Cholestatic liver diseases in adults

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Management of Hepatocellular Carcinoma A practical local guidelines prospective

Overview ofCholestatic liver diseases in adults

Ahmed adel abdelhakeem aminMBBCh, MScInternal medicine departmentGI & hepatology unitAssiut university hospital

Definition The termcholestasisoriginally derives from the Greek, and literally means a standing still of bile. This disruption of bile flow can occur on a cellular level in the hepatocyte, at the level of the intrahepatic biliary ductules, or from an extrahepatic mechanical obstruction of the bile ducts.

Definition Cholestasis is defined, therefore, both clinically and biochemically, with varying degrees of jaundice, pruritus, and elevated levels of conjugated bilirubin, alkaline phosphatase, -glutamyl transpeptidase, 5'-nucleotidase, bile acids, and cholesterol.

Classification A conventional categorization of cholestatic liver diseases has divided these factors into intrahepatic and extrahepatic causes.

Differentiation between the two types is made mainly by imaging.

Classification Intrahepatic causes:PBCPSCToxinsSepsisMalignancyGranulomas

Intrahepatic cholestasis of pregnancyHepatitis GeneticGVHDPost transplant

Classification Extrahepatic causes:CholedocholithiasisBile duct tumoursAmpullary tumoursPancreatic cancerMirrizis syndromeAIDS cholangiopathyParasitesPSC

Primary Biliary Cirrhosis (PBC)Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease predominantly affecting middle-aged women. Autoimmune mechanism, leading to damage of the biliary epithelial cells of small bile ducts.Patients who are asymptomatic at presentation have a longer survival than those who are symptomatic.PBC is most commonly diagnosed after the age of 40 years. Of patients with PBC, 90% are women. The prevalence is higher in northern European population groups.

Primary Biliary Cirrhosis (PBC)About one third of patients who are asymptomatic at presentation become symptomatic within 5 years. Symptomatic patients have an 8-year survival rate of approximately 50%.If PBC is diagnosed at an early histologic stage and treatment with UDCA is begun, recent studies have suggested that the long-term survival approaches that of a healthy control population. Patients with more advanced histologic disease at diagnosis, however, have 30% and 50% rates of requiring liver transplantation or death over 10 and 20 years, respectively, despite treatment.

Primary Biliary Cirrhosis (PBC)The most common initial symptom is fatigue, which occurs in approximately 70% of patients. Fatigue does not necessarily correlate with the severity of disease.Pruritus is also a common symptom, occurring in 50% to 60% of patients. As the disease progresses, patients can develop symptoms of portal hypertension, such as variceal hemorrhage and ascites. Xanthomata and xanthelasma are commonly found in patients with PBC.

Primary Biliary Cirrhosis (PBC)PBC is also associated with metabolic bone disease, resulting in premature osteoporosis.As the disease progresses, there can be fat-soluble vitamin malabsorption caused by a decrease in the biliary secretion of bile acids. There is an increased frequency of other autoimmune disorders in patients with PBC, including autoimmune thyroid disease

Primary Biliary Cirrhosis (PBC)A confident diagnosis of PBC may be made in cases with typical clinical presentation of PBC in the setting of: a positive AMA (1 : 40), and a cholestatic pattern of liver enzymes with alkaline phosphatase at least 1.5 times the upper limit of normal and AST less than five times the upper limit of normal without the obligation to perform a liver biopsy.The most characteristic laboratory finding in PBC is the presence of the AMA, generally in a titre of 1 : 40 or higher. More than 95% of patients with PBC have a positive AMA.

Primary Biliary Cirrhosis (PBC)A liver biopsy should be performed in atypical cases, in cases where an alternative diagnosis is suspected, and to obtain staging information. The liver biopsy findings include portal hepatitis, with granulomatous destruction of bile ducts. The histologic changes are divided into four stages, ranging from stage 1, characterized by portal inflammation and bile duct destruction, through stage 4, characterized by histologic cirrhosis. Overlapping stages can be found in individual patients.

Primary Biliary Cirrhosis (PBC)A subgroup of patients have a positive AMA with normal liver enzyme levels. Most of these patients ultimately develop biochemical evidence of cholestasis and symptomatic disease.

Another subgroup, with cholestasis and histology suggesting PBC, are AMA negative (AMA-negative PBC).

The natural history of AMA-positive and AMA-negative PBC appears to be similar.

