Download - Cholestatic liver diseases in adults

Overview ofCholestatic liver diseases in

adultsAhmed Adel Abdelhakeem Amin

MBBCh, MSCINTERNAL MEDICINE DEPARTMENT

GI & HEPATOLOGY UNITASSIUT UNIVERSITY HOSPITAL

Definition

The term cholestasis originally 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, γ-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:• PBC• PSC• Toxins• Sepsis• Malignancy• Granulomas

• Intrahepatic cholestasis of pregnancy

• Hepatitis • Genetic• GVHD• Post transplant

Classification

Extrahepatic causes:• Choledocholithiasis• Bile duct tumours• Ampullary tumours• Pancreatic cancer• Mirrizi’s syndrome• AIDS cholangiopathy• Parasites• PSC

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.


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.


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.


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


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.


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.


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.


Treatment options• Prevention of disease progression: UDCA is currently the recommended treatment at a

dosage of 13 to 15 mg/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 4 g/day, up to 16 g daily. At least 4 hours should elapse between taking cholestyramine and any other medication. Rifampicin 300 to 600 mg/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.


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 patient’s 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 Crohn’s 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.


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.


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.


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.


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 the disease. Most of these complications and treatments are similar to those listed earlier for the management of PBC.

Up to 20% of patients with PSC develop jaundice, cholangitis, or both, caused by a dominant stricture of the biliary tree, which can be treated with balloon dilation with or without the placement of a biliary stent. This is usually done endoscopically, but it can be done percutaneously.


Although there are no established guidelines for surveillance for cholangiocarcinoma in patients with PSC, a high index of suspicion should be maintained.

Liver transplantation is effective for patients who have evidence of end-stage liver disease or who have recurrent bouts of cholangitis that cannot be controlled with dilation of a dominant stricture.

Unfortunately, PSC recurs in 15% to 20% of cases after liver transplantation, and recurrence is often associated with loss of the graft, so re-grafting is the treatment in this setting.

Screening for IBD is mandatory.

PBC vs PSC

PBC PSCPopulation M:F = 1:9 M:F = 2:1

Bile ducts Intrahepatic Intra and/or extrahepatic

ERCP Normal Abnormal

AMA Positive Negative

UC association No Yes

CC risk No Yes

Drug-Induced Cholestasis

Drugs are a common cause of cholestasis. The spectrum of drug-induced liver injury can range from acute reversible cholestasis to chronic cholestasis with loss of bile ducts.

Acute cholestasis accounts for about 17% of liver-related adverse drug reactions. Drug-induced cholestasis can be categorized into acute and chronic forms. The acute forms are subdivided into cholestasis without inflammation (bland

cholestasis), cholestasis with inflammation, and cholestasis with bile duct injury. Chronic forms include a vanishing bile duct syndrome and a sclerosing cholangitis-like

syndrome.

Drug-Induced Cholestasis (Acute)

Cholestasis without HepatitisEstrogens

Anabolic steroids

Cyclosporine

Tamoxifen

Azathioprine

Cholestasis with HepatitisChlorpromazine

Macrolide antibiotics

Tricyclic antidepressants

Carbamazepine

Amoxicillin-clavulanate

Oxypenicillins

Nonsteroidal anti-inflammatory drugs

Azathioprine

Cholestasis with Bile Duct InjuryDextropropoxyphene

Flucoxacillin (floxacillin)

Carmustine

Toxins: paraquat, methylenedianiline

Drug-Induced Cholestasis (Chronic)

Vanishing Bile Duct Syndrome: a long list of drugs, most known ones are: Flucloxacillin, Amoxicillin-clavulanic acid, Azathioprine, Ibuprofen, Phenytoin, Clindamycin, Cotrimoxazole, Amitriptyline.

Sclerosing Cholangitis-like Syndrome: Intralesional and scolicidal agents such as Formaldehyde, Hypertonic saline and Absolute alcohol.


Drug-induced cholestasis can be accompanied by nausea, anorexia, malaise, and pruritus.

Symptoms can occur weeks to months after beginning treatment. Drugs that cause cholestasis with bile duct injury often are accompanied by

additional clinical features, such as fever, rigors, jaundice, and tender hepatomegaly mimicking acute cholangitis.

