cause fatal cholestatic hepatitis, and the NSAID diclofenac.

Rare causes of cholestasis

The causes of cholestasis are diverse, and some feature more prominently than others. Some rare causes include primary sclerosing cholangitis, primary biliary cholangitis, familial intrahepatic cholestasis, Alagille syndrome, sepsis, total parenteral nutrition-based cholestasis, benign recurrent intrahepatic cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.

Primary biliary cholangitis

Chronic cholestasis occurs in primary biliary cholangitis. PBC is a progressive autoimmune liver disease in which small intrahepatic bile ducts are selectively destroyed, leading to cholestasis, biliary fibrosis, cirrhosis, and eventually liver failure that requires transplantation. Prevalence of PBC ranges from 19 to 402 cases/million depending on geographic location, with a 9:1 female preponderance and median ages of diagnosis of 68.5 years for females and 54.5 years for males.
At diagnosis, 50% of PBC patients are asymptomatic, indicative of an early stage of disease, while another 50% report fatigue and daytime sleepiness. Other symptoms include pruritus and skin lesions, and in prolonged cholestasis, malabsorption and steatorrhea leading to fat-soluble vitamin deficiency. Disease progression is accompanied by intensifying portal hypertension and hepatosplenomegaly. Clinically, diagnosis generally requires a 1:40 or greater titer of anti-mitochondrial antibody against PDC-E2 and elevated alkaline phosphatase persisting for 6+ months.
Ursodeoxycholic acid is an FDA-approved first-line treatment for PBC. At moderate doses, UDCA has been demonstrated to slow disease progression and improve transplant-free survival. A complete response is achieved in 25–30% patients, and similar survival as the general population is expected in 2/3 of patients on UDCA. For the 1/3 non-responders, obeticholic acid is approved by the FDA as a second-line treatment.
The precise etiology of PBC remains poorly understood, though a clearer picture is starting to emerge. A loss of immune tolerance is indicated by the presence of AMAs and autoreactive CD4+ and CD8+ T cells targeting cholangiocytes that line the bile ducts. Cholangiocytes are normally responsible for 40% of bile flow, mostly through secretion of bicarbonate into bile via anion exchanger 2 on their apical membrane. The resulting bicarbonate "umbrella" that forms over cholangiocytes provides protection from toxic bile salts. However, in PBC there is repression of AE2 activity due to upregulation of miR-506. This results in decreased biliary bicarbonate secretion and consequently, cholestasis and injury to cholangiocytes by bile salts. Injury may induce cholangiocytes to undergo apoptosis, and during this process, the unique way in which cholangiocytes handle the degradation of PDC-E2 may be a trigger for PSC. Specifically, PDC-E2 in apoptotic cholangiocytes undergo a covalent modification that may render them recognizable to antibodies and thereby trigger a break in self-tolerance. The problem is compounded by cholangiocytes' peculiarly abundant expression of HLA-II and HLA-I, as well as adhesion and chemoattractant molecules, which recruit aid in recruitment of mononuclear immune cells.
Both genetic and environmental factors probably contribute to PBC pathogenesis. Genetic predisposition is suggested by high concordance between identical twins, higher incidence among relatives, and a strong association of disease with certain HLA variants. Disease is likely triggered in the genetically predisposed by some environmental factor, such as pollutants, xenobiotics, diet, drugs, stress, and infectious agents. Urinary tract infection with E. coli is a particularly strong risk factor for  PBC. A possible explanation is that E. coli possess a similar PDC-E2 as humans which could trigger autoimmunity via molecular mimicry.