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Disorders of the Liver Cholestatic Liver Disease Primary Biliary Cholangitis Primary biliary cholangitis (PBC), previously termed primary biliary cirrhosis, is an autoimmune disease affecting the small and medium bile ducts. The female-to-male predominance is 9 to 1. PBC is often asymptomatic but can present with fatigue and pruritus. Liver chemistry tests usually demonstrate a cholestatic pattern of injury, and the alkaline phosphatase may be significantly elevated. Diagnosis of PBC does not require liver biopsy when the ALP level is at least 1.5 times the upper limit of normal and antimitochondrial antibody results are positive or, if results are negative, other PBC-specific autoanti- bodies, including sp100 or gp210, are present. In patients with negative antibody results and strong suspicion for PBC, liver FIGURE 32. Magnetic resonance cholangiopancreatogram showing multifocal biopsy is necessary. Elastography can be used for fibrosis intrahepatic and extrahepatic bile duct stricturing (blue arrows) with a dominant staging. left-lobe stricture (white arrow) and upstream bile duct dilation consistent with the Initial treatment is ursodeoxycholic acid, which results in diagnosis of primary sclerosing cholangitis. histologic improvement, improves survival rates, and dimin- ishes the need for liver transplantation. Response to treatment Primary Sclerosing Cholangitis is defined by improvement of the ALP level to less than Primary sclerosing cholangitis (PSC) is an autoimmune 1.67 times the upper limit of normal. Patients who present fibroinflammatory disease of the large bile ducts, but it with normal bilirubin and albumin levels and respond to can also affect the small bile ducts (small-duct PSC). It is treatment have a life expectancy similar to that of individuals more common in men than women, which is unique without PBC. Patients whose disease does not respond to urso- among the autoimmune liver diseases. PSC often presents deoxycholic acid should receive fibrates (off label) or obet- without symptoms with a cholestatic pattern of liver icholic acid. enzyme abnormalities; pruritus may also be the presenting PBC is associated with other autoimmune conditions, par- feature. ticularly autoimmune thyroid disease. Thus, thyroid-stimulating PSC can be diagnosed noninvasively through magnetic hormone level should be checked yearly. In patients with cir- resonance cholangiopancreatography (MRCP) (Figure 32). thosis and a PBC score of 4.1 or greater (www.mayoclinic.org/ Diagnosis does not usually require liver biopsy; small-duct medical-professionals/model-end-stage-liver-disease/updated- PSC, which cannot be diagnosed by MRCP, is an exception. natural-history-model-for-primary-biliary-cirrhosis) or tran- Endoscopic retrograde cholangiopancreatography (ERCP) sient elastography results of 17 kPa or greater, upper endoscopy should be considered in patients with jaundice, worsening is indicated to assess for esophageal varices. pruritus, bacterial cholangitis, or a dominant stricture or bile Patients with advanced disease should be managed like duct mass on MRCP. other patients with cirrhosis and portal hypertension (see PSC is associated with inflammatory bowel disease (IBD) Complications of Advanced Liver Disease). In addition, men in about 85% of cases; up to 7.5% of patients with ulcerative with PBC and all patients with PBC and cirrhosis should be colitis have PSC. All patients with PSC without known IBD screened for hepatocellular carcinoma (see Hepatocellular should have a colonoscopy at the time of PSC diagnosis. Carcinoma for recommendations on screening and surveil- Patients with concomitant IBD may have a unique PSC-IBD lance). Patients with PBC have increased risk for osteoporosis phenotype, characterized by rectal sparing, mild pancolitis, and should ensure daily intake of 1000 to 1500 mg of calcium and backwash ileitis. This carries a higher risk for colon can- and 1000 IU of vitamin D. Bone mineral density should be cer, necessitating colonoscopy with surveillance biopsies every assessed every 2 years, and bisphosphonate therapy should be year from the time of diagnosis, as well as a higher risk for considered if the result is in the osteoporotic range. Patients pouchitis after total colectomy. with elevated lipid levels may be at risk for cardiovascular Patients with PSC have a 15% lifetime risk for cholangiocar- disease and can be considered for lipid-lowering therapy. Fat- cinoma. Yearly MRCP and measurement of carbohydrate 19-9 soluble vitamin deficiencies should be treated with parenteral are recommended for cholangiocarcinoma surveillance. The or wate1-soluble supplements. Liver transplant outcomes for incidence of cholangiocarcinoma is highest in the first 2 years patients with PBC are excellent, with a 1-year survival rate after PSC diagnosis. There is also an increased risk for gallblad- greater than 90% and a recurrence rate of approximately 20% der cancer in PSC; regular screening with ultrasonography at 5 years after liver transplantation. First-degree relatives of should be considered. The management of gallbladder polyps is patients with PBC, especially women, should be screened by discussed in the Disorders of the Gallbladder and Bile Ducts periodically checking ALP level. chapter.