Drugs that result in a vanishing bile duct syndrome can lead to progressive cholestasis, with prolonged jaundice, pruritus, and, occasionally, cirrhosis and liver failure.


The most important tool in the diagnosis of drug-induced cholestasis is a careful medical history, eliciting a history of taking prescribed, over-the-counter, or alternative medications, including herbs.

Biliary obstruction should be excluded with an imaging study, ultrasound, or computed tomography (CT) of the biliary tree.

The mainstay of treatment is withdrawal of the drug. Most cholestatic hepatic injury resolves with withdrawal of the offending medication. A small subgroup of patients develop progressive liver disease, resulting in biliary cirrhosis and liver failure.

Management of symptoms associated with cholestasis are similar to those for PBC.

Hepatitis

Occasionally, viral hepatitis (A, B and C) manifests with signs and symptoms of cholestasis characterized by jaundice and pruritus. The clinical course can last for several months.

Alcoholic hepatitis generally manifests with features of cholestasis. In Egypt, t is often under looked. It is usually accompanied by fever, and the clinical presentation can be confused with that of cholangitis. A careful medical history is essential to confirm a history of ethanol abuse or dependency. AST/ALT levels greater than 2:1, increased GGT levels and macrocytosis may also help in diagnosis of alcoholic aetiology.

Overlap syndrome, is an association between PSC/PBC and autoimmne hepatitis. ASMA, ANA, immunoglobulin levels and liver biopsy are diagnostic.

NASH is rarely a cause of cholestasis.

Post–Liver Transplantation Cholestasis

Cholestasis is often seen after liver transplantation and is caused by various conditions:• Infections: bacterial or viral, particularly cytomegalovirus.• Medications: both antibiotics and immunosuppressive drugs typically used after

transplantation, are also associated with cholestasis.• Acute cellular rejection is often heralded by the onset of abnormalities in cholestatic

liver enzyme levels. • HAT• Later after transplantation, other causes of cholestasis are more common, including

chronic rejection, recurrent original disease or chronic biliary complications.

Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) can occur in the second or third trimester. There appears to be a genetic component because it has been reported to occur in family members.

The hallmark clinical feature of intrahepatic cholestasis of pregnancy is pruritus. Jaundice can occur, and laboratory findings reveal the typical features of cholestasis, including elevated levels of serum bile acids, alkaline phosphatase, and total bilirubin.

UDCA has been used in ICP to relieve pruritus, and it appears to be safe for mother and fetus.

Symptoms resolve within several days of delivery but can recur during subsequent pregnancies.

DD: other conditions with hepatic affection with pregnancy: acute hepatitis, HELLLP syndrome, AFLP and gall bladder stones.

Granulomatous Liver Diseases

Granuloma formation in the liver occurs in various disorders, including: • Systemic infections from bacteria, viruses (HIV), fungi, rickettsia, spirochetes, and parasites; • Drugs and chemicals; • Immune-mediated diseases, such as sarcoidosis and primary biliary cirrhosis; and • Neoplasms, such as Hodgkin’s disease. Suspicion is raised when finding a granuloma on liver biopsy while investigating a case with

cholestasis. Evaluation should begin with a careful history including, for example, risk factors for HIV,

exposure to tuberculosis, or exposure to farm animals, which presents a risk for brucellosis. Because exposure to drugs is a common cause of granulomatous liver disease, a history of

medication use is essential.

Granulomatous Liver Diseases

Serologic evaluation for fungi, Brucella, Treponema, HIV, other viruses. Anti mitochondrial antibody Angiotensin-converting enzyme levels; Tuberculin skin testing; and special stains of the liver biopsy for fungus and acid-fast bacilli

(AFB). More-extensive evaluation, such as abdominal or chest CT scanning, may be necessary if

lymphoma is suspected. Idiopathic granulomatous hepatitis is treated with steroids. Empirical anti-tuberculous

therapy should be considered before instituting corticosteroids.

IgG 4 Cholangiopathy

a spectrum of systemic inflammatory disorders that affect multiple organ systems and are associated with elevated serum IgG4 levels or bile duct inflammation that includes IgG4 plasma cells.