Primary Biliary Cirrhosis (PBC)Treatment optionsPrevention of disease progression: UDCA is currently the recommended treatment at a dosage of 13 to 15mg/kg daily, either in divided doses or as a single daily dose. Methotrexate and oral budesonide are tried but not yet approved or recommended.Treatment of symptoms: The most common symptom of PBC requiring treatment is pruritus. First-line treatment consists of cholestyramine at a dosage of 4g/day, up to 16g daily. At least 4 hours should elapse between taking cholestyramine and any other medication. Rifampicin 300 to 600mg/day is second-line treatment for pruritus in patients who do not respond to cholestyramine. Opioid antagonists such as naltrexone have also been used in treatment-resistant cases, as has plasmapheresis. Unfortunately, there is no therapy proved to be of benefit for fatigue in PBC.

Primary Biliary Cirrhosis (PBC)Patients with PBC and cirrhosis can develop portal hypertension and should be screened for the presence of esophageal varices.If osteoporosis is present, consider treatment with a bisphosphonate. Fat-soluble vitamin deficiency should be considered and screened for in patients with hyperbilirubinemia, and oral replacement may be necessary. The association of thyroid disease with PBC has led to the recommendation of checking the serum thyroid-stimulating hormone level at the time of diagnosis and periodically thereafter. Hypercholesterolemia is commonly seen in PBC, but it has not been demonstrated that this is associated with increased cardiovascular risk. Hypercholesterolemia in these patients should be managed based on each patients cardiovascular risk profile.Decompensated LC: liver transplantation.

Primary Sclerosing Cholangitis (PSC)Primary sclerosing cholangitis (PSC) is a chronic, progressive, cholestatic liver disease resulting from inflammation, fibrosis, and destruction of the intrahepatic and/or extrahepatic bile ducts. This leads to multiple areas of stricturing in the biliary tree and eventually to cirrhosis.The estimated prevalence of PSC is 60 to 80 cases per 1 million population. There is a 2 : 1 male predominance. Approximately 80% of patients with PSC have inflammatory bowel disease, more commonly ulcerative colitis (85%) than Crohns disease (15%).There is a peri-ductal inflammation that leads to progressive multifocal stricturing of the intrahepatic and extrahepatic biliary tree. The pathophysiology of PSC is unclear, but there is evidence suggesting an autoimmune component to the disease. There is also a genetic predisposition.

Primary Sclerosing Cholangitis (PSC)Cholangiocarcinoma is a grave complication of PSC, occurring in 4% to 20% of patients; the incidence is even higher in autopsy studies.

The development of cholangiocarcinoma is often accompanied by clinical decline but can be difficult to diagnose, even when it is suspected, because of the low sensitivity of biliary brush cytology in this setting.

Survival after the diagnosis of cholangiocarcinoma is poor, and cholangiocarcinoma is often considered a contraindication to liver transplantation. Some centers have had favorable outcomes with liver transplantation preceded by radiation and chemotherapy.

Primary Sclerosing Cholangitis (PSC)It is common for patients with PSC to be asymptomatic. In one large study, only 56% of patients had one or more symptoms at the time of initial diagnosis.

The most common symptom is fatigue, which is nonspecific.

Other, less-common symptoms include pruritus, weight loss, and fever.

Occasionally, patients present with symptoms of portal hypertension, including the onset of ascites or variceal bleeding, or symptoms of bacterial cholangitis.

Jaundice and hepatosplenomegaly are present in up to 50% of patients.

Primary Sclerosing Cholangitis (PSC)The diagnostic test of choice for PSC is cholangiography, typically endoscopic retrograde cholangiography (ERCP: 88% and 97%) and (MRCP: 85% and 92%), Occasionally PTC.The cholangiogram typically shows multiple strictures of the intrahepatic and extrahepatic biliary tree. In one large study, 27% of patients had intrahepatic ductal involvement only and 6% had only extrahepatic ductal changes.Liver biopsy is not diagnostic for PSC, but findings often include ductopenia, bile duct proliferation, and peri-ductal fibrosis, with an onion-skin fibrosis and nodular fibrous scars. A liver biopsy is often not necessary for the routine diagnosis.Liver enzyme studies typically show an elevated alkaline phosphatase level of biliary origin, although there is a subgroup of patients with early PSC who present with a normal alkaline phosphatase level.

Primary Sclerosing Cholangitis (PSC)

Primary Sclerosing Cholangitis (PSC)

Primary Sclerosing Cholangitis (PSC)Currently, no medical therapy has been shown to be beneficial in PSC. No randomized, controlled trial proved that the use of UDCA at any dose is beneficial.

Medical management of PSC is therefore limited to complications that arise during the course of