Cholestatic Liver Disease Primary Biliary Cholangitis Primary biliary cholangitis (PBC), previously termed primary biliary cirrhosis, is an autoimmune disease affecting the small and medium bile ducts. The female-to-male predominance is 9 to 1. PBC is often asymptomatic but can present with fatigue and pruritus. Liver chemistry tests usually demonstrate a cholestatic pattern of injury, and the alkaline phosphatase may be significantly elevated. Diagnosis of PBC does not require liver biopsy when the ALP level is at least 1.5 times the upper limit of normal and antimitochondrial antibody results are positive or, if results are negative, other PBC-specific autoanti- bodies, including sp100 or gp210, are present. In patients with negative antibody results and strong suspicion for PBC, liver FIGURE 32. Magnetic resonance cholangiopancreatogram showing multifocal biopsy is necessary. Elastography can be used for fibrosis intrahepatic and extrahepatic bile duct stricturing (blue arrows) with a dominant staging. left-lobe stricture (white arrow) and upstream bile duct dilation consistent with the Initial treatment is ursodeoxycholic acid, which results in diagnosis of primary sclerosing cholangitis. histologic improvement, improves survival rates, and dimin- ishes the need for liver transplantation. Response to treatment Primary Sclerosing Cholangitis is defined by improvement of the ALP level to less than Primary sclerosing cholangitis (PSC) is an autoimmune 1.67 times the upper limit of normal. Patients who present fibroinflammatory disease of the large bile ducts, but it with normal bilirubin and albumin levels and respond to can also affect the small bile ducts (small-duct PSC). It is treatment have a life expectancy similar to that of individuals more common in men than women, which is unique without PBC. Patients whose disease does not respond to urso- among the autoimmune liver diseases. PSC often presents deoxycholic acid should receive fibrates (off label) or obet- without symptoms with a cholestatic pattern of liver icholic acid. enzyme abnormalities; pruritus may also be the presenting PBC is associated with other autoimmune conditions, par- feature. ticularly autoimmune thyroid disease. Thus, thyroid-stimulating PSC can be diagnosed noninvasively through magnetic hormone level should be checked yearly. In patients with cir- resonance cholangiopancreatography (MRCP) (Figure 32). thosis and a PBC score of 4.1 or greater (www.mayoclinic.org/ Diagnosis does not usually require liver biopsy; small-duct medical-professionals/model-end-stage-liver-disease/updated- PSC, which cannot be diagnosed by MRCP, is an exception. natural-history-model-for-primary-biliary-cirrhosis) or tran- Endoscopic retrograde cholangiopancreatography (ERCP) sient elastography results of 17 kPa or greater, upper endoscopy should be considered in patients with jaundice, worsening is indicated to assess for esophageal varices. pruritus, bacterial cholangitis, or a dominant stricture or bile Patients with advanced disease should be managed like duct mass on MRCP. other patients with cirrhosis and portal hypertension (see PSC is associated with inflammatory bowel disease (IBD) Complications of Advanced Liver Disease). In addition, men in about 85% of cases; up to 7.5% of patients with ulcerative with PBC and all patients with PBC and cirrhosis should be colitis have PSC. All patients with PSC without known IBD screened for hepatocellular carcinoma (see Hepatocellular should have a colonoscopy at the time of PSC diagnosis. Carcinoma for recommendations on screening and surveil- Patients with concomitant IBD may have a unique PSC-IBD lance). Patients with PBC have increased risk for osteoporosis phenotype, characterized by rectal sparing, mild pancolitis, and should ensure daily intake of 1000 to 1500 mg of calcium and backwash ileitis. This carries a higher risk for colon can- and 1000 IU of vitamin D. Bone mineral density should be cer, necessitating colonoscopy with surveillance biopsies every assessed every 2 years, and bisphosphonate therapy should be year from the time of diagnosis, as well as a higher risk for considered