Primary biliary cirrhosis: Pathophysiology, clinical presentation and therapy

Table 1 Primary biliary cirrhosis - autoimmune hepatitis overlap can present in the following ways

Immunoserological overlap: e.g., positive ANA/anti-smooth muscle antibody titers and elevated IgG in conjunction with AMA-positive PBC; or AMA positivity in AIH

Biochemical overlap: AST/ALT > 5 times upper limit of normal in patients with PBC or PSC; or AP > 3 times upper limit of normal in patients with AIH (or GGT > 5 times upper limit of normal in children)

Radiological overlap: clinical features of AIH with cholangiographic abnormalities indicative of inflammatory cholangiopathy; cholangiographic features of primary sclerosing cholangitis are randomly distributed annular strictures out of proportion to upstream dilatation[33]

Histological overlap: lymphoplasmacytic infiltrate and interface hepatitis on liver biopsy with bile duct lesions indicative of either PBC or PSC

Varying combinations of the above, including sequential presentations

ANA: Antinuclear antibodies; PBC: Primary biliary cirrhosis; AMA: Anti-mitochondrial antibodies; AIH: Autoimmune hepatitis; PSC: Primary sclerosing cholangitis; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: Gamma glutamyl transpeptidase.

Table 2 Clinical features of primary biliary cirrhosis

Clinical features	Prevalence	Mechanism
Fatigue	20%-85%[55,56,58]	Excessive manganese deposits in globus pallidum, elevated inflammatory cytokines
Pruritus	20%-75%[35,58]	Cholestasis, increased opiodergic tone
Jaundice	10%-60%[58]	Cholestasis
Xanthomas	15%-50%[58]	Hypercholesterolemia and hyperlipidemia[56]
Osteoporosis	35%[59]	Disturbances in bone remodeling due to metabolic changes in PBC
Dyslipidemia	> 75%[60]	Reduction in biliary secretion of cholesterol. Toxic effects of unconjugated bilirubin

PBC: Primary biliary cirrhosis.

Table 3 Drug therapy for primary biliary cirrhosis

Drug	Mechanism(s) of action	Adverse effects
Ursodeoxycholic acid	Protection of cholangiocytes, stimulation of biliary secretions of bile acids	Diarrhea, hepatic decompensation (rare)
Corticosteroids	Anti-inflammatory, especially useful for interface hepatitis	Cataracts, hyperglycemia, osteoporosis, immunosuppression, poor wound healing, weight gain
Budesonide	Anti-inflammatory, especially useful for interface hepatitis	Nausea, dyspepsia; systemic toxicity is much less than for other corticosteroids[73]
Obeticholic acid	Reduces bile acid synthesis, downregulates bile acid uptake proteins	Pruritus
Fibrates	Activates peroxisome proliferator-activated receptors	Myalgias, rhabdomyalysis, elevated liver enzymes[72]

Table 4 Drugs without efficacy in primary biliary cirrhosis as demonstrated in clinical trials

Drug	Ref.
Azathioprine	[106]
Chlorambucil	[107]
Methotrexate	[108-110]
Mycophenolate mofetil	[111]
Cyclosporine	[112]
Penicillamine	[113,114]
Colchicine	[115,116]
Malotilate	[117]
Thalidomide	[118]
Silymarin	[119]
Statins	[120]

Table 5 Complications of cirrhosis or portal hypertension in patients with primary biliary cirrhosis

Complication	Special considerations in PBC	Ref.
Hepatoma	Like other cirrhotics, patients with PBC have increased risk of developing hepatomas	[189,203-205]
	In patients with PBC who have not undergone a liver biopsy to document the diagnosis of cirrhosis, hepatoma screening should be initiated when the Mayo score > 4.1	[126]
	Surveillance for hepatoma in patients with cirrhosis from PBC should be performed every six months by abdominal ultrasound or an alternative modality of abdominal imaging	[206]
Spontaneous bacterial peritonitis	Diagnosed by abdominal paracentesis revealing > 250 polymorphonuclear leukocytes/mm3 in ascitic fluid	[207]
	Treated with a short course of multiple antibiotics, generally including either a third-generation cephalosporin or flouroquinolones	[208]
Hepatic encephalopathy	Diagnosed clinically by confusion, delirium, or stupor on physical examination, depending on degree of hepatic encephalopathy; possible presence of asterixis on physical examination; and elevated serum ammonia level in a cirrhotic patient	[209]
	Treatment options include rifaximin, lactulose, supportive care, and reversal of underlying precipitating causes, such as dehydration, infection, or gastrointestinal bleeding	[209-211]
HRS	Type 1 HRS defined as doubling of serum creatinine level, reaching a level > 2.5 mg/dL in < 2 wk. Type 2 HRS defined as a less severely elevated serum creatinine level. Must exclude other causes of renal failure, especially hypovolemia in both types of HRS	[212,213]
	Treatment includes avoidance of nephrotoxic medications; short-term trial of volume expansion; and administration of vasopressin analogues, such as terlipressin, and α-adrenergic agonists, such as norepinephrine or midodrine. Ultimate treatment for type 1 HRS refractory to therapy is liver transplantation	[213-215]
Esophageal varices	Usually occur only after Mayo score becomes > 4.1. Patients with advanced PBC can develop portal hypertension before developing established cirrhosis from nodular regenerative hyperplasia	[216-220]
	Esophageal varices usually diagnosed and graded by esophagogastroduodenoscopy
	Specific therapies for esophageal varices include: endoscopic banding, endoscopic injection therapy, and non-selective beta-blockers. Transjugular intrahepatic shunt is recommended for refractory variceal bleeding, especially when the MELD score < 18	[221,222]

PBC: Primary biliary cirrhosis; MELD: Model for end-stage liver disease; HRS: Hepatorenal syndrome.