Therapy for alcoholic liver disease

Table 1 Differential diagnosis of cirrhosis, excluding alcoholic cirrhosis¹

Diseases	Diagnostic studies	Liver biopsy
Wilson’s disease	Serum ceruloplasmin < 20 mg/dL; 24-h urine copper excretion > 100 μg/24 h; slit-lamp ophthalmologic examination for Kayser-Fleischer rings	Steatosis; glycogenated nuclei in hepatocytes; focal hepatocellular necrosis, fibrosis, and ultimately, cirrhosis, usually macronodular[34]; copper retention in hepatocytes; hepatic copper concentration > 250 μg/g dry weight
Hemochromatosis	Serum transferrin-iron saturation > 45%; serum ferritin typically > 1000 μg/L; genotyping for detection of HFE mutations: C282Y and H63D; non-contrast CT of liver demonstrates attenuation values of > 70 HU[36]	Grade 4 stainable iron in hepatocytes, with periportal distribution and sparing of Kupffer cells; hepatic iron concentration > 80 μmol/g dry weight; hepatic iron index > 1.9
Hepatitis C	Anti-HCV; HCV RNA in patients who test positive for HCV antibody	Triad of histological findings with acute infection: lymphoid aggregates in portal tracts, epithelial damage of small bile ducts, and prominent microvesicular and macrovesicular steatosis; chronic infection: periportal necrosis, intralobular necrosis, portal inflammation, and fibrosis; no characteristic pathognomonic features
Chronic hepatitis B	HBsAg; serum level of HBV DNA > 2000-20000 IU/mL	Acute infection: lobular disarray, ballooning degeneration, numerous apoptotic (Councilman) bodies, Kupffer cell activation, and lymphocyte-predominant lobular and portal inflammation; chronic infection: varying degree of predominantly lymphocytic portal inflammation with interface hepatitis and spotty lobular inflammation[34]; presence of HBcAg staining in the liver
Autoimmune hepatitis	Antinuclear antibody (ANA); smooth muscle antibody (SMA); antibodies to liver and kidney microsomes (anti-LKM1); anti-soluble liver antigen (anti-SLA); asialoglycoprotein receptor antibodies	Interface hepatitis at junction of portal region and liver lobule; lobular hepatitis with lymphocytoplasmacytic infiltration; intrahepatic bile ducts generally appear normal
α1-antitrypsin deficiency	Serum α1-antitrypsin genotype or phenotype (homozygous PiZZ or heterozygous PiSZ phenotype)	Giant-cell hepatitis with multinucleated giant cells; lobular disarray; cellular and canalicular cholestasis; neoductular proliferation; bridging hepatic fibrosis; PAS-positive and diastase-resistant cytoplasmic granules in periportal hepatocytes
Primary biliary cirrhosis	Antimitochondrial antibodies (AMA) ≥ 1: 80 titer; ANA, with immunofluorescence typically revealing speckled, homogeneous, nuclear dot, centromere, or rim-like patterns	Focal and segmental nonsuppurative cholangitis; “florid duct lesion”: bile duct surrounded by intense lymphocytic or granulomatous infiltrate with basal integrity of the bile duct breached by individual lymphocytes; granulomas in close proximity to bile duct; bile ductular proliferation (cholangioles or pseudoducts) along periphery of portal tract
Non alcoholic fatty liver disease	Diagnosis of exclusion, correlated with: metabolic syndrome: diabetes mellitus, hypertension, hyperlipidemia, abdominal obesity with waist circumference > 102 cm for men and > 88 cm for women; obesity (BMI ≥ 30 kg/m2); obstructive sleep apnea; sedentary lifestyle	Macrovesicular steatosis; early hepatocyte inflammation, predominantly neutrophilic; late nondescript fibrosis and cirrhosis

¹Patients may have more than one disease contributing to cirrhosis (e.g., alcoholism and iron overload, or alcoholism and hepatitis C). HFE: Human hemochromatosis protein; CT: Computed tomography; HU: Hounsfield units; HCV: Hepatitis C virus; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; DNA: Deoxyribonucleic acid; HBcAg: Hepatitis B core antigen; PAS: Periodic acid-Schiff; BMI: Body mass index.

Table 2 Meta-analyses of randomized controlled trials of corticosteroid therapy vs placebo for severe alcoholic hepatitis

Ref.	Inclusion criteria	Number of RCTs (total number of patients)	Endpoint parameters (primary endpoint listed on first line of each entry)	RR, HR or OR for primary endpoint	95%CI	Comments
Imperiale et al[102], 1990	RCTs of patients with acute AH receiving corticosteroids vs placebo	11 (562)	Mortality Hepatic encephalopathy	RR = 0.63	0.5-0.8	Positive study (P = 0.025)
Christensen et al[101], 1995	RCTs evaluating short term effect on survival of treatment with glucocorticoids vs placebo for AH	13 (659)	Mortality Age Serum bilirubin Ascites Male gender Hepatic encephalopathy	RR = 0.78	0.51-1.18	Negative study (P = 0.2)
Mathurin et al[55], 2002	RCTs during 1984-1992 of patients receiving glucocorticoids vs placebo	3 (215)	Survival Age Liver function tests DF Hepatic encephalopathy Gender Serum creatinine Ascites Leukocyte count	OR = 0.39	0.22-0.71	Positive study (P = 0.002) Used individual patient data analysis to increase statistical rigor for the meta-analysis
Rambaldi et al[100], 2008	RCTs of patients with severe, clinically overt AH diagnosed by clinical and biochemical criteria, treated with glucocorticoids vs placebo (or no intervention)	15 (721)	Mortality Liver-related mortality Symptoms and complications Liver function tests Liver histology Adverse events	RR = 0.83	0.63-1.11	Negative study (P = 0.21)
Mathurin et al[99], 2011	RCTs from 1984 to 2006 with specific data on DF ≥ 32 or hepatic encephalopathy, of corticosteroids vs placebo, enteral nutrition or antioxidants	5 (418)	Survival DF Lille score Liver function tests	Complete responder: HR = 0.18	Complete responder: 0.05-0.71	Positive study Complete responders (P = 0.005)
			Serum creatinine Ascites	Partial responder: HR = 0.38	Partial responder: 0.17-0.87	Partial responders (P = 0.03)
			Hepatic encephalopathy Age	Null responder: HR = 0.81	Null responder: 0.45-1.45	Null responders (P = 0.46)
			Gender Leukocyte count			Used individual patient data analysis to increase statistical rigor for the meta-analysis