if the result is in the osteoporotic range. Patients pouchitis after total colectomy. with elevated lipid levels may be at risk for cardiovascular Patients with PSC have a 15% lifetime risk for cholangiocar- disease and can be considered for lipid-lowering therapy. Fat- cinoma. Yearly MRCP and measurement of carbohydrate 19-9 soluble vitamin deficiencies should be treated with parenteral are recommended for cholangiocarcinoma surveillance. The or wate1-soluble supplements. Liver transplant outcomes for incidence of cholangiocarcinoma is highest in the first 2 years patients with PBC are excellent, with a 1-year survival rate after PSC diagnosis. There is also an increased risk for gallblad- greater than 90% and a recurrence rate of approximately 20% der cancer in PSC; regular screening with ultrasonography at 5 years after liver transplantation. First-degree relatives of should be considered. The management of gallbladder polyps is patients with PBC, especially women, should be screened by discussed in the Disorders of the Gallbladder and Bile Ducts periodically checking ALP level. chapter. 62

Disorders of the Liver There is no effective medical therapy for PSC; it often was changed to include the MELD-Na score because it is a requires liver transplantation and has the highest case-based more predictive model of 3-month mortality. mortality rate among the autoimmune liver diseases. In symp- The MELD score can estimate postoperative mortality in tomatic patients, ERCP is used to dilate strictures and remove patients with cirrhosis (www.mayoclinic.org/medical-profes- stones. sionals/model-end-stage-liver-disease/post-operative- Median transplant-free survival for patients with PSC is mortality-risk-patients-cirrhosis). 12 years. Transplantation should be considered for patients with decompensated cirrhosis, recurrent bacterial cholangitis, e The Model for End-Stage Liver Disease-sodium formula and hilar cholangiocarcinoma. Transplant outcomes for accurately predicts 3-month mortality and is used for patients with PSC are excellent, with 1-year survival rates of at liver transplant allocation. least 90% and recurrence rates of approximately 20% at 5 years after liver transplantation. Complications of Advanced e For primary biliary cholangitis, ursodeoxycholic acid treatment results in histologic improvement, better Liver Disease survival rates, and diminished need for liver trans- Patients with chronic liver disease from any cause are at risk for

Complications of Advanced e For primary biliary cholangitis, ursodeoxycholic acid treatment results in histologic improvement, better Liver Disease survival rates, and diminished need for liver trans- Patients with chronic liver disease from any cause are at risk for plantation. cirrhosis. Compensated cirrhosis is uncomplicated and may be asymptomatic or associated with nonspecific symptoms. e Primary sclerosing cholangitis is associated with inflam- Patients with decompensated cirrhosis have complications such matory bowel disease in about 85% of cases; these as ascites, hepatic encephalopathy, and variceal hemorrhage. patients have an increased risk for colon cancer and require surveillance colonoscopy at diagnosis and every Portal Hypertension 1 to 2 years. Portal venous hypertension develops in the setting of advanced e Patients with PSC have a 15% lifetime risk for cholangi- cirrhosis due to obstruction of blood flow caused by intrahe- ocarcinoma; annual MRCP and measurement of carbo- patic fibrosis, regenerating liver nodules, increased intrahe- hydrate 19-9 are recommended for cholangiocarcinoma patic vascular resistance, and increased flow via the portal surveillance. vein. Prehepatic causes, including portal vein thrombosis, and posthepatic causes, such as Budd-Chiari syndrome, can result in portal hypertension in the absence of cirrhosis. Classification of Liver Complications of portal hypertension include gastroesopha- Disease Severity geal varices, ascites, and spontaneous bacterial peritonitis. The The Child-Turcotte-Pugh (CTP) score (Table 36) and MELD presence of these complications heralds a high rate of further