Commonly associated with Autoimmune pancreatitis. Patients presenting with IgG4-related cholangiopathy are typically men aged 50-60 years, and

more than 75% will present with common bile duct obstruction and jaundice.[17]

Coexisting pancreatic disease, biliary strictures, bile duct masses, or head of pancreas mass (pseudo-tumour) can all be found.

Stricturing of the intra-pancreatic portion of the distal common bile duct is the most frequent bile duct finding. Narrowing of the ducts at the biliary hilum may also be seen (DD: CC).

Serum IgG4 elevation is the laboratory hallmark of IgG4 cholangiopathy. Treatment: steroids.

IgG 4 Cholangiopathy

PSC IgG4 CholangiopathyAge 40s or younger 50s or olderBile ducts Intra and/or extrahepatic Extrahepatic onlyAssociation IBD Autoimmune pancreatitisCC risk High Low ERCP Multifocal stricturing Lower CBD intra-pancreatic,

or hilar stricture (tumour like). Multifocal stricturing may occur but less than PSC.

LAB pANCA Raised IgG4 levelBiopsy Not essential. Ductopenia. Diagnostic. Plasma cell

infiltration.Therapy No specific therapy Steroids

Total Parenteral Nutrition

Total parenteral nutrition (TPN) is associated with liver dysfunction resulting in steatosis, cholestasis, and cirrhosis.

Intrahepatic cholestasis can occur after 2 to 3 weeks of TPN therapy and is associated with elevations in serum bilirubin and alkaline phosphatase levels.

Cholestasis usually reverses after TPN is stopped but is of concern if the patient requires long-term TPN. Progressive liver disease, including cirrhosis, may be associated with long-term TPN.

Genetic Disorders

Benign recurrent intrahepatic cholestasis: characterized by episodic jaundice and pruritus lasting for several weeks to months, with long symptom-free intervals. The disease does not progress to cirrhosis. Multiple family members can be affected.

Cystic fibrosis: can result in cholestasis caused by gene mutations at the level of the bile duct, resulting in inspissated bile.

Others

Malignancy: either primary HCC or CC, or liver secondaries. Cholestasis can also occur in patients as a paraneoplastic syndrome in the absence of metastatic disease to the liver. This non-metastatic cholestasis has been described in non-Hodgkin’s lymphoma, prostate cancer, and renal cell carcinoma.

Sepsis: Circulatory endotoxins associated with sepsis induce cytokine production, which results in impaired bile acid transport. The cholestasis of infection is often seen in severely ill hospitalized patients, often in the intensive care unit (ICU).

Graft vs host disease: It occurs in up to 50% of patients after bone marrow transplantation and is believed to be caused by T cells of the donor marrow reacting against host antigens, resulting in cytokine damage of the affected organ. GVHD can affect the skin, liver, and gastrointestinal tract.

Congestive hepatopathy

Cholestatic liver profile

Extrahepatic cause Normal abdominal US

AMA and ANA

+VE > PBC Negative

Drug history

Positive: discontinue and observe negative

Liver biopsy

Positive for a specific lesion Normal

MRCP or ERCP if high clinical suspicion

Positive Negative

Follow up and observe

History, examination and US

Clinical scenario

55 years old women presented for routine check up. She complains of mild fatigue, but otherwise she appears healthy. She is on no medications. His family history s negative for any gastrointestinal or liver diseases. On examination, you notice the presence of xanthomas and xanthelasma, as well as a liver that is slightly enlarged. She had laboratory tests done recently, and although she had a normal AST and ALT she has an ALP that was 2X the normal level. Her USS is normal.

Which of the following do you recommend?

ASMA AMA MRCP ERCP

Next,

AMA is done to the patient and it was 1/20. the patient continues to suffer fatigue and now is itchy with mild elevation of total and direct bilirubin. Which of the following do you recommend?

ERCP Liver biopsy MRCP

MRCP is done and failed to reveal a cause. What is the next step?

ERCP Liver biopsy CT abdomen Follow up

The following are possible causes in this case to be considered:

• AMA negative PBC• PSC affecting mainly intrahepatic small ducts• Other rare cause: granuloma, IgG4 cholangiopathy.

► Liver biopsy is the best to differentiate.

liver biopsy showed the following:

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