RCT: Randomized controlled trials; AH: Alcoholic hepatitis; DF: Discriminant function.

Table 3 Published randomized controlled trials of pentoxifylline vs placebo for severe alcoholic hepatitis n (%)

Ref.	n	Duration of treatment with pentoxifylline 400 mg PO tid	Mortality in placebo	Mortality in pentoxifylline	Relative risk or hazard ratio	95%CI	Comments
Akriviadis et al[110], 2000	101	28 d	24/52 (46)	12/49 (24)	RR = 0.59	0.35-0.97	Positive study (P = 0.037)
Fernández-Rodríguez et al[112], 2008	24	28 d	Not reported1	Not reported1	HR = 1.46	0.5-4.28	Negative study (P = 0.48)
Tyagi et al[107], 2011	612	6 mo	2/31 (6)	1/30 (3)	Not reported	Not reported	Negative study2 (P = 0.15)
Sidhu et al[109], 2012	50	28 d	10/25 (40)	5/25 (20)	RR = 0.5	0.19-1.25	Negative study (P = 0.216)

¹Fernandez-Rodriguez et al[112] reported no statistically significant difference in short-term or long-term survival based on actuarial survival curve;

²Tyagi et al[107] randomized 70 patients, but only 61 completed follow-up and were included in the analysis. The study did not show a significant difference in mortality, but showed a significant difference in the occurrence of hepatorenal syndrome. PO: Per overall survival; RR: Relative risk; HR: Hazard ratio.

Table 4 Management of complications of cirrhosis, per professional society guidelines¹

Complication	Screening/diagnosis	Treatment	Long-term management surveillance
Ascites	Diagnostic paracentesis for new-onset ascites: ascitic fluid analyzed for cell count and differential, total protein, and SAAG	Alcohol cessation; dietary sodium restriction; oral diuretics; discontinuation of NSAIDs	Refractory ascites: periodic large-volume therapeutic paracenteses; TIPS; midodrine; or peritoneovenous shunts
Spontaneous bacterial peritonitis	Diagnostic paracentesis: ≥ 250 polymorphonuclear cells/mm3	Empiric antibiotic therapy with cefotaxime 2 g every 8 h, while awaiting culture results	Prophylaxis with norfloxacin or trimethoprim-sulfamethoxazole after one documented episode of SBP or if patient presents with variceal bleeding
Esophageal and gastric varices	Esophagogastroduodenoscopy	Treatment depends upon size of varices or risk of variceal bleeding: Prophylaxis with nadolol or propranolol for small varices at high risk of bleeding or for medium/large varices; EVL for medium/large varices at high risk of bleeding	No varices: EGD every 3 yr (earlier if hepatic decompensation occurs) Small varices: EGD every 2 yr Medium/large varices: EGD every 6-12 mo
Hepatic encephalopathy	Diagnosed by serum ammonia level and clinical findings of confusion, personality and mental status changes, and asterixis (exclude other causes of mental status changes)	Investigation and correction of precipitating factors; lactulose and/or rifaximin, supportive care	Secondary prophylaxis with lactulose and/or rifaximin indefinitely
Hepatorenal syndrome (type 1-rapidly progressive renal insufficiency; type 2-slowly progressive renal insufficiency)	Serum creatinine > 1.5 mg/dL, in the absence of other identifiable cause of renal failure (exclude other causes by urine chemistries, urine culture, and/or renal imaging)	Initial fluid challenge; albumin and terlipressin or albumin and combined octreotide plus midodrine; dialysis; LT definitive	Serial serum creatinine monitoring
Hepatocellular carcinoma (HCC)	Abdominal ultrasound every 6 mo; alpha fetoprotein determination every 6 mo no longer recommended, but optional	For HCC treatment[124]	Abdominal ultrasound every 6 mo
Hepatopulmonary syndrome	Screening by arterial blood gas; Confirmation by CEE	Symptomatic management with long-term oxygen therapy; LT definitive
Portopulmonary hypertension	Screening by transthoracic Doppler echocardiography; Confirmation by right heart catheterization	Intravenous or inhaled prostacyclin; long-term oxygen therapy

¹American Association for the Study of Liver Diseases[124,128,129]; American College of Gastroenterology[125,126]; Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program[127]; European Association for the Study of the Liver[130]; and European Respiratory Society[131]. SAAG: Serum-ascites albumin gradient; NSAID: Non-steroidal anti-inflammatory drugs; TIPS: Transjugular intrahepatic portosystemic shunt; SBP: Spontaneous bacterial peritonitis; GI: Gastrointestinal; EGD: Esophagogastroduodenoscopy; EVL: Endoscopic variceal ligation; CEE: Transthoracic echocardiography with contrast enhancement.