plantation. cirrhosis. Compensated cirrhosis is uncomplicated and may be asymptomatic or associated with nonspecific symptoms. e Primary sclerosing cholangitis is associated with inflam- Patients with decompensated cirrhosis have complications such matory bowel disease in about 85% of cases; these as ascites, hepatic encephalopathy, and variceal hemorrhage. patients have an increased risk for colon cancer and require surveillance colonoscopy at diagnosis and every Portal Hypertension 1 to 2 years. Portal venous hypertension develops in the setting of advanced e Patients with PSC have a 15% lifetime risk for cholangi- cirrhosis due to obstruction of blood flow caused by intrahe- ocarcinoma; annual MRCP and measurement of carbo- patic fibrosis, regenerating liver nodules, increased intrahe- hydrate 19-9 are recommended for cholangiocarcinoma patic vascular resistance, and increased flow via the portal surveillance. vein. Prehepatic causes, including portal vein thrombosis, and posthepatic causes, such as Budd-Chiari syndrome, can result in portal hypertension in the absence of cirrhosis. Classification of Liver Complications of portal hypertension include gastroesopha- Disease Severity geal varices, ascites, and spontaneous bacterial peritonitis. The The Child-Turcotte-Pugh (CTP) score (Table 36) and MELD presence of these complications heralds a high rate of further score (https://optn.transplant.hrsa.gov/resources/allocation- complications and mortality and should prompt consideration calculators/meld-calculator/) are prognostic in patients with of liver transplantation. See Vascular Diseases of the Liver for cirrhosis. The 1-year survival rates for CTP class A, B, and C additional discussion of portal vein thrombosis and Budd- cirrhosis are 100%, 80%, and 45%, respectively. Chiari syndrome. The MELD formula includes bilirubin level, INR, and cre- atinine level and is accurate in predicting 3-month mortality. Esophageal Varices Another version of the MELD score, the MELD-Na (www. Esophageal varices are enlarged vessels within the lumen of mdcalc.com/meldna-meld-na-score-liver-cirrhosis) , incorpo- the lower esophagus that provide extrahepatic pathways of rates the sodium level. The MELD score was the basis for liver blood flow from the portal to the systemic circulation transplant allocation until 2016, when the allocation system (Figure 33).

score (https://optn.transplant.hrsa.gov/resources/allocation- complications and mortality and should prompt consideration calculators/meld-calculator/) are prognostic in patients with of liver transplantation. See Vascular Diseases of the Liver for cirrhosis. The 1-year survival rates for CTP class A, B, and C additional discussion of portal vein thrombosis and Budd- cirrhosis are 100%, 80%, and 45%, respectively. Chiari syndrome. The MELD formula includes bilirubin level, INR, and cre- atinine level and is accurate in predicting 3-month mortality. Esophageal Varices Another version of the MELD score, the MELD-Na (www. Esophageal varices are enlarged vessels within the lumen of mdcalc.com/meldna-meld-na-score-liver-cirrhosis) , incorpo- the lower esophagus that provide extrahepatic pathways of rates the sodium level. The MELD score was the basis for liver blood flow from the portal to the systemic circulation transplant allocation until 2016, when the allocation system (Figure 33). TABLE 36. Child-Turcotte-Pugh Score? 1 Point 2 Points 3 Points | Encephalopathy None Grade I-ll Grade Ill-IV | | Ascites None Mild/moderate Severe | Bilirubin <2 mg/dL (34.2 umol/L) 2-3 mg/dL (34.2-51.3 umol/L) >3 mg/dL (51.3 umol/L) Albumin >3.5 g/dL (35 g/L) 2.8-3.5 g/dL (28-35 g/L) <2.8 g/dL (28 g/L) Prothrombin time above <4s/<1.7 4-6 s/1.7-2.3 >6 s/>2.3 control/INR

Encephalopathy None Grade I-ll Grade Ill-IV | | Ascites None Mild/moderate Severe | Bilirubin <2 mg/dL (34.2 umol/L) 2-3 mg/dL (34.2-51.3 umol/L) >3 mg/dL (51.3 umol/L) Albumin >3.5 g/dL (35 g/L) 2.8-3.5 g/dL (28-35 g/L) <2.8 g/dL (28 g/L) Prothrombin time above <4s/<1.7 4-6 s/1.7-2.3 >6 s/>2.3 control/INR 85-6 points = Child-Turcotte-Pugh class A; 7-9 points = Child-Turcotte-Pugh class B; 10-15 points = Child-Turcotte-Pugh class C. | 63